synthesis and solid state studies of cryptophane based
TRANSCRIPT
SYNTHESIS AND SOLID-STATE STUDIES OF CRYPTOPHANE-BASED MATERIALS
A Dissertation
submitted to the Faculty of the
Graduate School of Arts and Sciences
of Georgetown University
in partial fulfillment of the requirements for the
degree of
Doctor of Philosophy
In Chemistry
By
Scott T. Mough, B. S.
Washington, DC
April 21, 2011
ii
SYNTHESIS AND SOLID-STATE STUDIES OF CRYPTOPHANE-BASED MATERIALS
Scott T. Mough, B.S.
Thesis Advisor: K. Travis Holman, Ph.D.
ABSTRACT
Continued political unrest in oil producing countries has led the United States
to search for new sources of energy technology, such as fuel cells and gas storage
materials. Natural gas, which is comprised primarily of methane, is a particularly
attractive energy source in that the United States has considerable natural gas
reserves. Unfortunately, methane gas is typically stored in gas cylinders due to
potential risks of explosion, which has prevented the significant use of natural gas in
small automobiles.
Gas storage on porous solid surfaces is one potential alternative for reversible
storage in gas cylinders. Gas storage has been observed in carbon nanotubes,
graphitic carbon, in metal hydrides, and in coordination polymers. However, gas
storage on carbon materials and current coordination polymers does not achieve the
United States Department of Energy goal of 6.5 mass % of hydrogen gas while metal
hydrides can suffer from poor kinetics of hydride formation.
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We proposed the use of irregularly shaped, functionalized “container
molecules” in metal-organic coordination polymers as new materials. Container
molecules, such as cryptophanes, have been shown to bind and store gases, such as
methane and xenon. Due to their unusual shape, container molecules pack
inefficiently in the solid-state. Specifically, we synthesized and characterized m-
xylyl bridge, exo-functionalized cryptophanes, and examined the solid-state behavior
of the resulting cryptophane based materials.
A single-crystal X-ray diffraction study of exo-functionalized cryptophanes
was performed, and solvent binding within the cryptophane was analyzed in the
solid-state. Aromatic guests were found to adopt a preferred orientation within the
cryptophane, likely due to CH-pi intermolecular interactions. Heating of an tris exo-
ester functionalized cryptophane resulted in the formation of an “imploded”
atropisomer in the solid-state, which was the first to be structurally characterized by
X-ray crystallography. The first cryptophane-based coordination polymer was
synthesized and characterized structurally. This material was found to spontaneously
desolvate, and the initial stages of this desolvation were found to occur in a single-
crystal to single-crystal fashion. The material was found to regenerate its initial
structure when reintroduced to mother liquor. However, this polymer was not found
to adsorb significant quantities of gas.
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ACKNOWLEDGEMENTS
There are so many people and groups that I need to recognize that I may need
to add an extra chapter. First, I must recognize my advisor K. Travis Holman. His
love of science is so pure, so enthusiastic and so infectious that it makes him the ideal
mentor. I would not be where I am without his help and guidance.
The Department of Chemistry has been far more patient and understanding
than I deserve. I thank everyone involved in the department, but I especially thank
my committee for their constructive criticism and Dr. Tong for his helpful pep talks.
If not for YuYe, I would not be completing this thesis.
I have many fellow classmates to recognize for their friendship and help, in
both good times and bad. My group mates Thai Binh Nguyen, Steven Drake, Sayon
Kumalah, and Robert Fairchild have all helped me in ways great and small. I also
need to acknowledge the work of John Goeltz and Katherine Zumberge, who worked
incredibly hard to further this research. The Wolf group was very helpful, and I
would like to thank Rachel Lerebours, Kim Yearick, Brian Reinhardt and Xuefeng
Mei for their friendship and guidance.
I would like to recognize aaiPharma Services for their support and help. I
truly enjoyed my time at AAI, and would like to thank Jim Murtagh and Bob Whittle
for taking me under their wings. I thank TJ Harper and John Burke for cracking me
up in the lab and to Kristie Willoughby for her support.
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Finally, I would like to thank my family. My father, John Mough, is the
smartest man that I have ever met. I admire the fact that he always strives to learn, to
grow, and to better himself. My mother, Virginia, has incredible intuition and has
taught me to trust my instincts. My brothers John and Michael are friends that I
know that I can count on when things become difficult, and they know that they can
count on me in the same way. Aaron Brentzel and Deidre Savisky, my brother and
sister from another mother, have always been there to listen and offer unfiltered
advice when needed.
Most of all, I would like to recognize my wife, Rhonda and my children
Nathan and Connor. Rhonda is a beautiful soul, and is the strongest person that I
have ever met. Her determination is a constant source of amazement and inspiration.
At the same time, she is a sensitive, loving, caring wife and mother. I am so blessed
to have met my soul mate, and that I get to spend the rest of my life with her. Nathan
is equally inspirational. He works hard to learn and understand the world around
him. He shows us flashes of a brilliant sense of humor and his caring nature, and he
is loved by all who know him. Connor is our comic relief. His natural brilliance and
charisma bring joy to all around him.
Finally, I would like to thank God for my good fortune. He is truly great and
I will never be able to appreciate all of His gifts.
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TABLE OF CONTENTS
Abstract ......................................................................................................................... ii
Acknowledgements ...................................................................................................... iv
List of Figures .............................................................................................................. xi
List of Schemes and Tables ...................................................................................... xxii
Chapter 1: Introduction ................................................................................................ 1
1.1. Introduction: Zeolites as Functional Materials ................................... 1
1.2. Crystal engineering: Designing alternatives to zeolites ....................... 3
1.2.1. Crystal Engineering of Coordination Polymers ....................... 5
1.3 Supramolecular Chemistry and Host-Guest Binding ........................... 9
1.3.1 Container Molecules: Potentially Useful Supramolecular CP
Ligands................................................................................................ 12
1.4. Cryptophanes ...................................................................................... 17
1.5. Research project: Synthesis and Characterization of Cryptophane
Container-Based Materials ................................................................. 20
1.6 References ........................................................................................... 22
CHAPTER 2: Synthesis, Characterization and Inclusion Compounds of m-xylyl
Bridged Cryptophanes ................................................................................................ 33
2.1. Introduction: Synthesis and characterization of cryptophanes .......... 33
vii
2.2. Solution vs. Solid-State Analyses of Supramolecular Host-Guest
Complexes .......................................................................................... 36
2.3. History of Crystallographic Analysis of Container Molecule Host-
Guest Complexes ................................................................................ 37
2.4. Syntheses of m-xylyl bridged cryptophanes ....................................... 39
2.5. Crystal Structures of m-xylyl Bridged Cryptophanes ......................... 44
2.5.1 SQUEEZE analysis of m-xylyl Bridged CryptophaneGuest
Structures ................................................................................ 45
2.6. m-xylyl CryptophaneAromatic Guest Complexes ........................... 46
2.6.1. Common Guest Binding Motif: The Importance of CH-
Interactions.............................................................................. 46
2.6.2 CH- Interactions: Weak Intermolecular Forces ................... 47
2.7. m-Xylyl Bridged Cryptophane Host Conformational Changes ............. 49
2.8. Halobenzene guests: Conglomorate vs. Racemate formation ............... 58
2.9. Complete Encapsulation vs. Partial Encapsulation................................ 60
2.10. Nonaromatic Guests ............................................................................. 64
2.10.1. Encapsulation of two guests ................................................. 64
2.10.2. Guest Disorder in Cryptophane Structures ........................... 66
2.10.3. Host Conformation Changes of Cryptophanes Binding
Nonaromatic Guests ................................................................ 67
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2.10.4. Crystal Structures of Host 7: High Symmetry Structures .... 72
2.11. Conclusions ......................................................................................... 74
2.12. Experimental ....................................................................................... 75
2.12.1 General Methods ..................................................................... 75
2.12.2. New Molecule Characterization ............................................. 76
2.12.3. Crystal Structures .................................................................... 82
2.13 References ......................................................................................... 101
CHAPTER 3: Synthesis and Characterization of an “Imploded” Cryptophane
Atropisomer .............................................................................................................. 107
3.1. Introduction to CTB “cup” inversion................................................ 107
3.2. Thermal Analysis of (±)-anti-4THF3THF ......................................... 110
3.3. Consequences of Desolvation: Atropisomerization of (±)-anti-4 ......... 111
3.3.1. 1H NMR of desolvated (±)-anti-4 material ............................. 111
3.3.2. 2D NMR of (±)-imp-4: COSY and ROESY ........................ 113
3.4. Kinetics of atropisomerization by 1H
NMR ...................................... 120
3.5. Single crystal structure of (±)-imp-411CHCl3 ................................. 123
3.6. Conclusions ....................................................................................... 125
3.7. Experimental ..................................................................................... 126
3.7.1. General Methods ................................................................... 126
3.7.2. New Molecule Characterization ........................................... 126
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3.7.3 Kinetics Experiments ............................................................ 127
3.7.4 Crystal Structure ................................................................... 128
3.8 References ......................................................................................... 130
CHAPTER 4: Synthesis and Characterization of Cryptophane-Based Metal-Organic
Polymer (CBMOP): Single Crystal to Single Crystal Partial Desolvation .............. 132
4.1. Introduction: Single Crystal to Single Crystal Processes ............... 132
4.2. A 1-D Cryptophane-Derived Coordination Polymer ........................ 138
4.3. Unit Cell Changes in CBMOP .......................................................... 143
4.3.1. X-Ray Single Crystal Structure of CBMOP-desolvated ...... 145
4.3.2. Explanation of Single Crystal Desolvation ........................... 146
4.4. Desolvation/Resolvation of Bulk CBMOP Observed by Powder X-ray
Diffraction ......................................................................................... 147
4.5. Gas Sorption Study on CBMOP-desolvated ..................................... 151
4.6. Synthesis of a Cryptophane-Dimer ................................................... 152
4.7. Conclusions ....................................................................................... 154
4.8. Experimental ..................................................................................... 155
4.8.1. General Methods ................................................................... 155
4.8.2. Synthesis of New Materials .................................................. 155
4.8.3. Crystal Structures .................................................................. 156
4.8.4. Unit Cell Analysis over time ................................................ 159
x
4.9 References ......................................................................................... 160
CHAPTER 5: Solid-State Kinetics of Supramolecular Host-Guest Clathrates: ...... 164
5.1. Introduction: Solid-State Kinetics ................................................... 164
5.2. Desolvation of Host-Guest Systems ................................................. 168
5.3. Isothermal TGA Analysis of CTVTHF0.5 ........................................ 169
5.4. Nonisothermal Kinetic Analysis of CTVTHF0.5 .............................. 174
5.5. Nonisothermal DSC Analysis of (±)-anti-8THF ........................... 175
5.6. Discussion of Activation Parameters ................................................ 179
5.7. Conclusions ....................................................................................... 180
5.8. Experimental ..................................................................................... 180
5.8.1. General Methods ................................................................... 180
5.8.2. Sample Preparation ............................................................... 181
5.9 References ......................................................................................... 182
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LIST OF FIGURES:
Figure 1.1. Dsolvated ZSM-5. The sustained pores are evident. Red, Oxygen;
Silicon, Pink .......................................................................................... 2
Figure 1.2. Crystal structures of organic carboxylic acids which show how
molecular structure can influence two-dimensional and three-
dimensional solid-state structure. a) 1D-chain structure of 1,4
terephthalic acid. b) Honeycomb structure of trimesic acid. Gray,
Carbon; Red, Oxygen; White, Hydrogen. ............................................. 5
Figure 1.3. Two canonical structures derived from metal cations and organic
linkers. Left: Cubic structure derived from octahedral metal cations
and linear organic linkers. Right: Adamantyl structure derived from
tetrahedral metal cations and linear organic linkers ............................. 6
Figure 1.4. Top. Zn4O cluster and 4 carboxylate CO2- groups leading to cubic
structures. Gray, Carbon; Red, Oxygen; Pink, Zinc, Bottom. Pore
volume and crystal density as a function of ligand length in Yaghi’s
Isoreticular cubic metal-organic frameworks ....................................... 7
Figure 1.5. Rebek’s self-recognizing “tennis ball” dimer. .................................... 10
Figure 1.6. Nine molecules included in Isaacs self-sorting study. ........................ 11
Figure 1.7. Kinetic barrier to decomplexation as a result of constrictive binding in
a container molecule ........................................................................... 13
Figure 1.8. Conformational gating mechanisms in container molecules that enable
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“constrictive binding”. ........................................................................ 14
Figure 1.9. Selective [2+2] photodimerization inside a metal-ligand container
molecule. This reaction occurs only in the presence of the container,
and yielded only the cross syn dimer. ................................................. 15
Figure 1.10. Left. General structure of (±)-anti cryptophane. Right. General
structure of syn cryptophane. In most common cryptophanes, A = Z =
OMe. ................................................................................................... 16
Figure 1.11. Descriptions of cryptophane regions. ................................................. 17
Figure 2.1. 1H
NMR of cryptophane E (propyl-bridged). ..................................... 35
Figure 2.2 Left: Alkynyl bridged hemicarcerand, which is defined by the C4
symmetric cavitands that make up the polar regions of the container.
Right. Crystal structure (YETKAJ) describing alkynyl bridged
hemicarcerand. The encapsulated molecule is 1,1,2,2
tetrachloroethane. ................................................................................ 38
Figure 2.3 Structure of Weber’s endo-carboxylate m-xylyl cryptophane.
Hydrogen atoms and guest molecules omitted for clarity. Carbon:
Gray; Oxygen: Red. ............................................................................ 40
Figure 2.4. Left) 1H NMR spectrum of (±)-anti-4. Right) H NMR spectrum of
syn-5. ................................................................................................... 44
Figure 2.5. Determination of distance for CH- interactions. Distance d is taken
from the guest proton to either the closest cryptophane aromatic
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carbon or the centroid defined by the six carbons in the appropriate
ring. Angle is defined as the C-H- angle where C = guest carbon,
H = guest hydrogen and = either the closest cryptophane aromatic
carbon or the centroid defined by the six carbons in the ring. ............ 47
Figure 2.6. Side and Top views of cryptophanearomatic guest complexes. Guest
molecules shown in space-fill form and cryptophanes shown in stick
form. a) (±)-anti-4C6H5NO2 b) (±)-anti-4C6H5CN c) (±)-anti-
4C6H5(CH2)2CH3 d) anti-4C6H5Br1 e) (±)-anti-4C6H5Cl f) 2-
(±)-anti-6m-C6H4(CH3)2 g) (±)-anti-6C6H5Br h) (±)-anti-61,2,4-
C6H3(CH3)3 i) (±)-anti-6o-C6H4(CH3)2 j) (±)-anti-4C6H5I1 k) (±)-
anti-4C6H5(CH2)5CH3 l) syn-5C6H5NO2 m) (±)-anti-6C6H5NO2.
Carbon: Gray; Hydrogen: White; Nitrogen: Blue; Oxygen: Red;
Chlorine: Yellow; Bromine: Yellow. 1
Forms conglomerate structures
(see vida infra). ................................................................................... 50
Figure 2.7. Measured torsion angle in cryptophanes. ........................................... 57
Figure 2.8. Left: CCTB-O-CH2-Cbridge torsion angles where CTB arene does not
engage in CH- interactions (CTB arene-methyl close contacts also
removed). Right: CCTB-O-CH2-Cbridge torsion angles where CTB
arene is engaged in CH- interactions. ............................................... 57
xiv
Figure 2.9. Top: Histogram describing the bimodal distribution of torsion angles
in which host-guest CH- interactions are observed. Bottom:
Histogram describing the distribution of torsion angles in which host-
guest CH- interactions are not observed. .......................................... 60
Figure 2.10. Top Left: (±)-anti-4PhBr looking down the –c axis. Top Right:
(±)-anti-4PhCl looking down the c-axis. Bottom: Interaction of
bromobenzene guest with ester of adjacent cryptophane. The
bromine-oxygen interaction is shown with the dotted red line. Guest
molecules shown in space-fill form and cryptophanes shown in stick
forms. Carbon: Gray; Hydrogen: White; Nitrogen: Blue; Oxygen: Red;
Chlorine: Yellow; Bromine: Yellow .................................................. 62
Figure 2.11. Top Left: Stick representation of (±)-anti-4C6H5(CH2)2CH3 with
spacefilled guest. Top Right: Stick representation of C6H5(CH2)2CH3
guest. Bottom Left: Stick representation of (±)-anti-
4C6H5(CH2)5CH3 with spacefilled guest. Bottom Right: Stick
representation of C6H5(CH2)5CH3 guest. Carbon: Gray; Hydrogen:
White; Oxygen: Red. .......................................................................... 63
xv
Figure 2.12. Left: Two encapsulated NO2Me molecules as packed within (±)-anti-
42NO2Me. Right: Two encapsulated CH2Cl2 molecules as packed
within (±)-anti-42CH2Cl2. ............................................................... 64
Figure 2.13. Left: Model of disordered, encapsulated DMF. Right: Model of
disordered, encapsulated CHCl3 ......................................................... 66
Figure 2.14. ArCTB-O-CH2-Arbridge torsion angles. .................................................. 72
Figure 2.15. Spacefill packing of syn-7 as seen down c-axis. Lattice solvent has
been deleted to show the channels that run between the cryptophane
molecules. ........................................................................................... 74
Figure 3.1. Crown inversion of CTBs. Note that the saddle-twist intermediate is
close in energy to the crown conformation (ΔΔG298 = ~12-16 kJ/mol
higher for saddle-twist intermediate). ............................................... 108
Figure 3.2. Saddle-twist rotation of CTBs. Arrows show one direction of rotation,
but rotation could occur in the other direction. ................................. 109
Figure 3.3. CTB oxide molecule in saddle-twist formation. ............................... 110
Figure 3.4. TGA of cryptophane materials. Top: Thermograms of (±)-anti-
4THF3THF and (±)-anti-4THF as a function of temperature. Note
that the THF molecules in the lattice can be separated from the
encapsulated THF molecule. Bottom: Isothermal thermogram of (±)-
anti-4THF3THF at 85C. This heating profile allows for removal of
only lattice THF molecules. .............................................................. 111
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Figure 3.5. 1H NMR of atropisomerization of (±)-anti-4 over time. .................. 112
Figure 3.6. Left: Model of a “cup-in-cup” cryptophane. Right: Model of a
“saddle-twist-cup” cryptophane. ....................................................... 113
Figure 3.7. COSY of (±)-imp-4 in CDCl3 at 25°C. Top: Full spectrum. Bottom:
Expanded spectrum. .......................................................................... 115
Figure 3.8 COSY of (±)-imp-4 in acetone-d6 at 25°C. ....................................... 116
Figure 3.9. ROESY of (±)-imp-4 in CDCl3 at 25°C.. ......................................... 118
Figure 3.10. 1H NMR of (±)-imp-4 at -55C. ........................................................ 119
Figure 3.11. Kinetics of inflation of (±)-imp-4 to (±)-anti-4 by 1H NMR integration
at 298 K. ............................................................................................ 121
Figure 3.12. Eyring plot derived from isothermal kinetic data. ............................ 122
Figure 3.13. Single crystal structure of (±)-imp-4. The 11 CHCl3 molecules in the
ASU have been removed for clarity. Left: Stick structure of (±)-imp-
4. Note that the saddle-twist CTB points a methoxy group into the
cup-shaped CTB. CTB arene rings are highlighted in blue. Right:
(±)-imp-4 in which the cup-shaped CTB unit is shown in CPK form,
and the saddle-twist CTB unit is shown in stick form. The saddle-
twist CTB arene rings are highlighted in blue. ................................. 124
Figure 3.14. Assigned 1H NMR of (±)-imp-4. ...................................................... 124
Figure 4.1. Single-crystal to single-crystal processes. ........................................ 133
xvii
Figure 4.2. a) [Ni2(C26H52N10)]3[BTC]46C5H5N36H2O bilayer viewed in stick
form (left) and spacefill (right). b) [Ni2(C26H52N10)]3[BTC]44H2O
bilayer viewed in stick form (left) and spacefill (right). ................... 134
Figure 4.3. a) Structure of tetrapyridone crystallized with isovaleric acid. b)
Structure of tetrapyridone after guest exchange with propionic acid.
Note the decrease in the c-axis with the smaller propionic acid. ...... 135
Figure 4.4. Single-crystal to single-crystal syntheses. Top left: Crystal structure
of 1,6 triene. Top Right: Crystal structure of photo-polymerized 1,6
triene. Bottom left: Hydrogen bond mediated assembly of 4,4’
bipyridyl ethylene. Bottom right: [2+2] Photochemical synthesis of
[2.2]paracyclophane. ......................................................................... 136
Figure 4.5. One dimensional chain of CBMOP-solvent as viewed down the b-
axis. Chain propagates along the [1 0 1] direction. Hydrogen atoms,
encapsulated DMF molecules, and solvent molecules omitted for
clarity. CTB arenes have been filled in............................................ 137
Figure 4.6. Coordination environment about metal centers. ............................... 139
Figure 4.7. Overlay of cryptophane in anti-(±)-H39 and CBMOPsolvent viewed
from top of cryptophane. Note the difference in the cryptophane
bridges on the left. While (±)-anti-H39 continues in a nearly straight
path, CBMOP-solvent is rotated approximately 60°. ...................... 140
xviii
Figure 4.8. Thermogravimetric Analysis of CBMOP-solvent. Top. CBMOP
mass as a function of heating at 10°C/min from room temperature to
380°C. Bottom. CBMOP heated at 0.2°C /min from room
temperature to 160°C , then held at 160°C for ~ 800 minutes. ....... 142
Figure 4.9. Unit cell change of CBMOP as a function of time at 25C. ............ 145
Figure 4.10. Changes in c-axis (top) and b-axis (bottom) before and after
desolvation. Green points represent individual CBMOP∙solvent
crystals, except for labeled spot. The orange points below the green
points represent CBMOP∙solvent crystals after desolvation
(CBMOP∙desolvated. ........................................................................ 147
Figure 4.11. Faces of crystal CBMOP. ................................................................ 148
Figure 4.12. Top: Spacefill representations of the single crystal structures of
CBMOPsolvent (top) and CBMOPdesolvated (bottom) as viewed
down the [001] direction. The lattice solvent molecules have been
removed for clarity. Note that the channels collapse upon desolvation.
Bottom: Connolly surface plot of CBMOP-solvent as viewed normal
to the [010] direction. The dark blue highlighted areas are the
channels observed above. The channels form a ladder-like structure
extending along the c-axis, and having rungs that run roughly along
the a-axis. .......................................................................................... 149
xix
Figure 4.13. Calculated powder X-ray diffractograms were determined using the
program LAZY-PULVERIX and the single-crystal x-ray diffraction
data for CBMOP-solvent and CBMOP-desolvated. The room
temperature unit cells for each material were used to more accurately
match the experimental data, which were collected at room
temperature. The powder x-ray diffraction (PXRD) experiment was
performed on one open capillary tube of CBMOP collected over time.
Experimental partial powder X-ray diffractograms (PXRD) of the
desolvation process of CBMOP∙solvent. a) Calculated PXRD pattern
using the unit cell CBMOP∙solvent obtained at room temperature. b)
Calculated PXRD pattern of CBMOP∙solvent that has been arbitrarily
broadened to more accurately reflect the peaks widths. c) Calculated
PXRD of CBMOP∙desolvated at room temperature. d) Experimental
PXRD pattern of CBMOP at t = 0. e) PXRD pattern of CBMOP at t
= 1 day. f) PXRD pattern of CBMOP at t = 6 days. g) PXRD pattern
of CBMOP at t = 8 days. h) PXRD pattern of CBMOP at t = 14 days.
i) PXRD pattern of CBMOP at t = 22 days. j) Experimental PXRD
pattern of the material in (i) after moistening the material with mother
liquor. ................................................................................................ 151
Figure 4.14. Proposed model of desolvation of CBMOF over time. ................... 152
xx
Figure 5.1. Series of xanthenol clathrates studied to relate structure and
desolvation kinetics........................................................................... 169
Figure 5.2. Crystal structure of CTV0.5THF. CTV molecules shown in stick,
THF molecules shown in spacefill form. .......................................... 170
Figure 5.3. Nonisothermal TGA experiments of CTVTHF0.5 as a function of
alpha (extent of desolvation) at 5C/min and 10/min. .................... 171
Figure 5.4. Top: Plot of alpha vs. time for an isothermal TGA experiment for the
desolvation of CTVTHF0.5 at 96.2 C. Bottom: Isothermal TGA data
after application of the three-dimensional diffusion model for the
desolvation of CTVTHF0.5. .............................................................. 172
Figure 5.5. Eyring plot of desolvation of CTVTHF0.5 derived from isothermal
TGA data........................................................................................... 173
Figure 5.6. DSC overlay of desolvation of CTVTHF0.5 at varying heating
rates .................................................................................................. 175
Figure 5.7. Ozawa plot derived from nonisothermal DSC experiments for the
desolvation of CTVTHF0.5 at various heating rates (1-20C/min). .. 176
Figure 5.8. Stucture of (±)-anti-8THF. Left: Side view of complex. Right:
view of complex. Carbon: Gray; Oxygen: Red; Hydrogen: White.. 176
Figure 5.9. DSC overlay of desolvation of (±)-anti-8THF at varying heating
rates. .................................................................................................. 177
xxi
Figure 5.10. Ozawa plot derived from nonisothermal DSC data for the desolvation
of (±)-anti-8THF. ........................................................................... 178
Figure 5.11. Side view of (±)-anti-4THF complex. ........................................... 179
xxii
LIST OF SCHEMES AND TABLES:
Scheme 2.1. Three potential synthetic pathways to cryptophane molecules. In most
cases, E = E’ = OCH3. ........................................................................ 33
Scheme 2.2. Synthesis of m-xylyl bridged cryptophanes. ....................................... 41
Table 1.1. Cryptand binding in water at 298K as a function of size. ................... 12
Table 1.2 Description of symbols used throughout text. .................................... 18
Table 1.3. Free energy of complexation for various cryptophanes in (CDCl2)2 at
300K.................................................................................................... 18
Table 2.1. Molecule Abbreviations ...................................................................... 45
Table 2.2. New m-xylyl bridged cryptophanes .................................................... 48
Table 2.3. CH- Interactions between cryptophanes and aromatic guests. .... 51-53
Table 2.4. X-Ray data for CryptophaneAromatic Guest materials. ............. 54-56
Table 2.5. Encapsulated guest volume in various cryptophane host molecule
materials. ............................................................................................. 65
Table 2.6. X-Ray data for CryptophaneNon-Aromatic Guest materials ...... 69-71
Table 2.7. Torsion angles found in cryptophanesnon-aromatic guest(s)
structures. ............................................................................................ 73
Table 3.1. Comparison of activation parameters for CTB conformers.............. 122
Table 4.1. Unit Cell data for CBMOP∙solvent and CBMOP∙desolvated at RT
and 173K. ................................................................................. 144
xxiii
Table 5.1. Solid-state rate expressions for several reaction models. ................. 166
Table 5.2. Nonisothermal kinetic models. ......................................................... 167
Table 5.3 Activation parameters for desolvation of CTV·THF0.5 and (±)-anti-
8THF. ............................................................................................. 178
1
CHAPTER 1: INTRODUCTION
1.1. Introduction: Zeolites as Functional Materials
The development of new functional materials is a burgeoning area at the
interface of materials science and chemistry. Existing materials, such as zeolites,
perform a variety of useful functions exploited by chemists at the academic and
industrial level.1 Zeolites are defined as “microporous crystalline aluminosilicates,
composed of TO4 tetrahedra (T = Si, Al) with O atoms connecting neighboring
tetrahedra (Figure 1.1).”1,2,3
Their structure can be described as corner sharing
tetrahedra, comprised mostly of SiO4 tetrahedra, but having some AlO4 substitution
(Figure 1.1). The substitution of silicon (Si4+
) for aluminum (Al3+
) gives the
frameworks a net negative charge; these anionic frameworks are filled with loosely
held water molecules and charge balancing metal cations. These materials exhibit
permanent porosity, which means that the material can be dehydrated and rehydrated
reversibly without collapse of the framework.4 Permanent porosity is an interesting
and potentially useful property of solid-state materials, and zeolitic materials have
uses in separations, catalysis, and gas storage.5,6
The sustained pores are evident in
Figure 1.1. In zeolites, as with many materials, their myriads of functions are
directly related to their interesting structures. They are commonly used in ion
exchange beds, which is not surprising given the fact that the zeolitic countercations
are loosely held inside their large cavities.7 Some zeolites, such as 4Å molecular
sieves, are used in synthetic laboratories to dehydrate common organic solvents. This
2
behavior is a specific
example of a more
common ability of
molecular sieves to
separate molecules based
on size and shape.3 This
size and shape selectivity
is commonly exploited in
Zeolite A, which absorbs
and thereby separates
straight chain
hydrocarbons from
aromatic or branched hydrocarbons.5,8 Separation of p-xylene from xylene mixtures
by silicalite is another example of size and shape based selectivity in zeolites.5,8
The
driving forces for these phenomena are the satisfaction of electrostatic and van der
Waals forces within the dehydrated zeolite. More simply, “Nature abhors a vacuum,”
even one on an atomic scale. Ion exchange also plays a major role in zeolite
catalysis, which is one of the most important functions of zeolites. By exchanging
metal cations with protons, one creates a highly acidic zeolite which is used in crude
oil cracking, isomerization reactions and fuel syntheses.9
Figure 1.1. Desolvated ZSM-5. The sustained pores are evident.
Red, Oxygen; Silicon, Pink.
3
1.2. Crystal engineering: Designing alternatives to zeolites
Though research into zeolites continues, it remains difficult to synthesize and
design new zeolite topologies. Chemists are attempting to create zeolites and zeolite-
like materials for the purpose of making new materials that are useful and interesting.
Some organic solid-state chemists are attempting to design similar materials from
different, modular building blocks.10
This strategy is predicated on the hypothesis
that material structure and function are intimately related, and that the global
structure of a crystalline material can be designed by using molecular symmetry
arguments and known or foreseeable intermolecular interactions (or synthons) in a
bottom-up design. This strategy has often been described in the research literature as
“crystal engineering”,11
and it constitutes a significant area of research for solid-state
organic chemists, materials scientists, and organometallic chemists.12
This
burgeoning field is semi-empirical in nature, as many noncovalent forces (London
dispersion, CH- interactions, - stacking, and dipole-dipole interactions for
example) simultaneously influence the overall structure and packing of a material.
Unfortunately, these weak intermolecular forces are difficult to quantify, thereby
making crystal structure prediction of even the most basic structures a scientific
achievement: Maddox claims “One of the continuing scandals in the physical
sciences is that it remains in general impossible to predict the structure of even the
simplest crystalline solids from a knowledge of their chemical composition.”13
While
Maddox’s statement is true even today, considerable progress has been made in the
4
design of crystalline structures through the exploitation of predictable strong,
directional solid-state synthons. For example, hydrogen-bond donor-acceptor
systems have been studied extensively, and have been successfully employed in
materials design.14,15
Hydrogen bonds are quite strong (generally considered to be 3-
5 kcal/mol, but have been found to be up to 40 kcal/mol per H-bond in the solid
state), directional (between discreet hydrogen bond donors and acceptor lone pairs),
and may contribute considerably to the overall lattice energy of a crystalline
molecular solid.16,17
For example, a typical O-H
O hydrogen bond brings two
neighboring oxygen atoms to a distance of 2.5-2.8 Å, with an energy of 4-10 kcal/mol
for moderately strong hydrogen bonds.14,16
Materials derived from organic molecules that have relatively strong,
directional intermolecular forces have been studied extensively for their structural
properties. Carboxylic moieties have been observed to form one-dimensional chains,
two-dimensional sheets, and three-dimensional structures, from linear linkages (1,4
benzene dicarboxylic acid),18
triangular linkages (1,3,5 benzene tricarboxylic acid)19
and tetrahedral linkages (adamantane tetracarboxylic acid),20
respectively (Figure
1.2). The adamantyl structure is especially important because it was a designed
structure.
Research continues into finding and exploiting useful, noncovalent
intermolecular (supramolecular) synthons in the solid-state.11
,21
However, materials
that are organized by weak intermolecular forces are often of insufficient strength to
5
sustain permanent porosity, as their structures often collapse upon desolvation.22
On
the other hand, materials held together by coordinate covalent linkages have proven
to be more robust, and therefore of greater conceivable utility.
Figure 1.2. Crystal structures of organic carboxylic acids which show how molecular structure
can influence two-dimensional and three-dimensional solid-state structure. a) 1D-chain
structure of 1,4 terephthalic acid. b) Honeycomb structure of trimesic acid. Gray, Carbon;
Red, Oxygen; White, Hydrogen.
1.2.1. Crystal Engineering of Coordination Polymers
Recently, crystal engineering research has focused greatly on the ubiquitous
coordination polymer (hereafter CP) or “Metal-Organic Framework (MOF).”23
CPs
are well-defined, stoichiometric assemblies that are composed of metal cations and
coordination ligands that form infinite polymers (1-D) or infinite networks (2-D or 3-
D). In most cases, the metal acts as a node, and the coordination ligand acts as
spacers or bridges that link the nodes (Figure 1.3). Some of these materials can be
described as being “zeolite-like” or as “designer zeolites,” as they often exhibit the
most useful properties of zeolite materials: permanent porosity,24
catalysis,25
ion
exchange,26
and selective sorption of isomers.27
6
The potential of CPs was first described in detail by Robson, in his seminal
1990 paper “Design and construction of a new class of scaffolding-like materials
comprising infinite polymeric frameworks of 3D-linked molecular rods.” This paper
presented a reappraisal of the zinc cyanide and cadmium cyanide structures and the
synthesis and structure of the diamond-related frameworks [N(CH3)4][CuIZn
II(CN)4]
and CuI[4,4',4'',4'''-tetracyanotetraphenylmethane]BF4.xC6H5NO2.”
28 This work
describes the potential utility of CPs, as well as some potentially interesting structural
targets, including diamondoid and cubic networks. While infinite inorganic
frameworks such as Prussian Blue29
had been known for over 40 years, Robson truly
ushered in a new area of chemistry by describing how and why metal-organic
materials should be pursued. He essentially laid out a blueprint for solid-state
chemists to follow.
Figure 1.3. Two canonical structures derived from metal cations and organic linkers. Left:
Cubic structure derived from octahedral metal cations and linear organic linkers. Right:
Adamantyl structure derived from tetrahedral metal cations and linear organic linkers.
7
CP research has increased
dramatically over the past several
years; the terms “coordination
polymer” or “metal-organic
framework” was cited in 14 ACS
journal articles in 1995 and 441 times
in 2010. The dramatic increase in
research of CP-based materials is a
result of the recognition of many
advantages derived from using
organic and coordination chemistries.
Organic ligand spacers are versatile,
modular, easily functionalized, and
react in a robust, well-understood
manner. One can, for instance,
change the length of the spacer to
modulate pore size. This has been
beautifully illustrated by Yaghi and
coworkers in their 2002 Science
article “Systematic Design of Pore
Size and Functionality in Isoreticular
Figure 1.4. Top. Zn4O cluster and 4 carboxylate CO2-
groups leading to cubic structures. Gray, Carbon;
Red, Oxygen; Pink, Zinc, Bottom. Pore volume and
crystal density as a function of ligand length in
Yaghi’s Isoreticular cubic metal-organic frameworks.
8
MOFs and Their Application in Methane Storage”30
(Figure 1.4.). One also can
functionalize the spacer so as to functionalize the pore.31
Coordination chemistry
also has many advantages, including well-defined metal coordination geometries,
potentially labile metal-ligand interactions, and metal-ligand directionality (cis vs.
trans).2
In CPs, predictable metal-ligand or metal cluster-ligand geometries have been
observed, and have been exploited in numerous examples. These predictable units
can be described as solid-state synthons, and are also commonly described as
“Secondary Building Units (hereafter SBUs).32
SBUs provide a geometric construct
for the metal nodes, which may be combined with the ligand spacer of varying
symmetries to form frameworks of predictable topologies. For example, a linear
spacer combined with an octahedral node can form a cubic network, while linear
spacers can combine with square nodes to form two-dimensional square networks. In
general, the resultant CP materials are stronger and more stable to desolvation than
similar hydrogen-bonded materials.
In the years since Robson’s seminal paper, a number of chemists have
synthesized CP materials with varied functional properties: magnetism,33
porosity
and gas storage,34
sensing,35
catalysis22b,36
and separations.37
Yaghi and coworkers
have been quite successful in designing metal carboxylate materials exhibiting
permanent porosity, and some of Yaghi’s MOFs have been shown to have the highest
surface area and lowest density known for crystalline materials. Yaghi, along with
9
Kitagawa,38
Rosseinsky,39
Long,40
and other41
s have designed materials that
reversibly adsorb gases, such as H2 and CO2, O2 and C2H2. Others, including Lin42
and Hupp,43
have designed CP materials that function as heterogeneous catalysts,
catalyzing asymmetric addition to aldehydes, olefin epoxidation, and hydrogenation
of ketones. Zaworotko44
and Eddaoudi45
have designed spin frustrated CP materials
that form a Kagome’ lattice, while van Koten46
designed a sensing material which
reversibly binds and releases SO2 gas. The result is a relatively new area of research
that is as versatile and has the potential for large-scale industrial use.
1.3 Supramolecular Chemistry and Host-Guest Binding
Donald Cram, Jean-Marie Lehn, and Charles Pedersen shared the Nobel Prize
in Chemistry in 1987 for their contributions to science, specifically in supramolecular
chemistry.47
Supramolecular chemistry can be broadly defined as the study and
understanding of non-covalent interactions between molecules, as well as the
response of molecules to these intermolecular forces.48
Biochemistry has shown that
these relatively weak interactions are often highly important in biological systems
(hydrogen bonding of complimentary DNA strands,49
proper folding of proteins,50
antigen-antibody recognition51
). As in Nature, supramolecular chemists aim to
control and manipulate molecules in space through these non-covalent interactions.
Two major areas of research for supramolecular chemists are molecular
recognition52
and host-guest binding.53
Molecular recognition describes the ability of
10
an entity (enzyme, molecular host) to be able to discriminate between similar yet
distinct species (ion, molecule). Julius Rebek has successfully designed a series of
cup-shaped molecules (hereafter cavitands) that recognize one another in solution to
form a hydrogen-bonded dimer in solution54
(Figure 1.5). These molecules are
structurally
programmed to
interact with one
another; they are
complimentary in
the same sense that
DNA strands are
complimentary. Rebek
has developed a rich chemistry based on hydrogen-bonded dimeric capsules, which
have been shown to exhibit interesting isomerism,55
accelerate inner-phase
reactions,56
and bind three different guests.57
Lyle Isaacs and coworkers, in the
paper “Self-Sorting: The Exception or the Rule?”,58
have performed an elegant
experiment in which several synthetic systems shown to recognize like molecules
were mixed. Issacs found that despite the chemical similarity of many systems,
thermodynamic self-sorting occurred; this indicates that each of the eight components
in solution (Figure 1.6) exhibited recognition of self.
Figure 1.5. Rebek’s self-recognizing “tennis ball” dimer.
11
Host-guest binding is similar to molecular recognition, in that both require a
structural matching of at least two components. Guest binding is a specific example
of the more general concept of molecular recognition, in that binding requires a
recognition event as well as an immobilization of a guest by a host. Crown ethers59
and cryptands60
are quintessential examples of molecular hosts that bind metal
cations. Each host has structural features (electron lone pairs) that are selective
toward cations; furthermore, the size and shape of these hosts are adaptable to select
toward cations of a specific size. Table 1.1 describes the binding constant of a series
of cryptands with their preferred group 1 cation.60b
As expected, the selectivity of the
cryptand is intimately related to the size of the host: the larger cations preferentially
bind larger cations. One ethyleneoxy (OCH2CH2) group has dramatic effects on
binding selectivity, showing how small structural changes can impact their binding
properties.
Figure 1.6. Nine molecules included in Isaacs self-sorting study.
12
Of course, container molecules are a specific class of supramolecular host;
they are capable of binding neutral guest molecules on the basis of size and polarity.
There are few strongly selective structural features in container molecules, mainly the
size of the host portals and the concave nature of the host interior.61
Obviously, van
der Waals forces predominate in container-guest complexes; however, other
interactions (solvophobic effects, ion-dipole, cation-, - interaction) may provide
stability to these complexes.62
1.3.1 Container Molecules: Potentially Useful Supramolecular CP Ligands
While much effort has been exerted in the basic study of CP topology and
supramolecular isomerism (i.e. polymorphism) of CP materials, far less effort has
gone into the incorporation of potentially functional ligands. Many materials have
been derived from simple, aromatic ligands such as terephthalic acid,23b,63
and 4-4’
bipyridine,64
or linear aliphatic ligands such as succinic acid,65
and glutaric acid.66
The incorporation of functional ligands, however, has resulted in more useful
materials (Lin, Hupp). Furthermore, little work has been done to incorporate
macrocyclic ligands. Importantly,
many macrocycles, such as cryptands,
cyclodextrins and cucubiturils, have
well-defined supramolecular functions
Cryptand log Ka Preferred Group 1
Cation (M+)
[2.1.1] 5.5 Li+
(1.36Å)
[2.2.1] 5.4 Na+
(1.90Å)
[2.2.2] 5.4 K+
(2.66Å)
Table 1.1. Cryptand binding in water at 298K
as a function of size.
13
(atomic or molecular binding, reaction selectivity) that may be exploited in new
macrocycle-based CP materials.
One specific class of macrocycle that has function which may be useful in
CPs are the so-called “container molecules”, which, as the name implies, have the
ability to complex and completely encapsulate small molecular substrates. Container
molecules are hollow molecules with enforcedly rigid cavities that are capable of
binding a variety of smaller molecules based on favorable electrostatic and van der
Waals interactions. Well known supramolecular hosts of this type include
cryptophanes,67
(hemi) carcerands,68
metal-organic polyhedra,69
and hydrogen
bonded self-assembled
capsules.70
Although
container molecules differ
in size, shape and
connectivity, they are all
known to form stable
molecule-within-molecule
complexes.
An intriguing and
potentially useful property
of container molecules is
that they have the capacity
Figure 1.7. Kinetic barrier to decomplexation as a result of
constrictive binding in a container molecule.
14
Figure 1.8. Conformational gating mechanisms in container molecules that enable
“constrictive binding”.
to strongly hold other species. The binding behavior is not necessarily
thermodynamically driven; the free energy difference between free species and bound
host-guest complexes is generally small (ΔG often < 20 kJ/mol). Instead, the
stability of these container-guest complexes is kinetic in nature. Because of the near
closed-surface nature of these hosts, there are typically high activation barriers to
guest decomplexation. Moreover, even complexes of low intrinsic thermodynamic
stability can exhibit remarkable kinetic stability due to high kinetic barriers
associated with the ingress and egress of guests (Figure 1.7). Donald Cram described
this behavior as “constrictive binding,”61a,71
and defines the constrictive binding
energy as ∆G‡
comp= ∆G‡
decomp- ∆Go. Essentially, for molecules to enter or leave the
cavity, the host must go through a high-energy conformation, behavior that has been
described by Houk as “conformational gating”72
(Figure 1.8).
Binding of gas molecules by supramolecular species is an even more daunting
task than binding of ions or larger neutral molecules, due to the entropic cost of
15
binding. However, gas encapsulation has been observed in many supramolecules and
Rudkevich has written two reviews related to gas encapsulation in open cavity
species such as α-cyclodextrin, calixarenes, cucubiturils, and “surgically opened”
fullerenes as well as in closed-surface molecules such as carcerands/hemicarcerands,
Rebek’s self-assembled capsules, and cryptophanes.73
Supramolecules that bind gases
effectively generally possess small cavities and are dissolved in solvent molecules
that cannot fit easily into the pore of the supramolecule. This binding was generally
studied in solution by various NMR techniques; few solid-state studies of gas binding
have been reported. While single crystal analyses of gas complexes of clathrate
hydrates, decamethyl-cucubit[5]uril74
and Atwood’s calix[4]arene have been
reported, no single crystal analyses have been performed on container-gas complexes.
Container molecules not
only hold onto molecular species
very strongly, they also strongly
discriminate between similar
molecules on the basis of size and
charge. This binding behavior
may be exploited to perform
interesting chemistry, such as
stereoselective synthesis75
and
stabilization of reactive
Figure 1.9. Selective [2+2] photodimerization inside a
metal-ligand container molecule. This reaction occurs
only in the presence of the container, and yielded only
the cross syn dimer.
16
intermediates.76
For example, Fujita and coworkers have performed selective [2+2]
photodimerization reactions inside a metal-organic container; one example is
illustrated in Figure 1.9.69b
The photodimerization reaction occurs exclusively inside
Fujita’s polyhedra; no reaction occurs in the bulk solution. Clearly, the container
preorganizes the two substrates in a specific conformation. In contrast, Warmuth and
coworkers have performed the opposite task by protecting reactive intermediates
from reaction by confinement within an unreactive hemicarcerand container.69b,77
Warmuth (and Cram before him) has stabilized and characterized many highly
reactive species, including the antiaromatic cyclobutadiene, benzyne, and carbenes
and nitrenes. The “inner phase” and “outer phase” of a molecular container often
differ dramatically in electronic character; Cram described the inner phase of a
hemicarcerand as a “new phase of matter.”78
Figure 1.10. Left. General structure of (±)-anti cryptophane. Right. General structure of syn
cryptophane. In most common cryptophanes, A = Z = OCH3.
17
1.4. Cryptophanes
Cryptophanes are one class of container molecules, initially reported in 1981
and intensively studied by the late Andre Collet.79
They are composed of two axially
chiral C3 symmetric cyclotribenzylenes (hereafter CTBs), that are connected to one
another by three spacers. Each cryptophane has two chiral units, resulting in two
diastereomers: the syn form and the anti form (Figure 1.10). The syn diastereomer
has the groups A and Z on the same side of the bridging unit (X), while the anti
diastereomer has the groups A and Z on opposite sides with respect to the bridge.
The syn diastereomer is achiral (C3h) when A = Z, but is chiral (C3) when A and Z are
not the same (Figure 1.10). The anti diastereomer is inherently chiral, with C3
symmetry when A and Z are different and D3 symmetry when A = Z. It is important
to note that unless otherwise stated, cryptophane syntheses result in both anti
enantiomers. Table 1.2 describes the notation for racemic anti-cryptophane
molecules.
Cryptophanes are essentially spheroidal molecules that have a distinct “inner
phase” with “equatorial”
and “polar” regions (Figure
1.11). The “inner phase” is
the interior of the
cryptophane, which has two
concave surfaces from the
Figure 1.11. Descriptions of cryptophane regions.
18
Symbol Description Example
(±)-anti Racemic mixture of cryptophanes (±)-anti-4
Cryptophane encapsulates following guest molecule (±)-anti-4THF
Table 1.2. Description of symbols used throughout text.
CTB “poles”. The equatorial region consists of the three bridges and three container
openings or pores. These different regions often have truly different chemical and
electronic behavior. Within the inner phase, there are large differences in sterics and
electronics in the polar regions of the container relative to the equatorial region.
Cryptophane molecules have a rich history of host-guest chemistry, with
behavior that is similar to that of other container molecules. A variety of cryptophane
molecules have been synthesized, in which variations have been made to the three
bridges (X, see Figure 1.10), as well as to the CTB subunits (A, Z, Figure 1.10), and
Collet gave the cryptophanes a letter designation based upon their order of synthesis
(Cryptophane A, B, C, etc.). In general, ∆G‡
decomp decreases with an increase in
bridge length as the opening to the container becomes larger and less restrictive to
guest entry. Cryptophanes, like other container molecules, exhibit a strong size
dependence on molecular binding, as shown in Table 1.3.80
Though each
Cryptophane X X’ Y Ideal Guest Ideal Guest
Volume(Å3)
-∆Go (kJ/mol)
A OCH3 OCH3 (CH2)2 Xe 41 20.6
C H OCH3 (CH2)2 CH2Cl2 57 15.4
E
(neutral guests) OCH3 OCH3 (CH2)3 CHCl3 72 15.3
E
(cationic guests) OCH3 OCH3 (CH2)3 N(CH4)4
+ 96 30.9
Table 1.3. Free energy of complexation for various cryptophanes in (CDCl2)2at 300K.65
19
cryptophane is capable of binding guests of varying size (neutral cryptophane E
guests range from 40 to 95 Å3), it is clear that each cryptophane has a guest of
optimum size that is bound most effectively. It is also important to note that
cryptophane A shows a substantial affinity to bind gases such as xenon (ΔG ~ 20
kJ/mol) and methane (ΔG ~ 12 kJ/mol).81
Cryptophanes’ molecular recognition and binding have been exploited in
several situations. Recently, biofunctionalized cryptophane molecules have been
used as a biosensor.82
Remarkably, xenon encapsulated within the cryptophane
exhibits measurable changes in the Xe NMR chemical shift based on the binding
events on the exterior of the cryptophane. For instance, a biotin-functionalized
cryptophane has been introduced to the protein avidin, and the Xe NMR response of
the biotinylated cryptophane AXe has been shown to shift downfield and broaden
after the functionalized cryptophane has been introduced to avidin (See Table 1.2 for
description). Also, a specifically designed cryptophane molecule ((+)-Cryptophane
C) was used to bind the racemic CHFClBr83
and the difference in relative stability of
the resulting diastereomeric complexes was calculated (ΔΔG~1.1 kJ/mol). The
enantiomeric excess of (+)-CHFClBr was calculated by NMR (ee = 4.3±1%), which
allowed for the experimental determination of the halomethane’s specific optical
rotation.
20
1.5. Research project: Synthesis and Characterization of Cryptophane
Container-Based Materials
The overall purpose or goal of this research project is multipronged. First,
new exo-carboxylic acid functionalized m-xylyl bridged cryptophane molecules and
materials have been synthesized and characterized, with the ultimate goal of using
these container molecule ligands to synthesize rigid, porous coordination polymers.
Since cryptophanes are spheroidal in shape, the resulting cryptophane-based solid
was hypothesized to pack inefficiently and not be able to generate interpenetrating
coordination networks. The resulting material should be porous in nature.
Furthermore, the network would also be imparted with container molecules that are
capable of size and shape-selective binding. The resulting materials should have
interesting structural features and functionality.
We chose to synthesize the exo-carboxylic acid cryptophane species as metal-
carboxylates can often form well-defined SBUs such as the copper-carboxylate
paddlewheel and the zinc-carboxylate octahedron. Knowing the potential SBUs for
zinc-carboxylates, and that the cryptophane has a C3 axis allows structural predictions
to be made about the potential cryptophane-based materials.
A second goal for this research project was to identify and possibly quantify
the “constrictive binding” that occurs in cryptophane based materials, as it is our
hypothesis that constrictive binding is a universal container behavior, not simply a
solution-based behavior of containers. This study requires that these materials be
21
studied by thermal techniques, such as differential scanning calorimetry (DSC) and
thermogravimetric analysis (TGA) to determine the kinetics of
desolvation/decomplexation in cryptophane-based materials. Structural information
about the cryptophaneguest complex is important information in this study, as it
confirms the cryptophaneguest stoichiometry as well as the guest(s) conformation
inside the cryptophane host. The material’s structure is also crucial in that it may
identify additional lattice solvent molecules whose desolvation may overlap or
interfere with the included solvent guest.
22
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24
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33
CHAPTER 2: SYNTHESIS, CHARACTERIZATION AND INCLUSION
COMPOUNDS OF M-XYLYL BRIDGED CRYPTOPHANES
2.1. Introduction: Synthesis and characterization of cryptophanes
There are three published synthetic pathways that have been used to synthesize
cryptophanes: the “two-step method”,1 the “template method”
2 and the so-called
“capping method”3 (Scheme 2.1). Each method has its own relative strengths and
weaknesses; however, all three methods require the formation of cup-like CTB
subunits. The CTB cyclization reaction is generally an acid-catalyzed dehydration and
cyclization of vanillyl alcohol derivatives, with vanillyl alcohol being 3-methoxy-4-
Scheme 2.1. Three potential synthetic pathways to cryptophane molecules. In most cases, E = E’
= OCH3.
34
hydroxybenzyl alcohol. Three vanillyl groups react regioselectively to make up each
CTB subunit.
The two-step method is the middle pathway shown in Scheme 2.1, and can be
described as initially synthesizing one third of the cryptophane by joining one bridging
subunit with two cyclotribenzylene (CTB) precursors (usually 3-methoxy-4-
hydroxybenzyl alcohol, commonly known as vanillyl alcohol). The second step is the
cryptophane synthesis, in which the cryptophane molecule(s) are synthesized by the
cyclization reaction that forms both CTB subunits by performing six regioselective
electrophilic aromatic substitution reactions. This reaction synthesizes cryptophane
molecules in the fewest number of synthetic steps, and is most useful in the synthesis
of symmetric cryptophanes, which is a cryptophane in which all bridges are identical.
However, the cryptophane cyclization reaction yields are low (<20%) and generally
produce different quantities of syn and anti diastereomers, as a function of bridge
length, and the two-step method usually produces more of the anti diastereomer.
The template method is more challenging and time-consuming synthetically
(Scheme 2.1, top), but is usually higher yielding in the final cyclization step. Also, the
template method can be used to create asymmetric cryptophanes that have different
bridging subunits.4 The template in the so-called template method is an already
synthesized CTB subunit, which holds the three CTB precursors in close proximity to
one another and makes the cryptophane cyclization reaction more successful when
performed under highly dilute conditions.
35
The capping method (Scheme 2.1, bottom) brings one CTB subunit together
with a second CTB subunit. The advantage of this type of reaction is that it allows for
differentiation of the two cryptophane caps. Also, interesting chemistry can be used to
perform the capping reaction. Shinkai provides one example in which a Pd-pyridine
interaction was used to assemble novel cryptophane.5
The 1H NMR spectra of cryptophane molecules and related cup-shaped CTB
molecules have several characteristic features. The methylene groups at the base of the
[1.1.1]orthocyclophane cups exhibit an unusual NMR splitting (Figure 2.1); the
equatorial proton gives a doublet at approximately 3.5 ppm while the axial proton
gives a doublet at approximately 4.7 ppm.6 The axial protons are in such close
proximity to one another that their electrons repel, resulting in proton deshielding from
mutual electron repulsion. Consequently, Ha resonate significantly downfield (~1.2
ppm) from He. Symmetric cryptophanes (Figure 1.10) are also characterized by two
singlets (or weakly coupling doublets) resulting from arene protons on the CTB, while
Figure 2.1. 1H
NMR of cryptophane E (propyl-bridged).
36
the remaining protons come from the bridges. The NMR spectrum of a symmetric
cryptophane (cryptophane E, Figure 2.1) has relatively few peaks for such a large
molecule, due to its high (D3) point group symmetry.
The 1H NMR shown in Figure 2.1 was performed in (CDCl2)2, and has two
interesting NMR peaks that are identified as free and bound CHCl3, which were
observed at about 7.3 and 2.8 ppm, respectively. The two NMR peaks indicate that the
chloroform binding is in a slow exchange regime, and the highly upfield shift (~4.5
ppm) of bound chloroform is a result of its position within the highly shielding
cryptophane molecule. This NMR demonstrates the selective guest binding of
cryptophane E for chloroform relative to d2-1,1,2,2 tetrachloroethane, which has two
additional non-hydrogen atoms. Variable temperature 200 MHz 1H NMR experiments
were performed, and the chloroform peaks disappeared above 360K (the fast exchange
chloroform peak could not be obtained due to temperature restraints). The stability
constant of the cryptophane-ECHCl3 in (CDCl2)2 is 470 M-1
.7
2.2. Solution vs. Solid-State Analyses of Supramolecular Host-Guest
Complexes
Most host-guest binding studies to date have been performed in solution. In
solution, one observes the “real life” binding of a guest molecule to its host, as most
biomolecular and molecular hosts are designed to bind guest(s) in solution. Even more
importantly, quantification of the binding constant and the free energy of binding are
37
possible through solution studies.8 Furthermore, a large number of techniques are
available to study the solution binding of these systems (NMR,9 Isothermal Titration
Calorimetry or ITC,10
and UV/VIS11
).
Though solution-based binding studies are important for the reasons stated
above, many factors can complicate these experiments. In container molecules, the
guest molecules are neutral organic species that are often similar to the solvent. Often,
a noncompeting solvent is employed; however, such a solvent is not always available.
If the bulk solvent competes for binding, it can be impossible to determine the binding
constant for a specific guest. Also, large pore container molecules do not
constrictively bind as effectively as cryptophanes with shorter bridges. The resulting
host-guest complexes, therefore, are not as kinetically stable and the guest/solvent is in
fast exchange with the bulk solvent.
An alternative to NMR binding studies is a crystallographic analyses of host-
guest complexes. One can observe the host conformations sampled in various host-
guest complexes.12
One obtains a “snapshot” of the guest molecule inside of the host,
which allows for an analysis of the host-guest interactions governing the complexation
event. Furthermore, understanding the structure of the host-guest complex may help
explain the solid-state behavior (i.e. desolvation) in host-guest materials.
2.3. History of Crystallographic Analysis of Container Molecule Host-Guest
Complexes
38
While cryptophanes have existed for 25 years, there are surprisingly few crystal
structures of cryptophanes reported in the Cambridge Structural Database (CSD). In
fact, only fifteen cryptophane structures have been reported.13
This lack of data on
container molecule complexes is not limited to cryptophanes. Another container
molecule, [hemi]carcerands (Figure 2.2), have been extensively studied; however,
there are only 29 [hemi]carcerand crystal structures deposited in the CSD.14
Several
factors may contribute to this low number, including not reporting crystal structures to
the CSD and the relative difficulty in obtaining high quality crystals of fairly large
container molecules.
Figure 2.2. Left: Alkynyl bridged hemicarcerand, which is defined by the C4 symmetric cavitands
that make up the polar regions of the container. Right. Crystal structure (YETKAJ) describing
alkynyl bridged hemicarcerand. The encapsulated molecule is 1,1,2,2 tetrachloroethane.
39
Cram and coworkers performed a detailed structural analysis of
hemicarceplexes in a paper entitled “Correlations of Structure with Binding Ability
Involving Nine Hemicarcerand Hosts and Twenty-Four Guests,”15
reported in 1997.
This work looks at the effects of different bridges (aliphatic vs. aromatic), different
bowl spanners (OCH2O, O(CH2)2O, O(CH2)3O), and of asymmetric containers on
guest complexation and host conformation. This comprehensive analysis successfully
explained the difference in chemical shift between free and incarcerated guest signals
in 1H NMR as a function of their position in the cavity.
The other major crystallographic study that included hemicarcerands and
cryptophanes was a CCD database analysis of supramolecular systems. Nishio, in
“CH- Interactions as Demonstrated in the Crystal Structures of Host-Guest
Compounds: A Database Study,”16
examined the CH- interactions in a variety of
systems, including calix[4]arenes, cyclodextrins, pseudorotaxanes as well as
cryptophanes. Nishio found a number of short CH- contacts in these systems,
indicative of weak interactions between host and guest.
2.4. Syntheses of m-xylyl bridged cryptophanes
o-, m-, and p-xylyl bridged cryptophanes have been synthesized previously.17
An endo-acid functionalized m-xylyl bridged cryptophane was reported by Weber and
coworkers, and provides an interesting contrast to the exo-functionalized species that
this research targeted. The endo-functionalized m-xylyl cryptophane, seen in Figure
40
Figure 2.3. Structure of Weber’s endo-carboxylate m-
xylyl cryptophane. Hydrogen atoms and guest
molecules omitted for clarity. Carbon: Gray;
Oxygen: Red.
2.3, points its carboxylate functional groups into the cavity of the cryptophane. The
resulting cryptophane was studied for its metal-cation binding properties, and a crystal
structure of the cryptophane showed that the cryptophane had a crystallographic space
group of P-6, which reflects the idealized point group symmetry of the molecule (C3h).
In contrast, the synthetic targets in this research are exo-functionalized m-xylyl bridged
cryptophanes, which can be used to create three-dimensional materials that are
embedded with container-based molecules. To create an exo-functionalized
cryptophane, the m-xylyl bridges were designed such that the appropriate functional
groups were meta to each of the xylyl groups, which placed the functional groups
normal to the C3 axis of the cryptophane. CPK models strongly suggested that the
functional groups would be unable to
turn into the cryptophane, and that
they would point away from the
cryptophane pore. The resulting exo-
functionalized cryptophane could
then be viewed as a three-fold
organic spacer, similar to trimesic
acid, and plausible materials can be
designed from these cryptophane
spacers, in theory.
Specifically, the exo-acid cryptophane was targeted for its potential in the
41
Scheme 2.2. Synthesis of m-xylyl bridged cryptophanes.
design of metal-carboxylate materials, or in hydrogen-bonded networks. The exo-
bromobenzene cryptophane was targeted because of the potential for additional
chemistry via cross coupling reactions such as Suzuki, Stille or Negishi coupling
42
reactions.18
For example, coupling chemistry could generate exo-functionalized
cryptophanes that have interesting functionalization that is quite distant from the
cryptophane pore. Also, the bridging reactions can be used to systematically examine
the effect of functional group position and type on their corresponding solid-state
materials.
Syntheses of various m-xylyl bridged cryptophanes were performed using the
“two-step” method (Scheme 2.2). This method was chosen because the desired
symmetric cryptophanes could be synthesized and isolated in approximately 1-2
weeks. Appropriately functionalized bis(bromomethyl)benzenes19
were reacted with
two equivalents of vanillyl alcohol to yield the corresponding diols in good yields (75-
90%). The diol molecules are essentially a monomer in a cyclic trimerization, as they
correspond to ~1/3 of the cryptophane molecule. The cyclization reaction requires an
acid catalyst, which is typically formic acid. In fact, formic acid acts both as solvent
and catalyst. This reaction is performed at high dilution (~1 mM) to minimize
unwanted polymerization side-reactions.
The cyclization reactions forming exo-ester cryptophanes (±)-anti-4 and syn-5,
m-xylyl bridged (±)-anti-6 and syn-7, and exo-bromo cryptophane (±)-anti-8 were
somewhat successful. The cryptophanes were isolated by flash column
chromatography; followed by recrystallization from the appropriate solvent. The
overall yield of cryptophane molecules is low (1-12%), and these yields were
somewhat lower than reported yields for other cryptophanes synthesized using the two-
43
step method (2-20%).1 The lower yield for m-xylyl bridged cryptophanes relative to
aliphatic bridged cryptophanes is not surprising, because unwanted electrophilic
aromatic substitution (EAS) reactions can occur on the aromatic bridges. The anti
isomers were higher yielding than the syn isomers, and the syn form of the exo-bromo
cryptophane was never isolated (Scheme 2.2).
The ester-functionalized cryptophanes (±)-anti-4 and syn-5 required a
deprotection step before it could be employed as a coordinating ligand. Acid-catalyzed
Fischer de-esterification was not successful in the synthesis of (±)-anti-H39 or syn-
H310; base-catalyzed hydrolysis with NaOH resulted in an intractable solid. The
deprotection was successfully completed, however, in two steps as shown in Scheme
2.2: Saponification was performed with NMe4OH followed by immediate acidification
with aqueous HCl. The organic base was employed for its improved solubility
properties in organic solvents, as the tristetramethylammonium cryptophane salt is
somewhat soluble in organic solvents. 1H NMR confirmed the formation of (±)-anti-
H39 and syn-H310, most notably through the loss of the ester peak near δ 3.9 ppm.
1H NMR spectra for these cryptophanes are similar and representative spectra
of (±)-anti-4 and syn-5 are shown in Figure 2.4. It is important to note that in the
absence of a chiral shift reagent, NMR alone cannot distinguish between the syn and
anti diastereomers, as these isomers have the same number and type of unique protons.
For cryptophanes 4-10, single-crystal x-ray crystallography was required to determine
the identity of the diastereomers (vide infra).
44
Figure 2.4. Left) 1H NMR spectrum of (±)-anti-4. Right) H NMR spectrum of syn-5.
2.5. Crystal Structures of m-Xylyl Bridged Cryptophanes
Cryptophanes (±)-anti-4, syn-5, (±)-anti-6, syn-7, (±)-anti-8, (±)-anti-H39, and
syn-H310 were all characterized by single crystal X-ray diffraction, confirming the
stereochemical assignments as either syn or anti diastereomers. In all, 26 single crystal
structural determinations were performed and will be described in the following
sections. See Table 2.1 for a list of abbreviations used in the forthcoming chapters.
In all cases, the cryptophane hosts contain encapsulated guests, extracted from
the solvent, in the solid state. Much attention was directed (22 structures) on the anti-
diastereomer, and these structures will be discussed in detail in the ensuing sections.
The data quality of the syn-H310 sample was extremely poor. The structure was
solved, confirming the presence of the syn-H310 diastereomer, but the refinement was
45
disagreeable and the details are not formally reported.
2.5.1 SQUEEZE analysis of m-xylyl Bridged CryptophaneGuest Structures
Numerous cryptophaneguest crystal structures were collected; however, the
subroutine SQUEEZE20
was often employed in the solution. SQUEEZE was used to
Table 2.1. Molecule Abbreviations.
model diffuse electron density
in highly disordered regions of
the model. SQUEEZE proved
to be a useful technique for
these systems for several
reasons:
Twenty six
cryptophaneguest crystal
structures were collected, and
the subroutine SQUEEZE was
often employed in the
refinement in order to model
diffuse electron density
associated with highly
disordered regions of the refinement model. Unless explicitly stated, only lattice
Abbreviation Molecule Name Molecule Formula
n-hexPh n-hexylbenzene C6H5(CH2)5CH3
n-prPh n-propylbenzene C6H5(CH2)2CH3
1,2,4PhMe3 1,2,4-trimethylbenzene 1,2,4-C6H3(CH3)3
o-xylene 1,2-dimethylbenzene 1,2-C6H4(CH3)2
m-xylene 1,3-dimethylbenzene 1,3-C6H4(CH3)2
PhI Iodobenzene C6H5I
NO2Ph Nitrobenzene C6H5NO2
PhBr Bromobenzene C6H5Br
PhCN Benzonitrile C6H5CN
PhCl Chlorobenzene C6H5Cl
Et2O Diethyl ether C4H10O
THF Tetrahydrofuran C4H8O
NO2Me Nitromethane CH3NO2
DMSO Dimethyl sulfoxide CH3SO
DMF N,N-Dimethylformamide (CH3)2NCHO
46
solvent molecule(s) have been modeled using SQUEEZE. Generally, the encapsulated
guests are highly ordered, or can be adequately modeled which is undoubtedly a
consequence of the container effect in the solid state. The following discussion on the
geometrical parameters associated with the host-encapsulated guest interactions
observed in the solid state. Although there are certainly packing effects resulting from
the lattice solvent molecules, it is believed that this effect is minimalized in highly
disordered systems. Where possible, both SQUEEZE refinement models and the non-
SQUEEZEd models are included for direct comparison.
2.6. M-m-xylyl CryptophaneAromatic Guest Complexes
2.6.1. Common Guest Binding Motif: The Importance of CH- Interactions
Guest binding within a host balances both satisfaction of favorable interactions
as well as avoidance of unfavorable interactions. From a strictly steric repulsion
standpoint, one would expect that a bound guest molecule would adopt an orientation
that would minimize host-guest close contacts. A loosely bound guest molecule is also
entropically favored, as the guest molecule would have increased movement in the
host.21
As a result, one would expect that the bound aromatic guest molecule would
reside in the most spacious region of the cryptophane, which is along its C3 axis, where
the likelihood of guest movement is highest. However, the aromatic guest molecules
singularly adopt an orientation away from the C3 axis by approximately 10. A closer
analysis of these structures revealed that the guest molecules tilted from the C3 in order
47
to maximize the CH- interactions between cryptophane host and aromatic guest
(Figure 2.5). It is also noteworthy that the guests were well ordered, with no evidence
of guest rotation within the cryptophane host. In most cases, the substituted benzenes
were partially protruding from the opening of the cryptophane, which further
prohibited guest rotation in the interior of the cryptophane.
2.6.2 CH- Interactions: Weak Intermolecular Forces
Intermolecular forces exist in a continuum, ranging from weak (van der Waals
forces, induced dipole-induced dipole interactions) to
very strong (Hydrogen bonding, ion-ion electrostatic
interactions).22
CH- interactions are relatively weak,
estimated to be worth 0.5-2.5 kcal/mol per interaction.23
Despite the small energy contribution of these
interactions, reaction selectivity, crystal packing in
organic compounds,24
and DNA and protein structure are
influenced by CH- interactions.25
It is important to define the parameters that are
associated with a CH- interaction. Nishio defined a
number of geometric parameters to define a CH-
interaction in the solid state, including the H- distance
Figure 2.5. Determination of
distance for CH-
interactions. Distance d is
taken from the guest proton to
either the closest cryptophane
aromatic carbon or the
centroid defined by the six
carbons in the appropriate
ring. Angle is defined as the
C-H- angle where C = guest
carbon, H = guest hydrogen
and = either the closest
cryptophane aromatic carbon
or the centroid defined by the
six carbons in the ring.
48
Table 2.2. New m-xylyl bridged cryptophanes
Molecule L
(±)-anti-4 COOMe
syn-5 COOMe
(±)-anti-6 H
syn-7 H
(±)-anti-8 Br
(±)-anti-H39 COOH
syn-H310 COOH
(3.05Å). However, Nishio’s system is unnecessarily unwieldy; therefore, I defined a
simpler system to measure H- distances and C-H- angles, as seen in Figure 2.5. I
simply measure the distance between a guest proton to each host aromatic carbon as
well as the centroid defined by each of the six aromatic host carbons, and report the
closest contact.
In every cryptophane, multiple CH- interactions were found for each
cryptophaneguest complex (Table 2.3). In thirteen structures (Figure 2.6) with
fourteen total cryptophanes, forty CH- interactions were identified where the H-
distance was on or below 3.05Å. There are 65 hydrogen atoms on the guest molecules
49
that are available for CH- interaction, meaning that 62% of available guest protons
participate in these interactions. However, only four CTB arene rings can interact with
any given guest. Taking this into account, only 55 hydrogen guest atoms could interact
with the cryptophane CTB arenes; thus 73% of possible CH- interactions are
observed.
The crystallographic data revealed the favored binding motif for aromatic guests;
however, it does not completely explain why this behavior is observed. One
explanation for this guest orientation is that the low temperature at which all structures
were collected (173K) favors enthalpic contributions to guest binding and disfavors the
thermal disorder associated with entropic binding. In effect, the low temperature
structures may simply “freeze” the guest in one conformation. Another possible
explanation for this observation may be that tilting the guest relative to the cryptophane
improves the steric relationship between the guest substituents (i.e. methyl groups,
chloro groups, etc.) and the windows of the cryptophane.
2.7. m-Xylyl Bridged Cryptophane Host Conformational Changes
M-xylyl bridged cryptophanes have rigid [1.1.1] orthocyclophane caps and m-
xylyl linkages. One would surmise that the resultant molecules would have little
flexibility; however, we observe host cryptophanes with more degrees of freedom than
50
Figure 2.6. Side and Top views of cryptophanearomatic guest complexes. Guest molecules
shown in space-fill form and cryptophanes shown in stick form. a) (±)-anti-4C6H5NO2 b) (±)-
anti-4C6H5CN c) (±)-anti-4C6H5(CH2)2CH3 d) anti-4C6H5Br1 e) (±)-anti-4C6H5Cl f) 2-(±)-
anti-6m-C6H4(CH3)2 g) (±)-anti-6C6H5Br h) (±)-anti-61,2,4-C6H3(CH3)3 i) (±)-anti-6o-
C6H4(CH3)2 j) (±)-anti-4C6H5I1 k) (±)-anti-4C6H5(CH2)5CH3 l) syn-5C6H5NO2 m) (±)-anti-
6C6H5NO2. Carbon: Gray; Hydrogen: White; Nitrogen: Blue; Oxygen: Red; Chlorine: Yellow;
Bromine: Yellow. 1 Forms conglomerate structures (see vida infra).
51
Table 2.3. CH- Interactions between cryptophanes and aromatic guests.
Host Guest Guest
Volume[a]
(Å3)
d-CH- [b]
(Å)
CH- [c,d]
()
Torsion Ar-O-CH2-Ar [d]
(||)
(±)-
anti-4
n-
hexPh
174[e]
2.74-c
2.81-c
3.00-c
3.06-c
153.0
177.1
158.5
155.1
91.8, 163.8
77.5, 152.4
82.7, 170.5
(±)-
anti-4
n-prPh
126 2.78-c
2.81-c
156.0
147.9
81.0, 147.8
159.4, 161.3
82.3, 155.4
(±)
-anti-6
1,2,4
PhMe3
125 2.58-c
2.74-c
176.9
163.5
84.9, 160.3
86.6, 159.4
74.0, 144.9
(±)-
anti-6
o-
xylene
110 2.71-c
2.79-c
164.3
167.1
84.2, 157.4
73.3, 147.5
83.6, 161.7
(±)-
anti-6[f]
m-
xylene
109 2.64-c
2.73-c
2.94-a
2.60-c
2.80-a
2.85-a
149.4
153.3
158.8
150.0
164.8
164.1
87.5, 170.6
175.0, 94.0
148.6, 170.7
159.4, 157.2
83.5, 176.3
107.4, 167.9
anti-4[g]
PhI
105 2.63-c
2.67-c
2.74-c
2.80-c
153.4
156.1
169.7
177.0
95.6, 145.8
88.7, 166.5
80.4, 167.2
52
Table 2.3. cont. CH- Interactions between cryptophanes and aromatic guests.
Host Guest Guest
Volume[a]
(Å3)
d-CH- [b]
(Å)
CH- [c,d]
()
Torsion Ar-O-CH2-Ar [d]
(||)
(±)-anti-4
NO2Ph
102 2.60-c
2.87-c
2.98-a
3.38-c
163.2
156.1
166.4
165.0
80.6, 119.1
151.4, 171.2
149.3, 170.1
syn-5 NO2Ph
102 2.77-c
2.96-c
3.16-c
155.7
170.5
163.8
88.8, 165.0
168.9, 152.4
76.4, 163.9
(±)-anti-8 NO2Ph
102 2.68-c
2.79-c
2.85-c
2.89-c
166.7
163.3
167.3
172.6
85.9, 144.8
78.2, 166.5
77.9, 156.3
anti-4[g]
PhBr
101 2.71-c
2.73-c
2.74-c
2.85-c
152.6
156.8
172.2
176.5
147.6, 95.8
90.9, 155.4
79.0, 168.7
(±)-anti-6
PhBr
101 2.62-c
2.69-c
2.77-c
2.88-c
153.0
164.1
175.8
179.5
82.5, 172.6
85.3, 176.9
90.6, 156.3
(±)-anti-4
PhCN
97 2.69-c
2.98-c
2.99-a
3.12-c
170.4
162.1
172.2
176.0
148.9, 171.5
149.0, 171.0
84.6, 109.3
53
Table 2.3. cont. CH- Interactions between cryptophanes and aromatic guests.
Host Guest Guest
Volume[a]
(Å3)
d-CH- [b]
(Å)
CH- [c,d]
()
Torsion Ar-O-CH2-Ar [d]
(||)
[a] Molecular volume determined by X-SEED. [b] Distance d as defined in Figure 2.5. Label c
denotes the H- distance measured to -ring centroid, while a denotes that the distance was
measured to an atom on the -ring. [c] Angle as defined in Figure 2.5. [d] Italicized values
indicate CH- interactions while underlined values correspond to CH- interactions that are
greater than the 3.05Å value defined as being significant by Nishio. Bolded angles correspond to
angles influenced by guest methyl groups. [e] Guest not completely encapsulated within the
cavity. [f] Two crystallographically distinct cryptophanes. [g] Forms conglomerate structures
(see vida infra).
previously hypothesized from CPK models. Most structural changes in the
cryptophane host can be attributed to the ArCTB-O-CH2-Arbridge linkage (Figure 2.7).
This region of the cryptophane molecule is the only part of the molecule with
significant degrees of rotational freedom, since the vast majority of the molecule is
aromatic and rigidly locked into place. Torsion about these bonds influences how the
m-xylyl bridges turn with respect to the C3 axis; it also affects the angle between the
two caps and their distance from one another. Torsion may also allow closer CH-
contacts between host and guest. Analysis of Ar-O-CH2-Ar torsion angles across all
cryptophanearomatic guest structures reveals some interesting general trends. First,
the distribution of this torsion angle is bimodal, with one grouping between 140 and
(±)-anti-4
PhCl
95 2.78-c
3.08-c
3.09-c
171.7
170.6
157.4
83.0, 114.9
150.4, 170.5
149.5, 171.9
54
Table 2.4. X-Ray data for CryptophaneAromatic Guest materials.
Host Guest
Lattice
Solvent Sqz?1
S. G.2
a (Å)
b (Å)
c (Å)
α (°)
β (°)
γ (°)
Vol3
(Å3) R1 wR2 GOF
(±)-
anti-4
n-
hexPh
n/a No P21/n
16.503
26.981
16.729
90
99.65
90
7344 0.072 0.177 0.869
(±)-
anti-4
n-prPh
n-prPh
1.5
CH2Cl2
No P-1
13.829
15.207
22.304
74.60
73.37
81.35
4319 0.101 0.280 0.905
(±)-
anti-6
1,2,4
PhMe3
1,2,4
PhMe3
No P21/n
23.323
13.767
24.591
90
112.89
90
7274 0.060 0.180 1.078
(±)-
anti-6
o-
xylene
o-
xylene
No P21/n
23.831
13.504
24.063
90
112.81
90
7138 0.070 0.233 0.978
2_(±)-
anti-6
2_m-
xylene
2_m-
xylene
No P21/n
22.306
22.435
26.475
90
109.78
90
14134 0.061 0.162 0.752
1 SQUEEZE subroutine.
2 Space Group.
3 Unit Cell Volume.
55
Table 2.4. cont. X-Ray data for CryptophaneAromatic Guest materials
Host Guest
Lattice
Solvent Sqz?1 S. G.
2
a (Å)
b (Å)
c (Å)
α (°)
β (°)
γ (°)
Vol3
(Å3) R1 wR2 GOF
anti-4 PhI PhI
Yes
(PhI)
P21
14.114
17.369
17.861
90
101.38
90
4293 0.044 0.115 1.043
(±)-
anti-4
NO2Ph NO2Ph No P21/c
24.793
12.450
25.788
90
104.13
90
7719 0.103 0.321 0.991
syn-5 NO2Ph 4NO2Ph No P-1
11.627
14.792
27.340
87.84
85.54
82.67
4648 0.051 0.108 0.826
(±)-
anti-8
NO2Ph
2.4
NO2Ph
Yes
(0.4
NO2Ph)
P-1
13.908
14.660
23.346
84.23
78.34
64.22
4191 0.049 0.140 1.005
anti-4 PhBr 2 PhBr
Yes (2
PhBr)
P21
14.133
17.466
17.844
90
101.71
90
4313 0.071 0.175 0.831
1 SQUEEZE subroutine.
2 Space Group.
3 Unit Cell Volume.
56
Table 2.4. cont. X-Ray data for CryptophaneAromatic Guest materials
Host Guest
Lattice
Solvent Sqz?1 S. G.
2
a (Å)
b (Å)
c (Å)
α (°)
β (°)
γ (°)
Vol3
(Å3) R1 wR2 GOF
(±)-
anti-6
PhBr
2.5
PhBr
No C2/c
25.609
12.116
47.281
90
103.04
90
14292 0.080 0.260 1.077
(±)-
anti-4
PhCN
Et2O
0.5
PhCN
Yes
(C4H10O
0.5
PhCN)
P21/c
24.834
12.538
25.847
90
104.53
90
7790 0.065 0.175 0.787
(±)-
anti-4
PhCl
Et2O
0.5
PhCl
No P21/c
24.890
12.453
25.884
90
104.52
90
7766 0.068 0.197 1.018
1 SQUEEZE subroutine.
2 Space Group.
3 Unit Cell Volume.
180 and a second grouping while the second group represents a nearly eclipsed
conformation. Hyperchem 7.5 was employed to determine the energy difference
between these torsion angles. A simplified fragment that contained a methoxy
functionalized arene and one ester-functionalized m-xylyl group was allowed to sample
57
various conformations through MM+ molecular dynamics
calculations; geometric optimization was performed
immediately after the molecular dynamics calculation.
Although this model is quite crude (based on gas phase,
discounts CTB cone conformation), the calculations
confirmed that the staggered conformation was lowest in
energy (174.5; 3.92 kcal/mol for torsion angle and 13.00
kcal/mol total energy), and that the eclipsed conformation
was slightly higher in energy (114.0; 4.33 kcal/mol for
torsion angle and 13.85 kcal/mol total energy).26
`
ArOCH2Ar torsion angles were calculated for CTB arenes involved in CH-
interactions, and compared to the torsion angles in which no CH- interactions were
Figure 2.8. Left: CCTB-O-CH2-Cbridge torsion angles where CTB arene does not engage in CH-
interactions (CTB arene-methyl close contacts also removed). Right: CCTB-O-CH2-Cbridge
torsion angles where CTB arene is engaged in CH- interactions.
Figure 2.7. Measured tor-
sion angle in cryptophanes.
58
observed. The torsion angles observed for ArCTB moieties that do not participate in
and 180, with a mean of 146 and standard deviation (hereafter SD) of 32. An CH-
interactions primarily fall between 150analysis of the torsion angles observed below
120 (82.7 and 76.4) revealed that two of these angles contained CH- distances
(3.06Å, 3.16 Å) that were slightly longer than the 3.05Å cutoff described previously.
Also, two torsion angles below 120 (94.0 and 83.6) were found to have close
contacts (3.01Å and 2.96 Å) between the host arene ring centroids and guest methyl
protons, while two torsion angles below 120 (83.5 and 86.6) were found to have
longer distances between the host arene ring centroids and guest methyl protons
(3.34Å and 3.15Å). Figure 2.8 shows the scatter plot for this data, including the six
data points discussed previously, while Figure 2.9 shows the data in histogram form.
The dramatic bimodal distribution observed in CH- influenced systems may
indicate that the cryptophane host is adapting to its guest in order to maximize host-
guest CH- interactions. The rationale for describing this phenomon is that the host-
guest attraction pulls the CTB arene toward the guest. The bridging unit of the
cryptophane adjusts to allow for closer contact between guest and host; the result is a
reduction in the given torsion angles. The energetic penalty associated with the nearly
eclipsed conformation is apparently compensated by the energetic gain due to the CH-
interactions.
2.8. Halobenzene guests: Conglomorate vs. Racemate formation
59
Racemic cryptophanes can crystallize from solution as either racemates or
conglomerates (wherein the enantiomers are spontaneously resolved in individual
crystals). Conglomorate formation can be a useful technique to separate enantiomers
using preferential crystallization;27
however, racemic crystals are much more common.
It is interesting to note that the ability of cryptophanes to form host-guest complexes,
with a variety of crystalline structures, generates greater opportunities for
conglomerate formation than do compounds with less propensity to form inclusion
complexes.
It was discovered that cryptophane (±)-anti-4 forms isostructural, conglomerate
crystals (±)-anti-4PhX2.5PhX (X=Br, I) when crystallized by ether precipitation
from PhX solvent. However, ether crystallization of (±)-anti-4 from PhClforms a
racemate crystal, despite the similarity of chlorobenzene, to bromobenzene or
iodobenzene. A comparison of the structural features of the conglomerate (±)-anti-
4PhX (X= Br, I) complexes with the racemate (±)-anti-4PhCl shows that there are
several important differences that may possibly explain their different packing. The
halogen atom of the guest halobenzene makes a close contact with a second host
molecule through the methanolic ester oxygen (Br(1S)-O(4B) = 3.56Å, C(1S)-Br(1S)-
O(4B) = 154.0); I(1S)-O(4B) = 3.48Å, C(1S)-I(1S)-O(4B) = 152.6). This
interaction continues such that the resulting chain of cryptophanes forms a helix
propagating along the b axis. The resultant helix must recognize the appropriate M or
P enantiomer, bringing about the formation of the conglomerate crystal (Figure 2.10).
60
Interestingly, while (±)-anti-4PhBr
and PhI formed conglomerate structures,
(±)-anti-4PhCl crystallized in the
centrosymmetric space group P21/c. The
(±)-anti-4PhCl cryptophane complexes
form antiparallel 1-D sheets parallel to the
ab plane (Figure 2.9). The chlorobenzene
may be too small to interact effectively with
the next nearest cryptophane in the crystal,
preventing the interaction that likely causes
the conglomerate crystal to form. Also,
attempts to generalize this phenomenon to
similar cryptophanes were unsuccessful, as
the crystal structure of (±)-anti-6PhBr was
also centrosymmetric (C2/c). This was not
unexpected, since the guest’s interaction
with the ester functionality appeared to drive the formation of the conglomerate crystal.
2.9 Complete Encapsulation vs. Partial Encapsulation
One goal for this study was to probe the effective size of the container cavity
crystallographically by crystallizing with continually larger guest molecules. (±)-
Figure 2.9. Top: Histogram describing the
bimodal distribution of torsion angles in
which host-guest CH- interactions are
observed. Bottom: Histogram describing the
distribution of torsion angles in which host-
guest CH- interactions are not observe
61
anti-4 was dissolved in a mixture of CH2Cl2 and n-propylbenzene and the CH2Cl2 was
slowly evaporated from the solution. The resulting crystal, (±)-anti-
4C6H5(CH2)2CH3 C6H5(CH2)2CH31.5CH2Cl2, revealed that the cryptophane
encapsulated the large aromatic guest, which has a guest size of 126Å3 and contains
nine heavy atoms. The aromatic portion of the guest resides inside the center of the
cryptophane pore (to satisfy CH- interactions), while the alkyl chain is found near the
cryptophane’s opening. The alkyl chain is very nearly equidistant from the two CTB
subunits (C8A-C9S = 4.07Å, O1A-C9S = 3.70Å; C26B-C9S = 3.97Å, O6B-C9S =
3.81Å). The guest’s benzene ring makes only two CH- contacts, and is not found to
be centered inside of the cryptophane. The center of the cryptophane is defined as the
centroid which described by the six inward methylene groups from both CTB subunits
(Ha), and the center of the guest arene is defined as the centroid which described by the
six arene carbon atoms. The distance between the center of the cryptophane and the
center of the arene ring is 1.26Å. The guest adopts this orientation to remain
completely encapsulated within the cryptophane. The alkyl chain of the guest, shown
in Figure 2.11 also adopted a less favored conformation to remain encapsulated within
the cryptophane. The major torsion angle describing the propyl chain were
gauche(C6S-C7S-C8S-C9S = 60.9) rather than the more energetically favored anti
conformation. Not surprisingly, the choice of a larger alkylbenzene, n-hexylbenzene,
resulted in partial guest encapsulation. In the structure (±)-anti-4C6H5(CH2)5CH3, the
62
cryptophane preferentially binds the aromatic ring while the alkyl chain dangles out of
the cryptophane through its opening. The alkyl chain, no longer confined to the
cryptophane, adopts the anti conformation about the C97-C103, C103-C106, and the
C75-C106 bonds and a gauche conformation about the C98-C97 bond.
The hexylbenzene guest arene was also affected by the partial encapsulation
Figure 2.10. Top Left: (±)-anti-4PhBr looking down the –c axis. Top Right: (±)-anti-
4PhCl looking down the c-axis. Bottom: Interaction of bromobenzene guest with ester of
adjacent cryptophane. The bromine-oxygen interaction is shown with the dotted red line.
Guest molecules shown in space-fill form and cryptophanes shown in stick forms. Carbon:
Gray; Hydrogen: White; Nitrogen: Blue; Oxygen: Red; Chlorine: Yellow; Bromine: Yellow.
63
event. The arene ring “recenters” itself, since the alkyl chain is no longer contained
within the cryptophane (0.50Å distance between cryptophane center and guest arene
centroid). The arene ring satisfies four CH- interactions, as a function of its centered
position. The volume of the encapsulated portion of the hexylbenzene is hard to
estimate, but falls between 110Å3 (Ph(CH2)2) and 125Å
3 (Ph(CH2)3). The upper limit
for guest size appears to be near 125 Å3 or nine non-hydrogen atoms (see also the
encapsulation of 1,2,4 C6H3Me3).
Figure 2.11. Top Left: Stick representation of (±)-anti-4 C6H5(CH2)2CH3 with spacefilled guest.
Top Right: Stick representation of C6H5(CH2)2CH3 guest. Bottom Left: Stick representation of
(±)-anti-4C6H5(CH2)5CH3 with spacefilled guest. Bottom Right: Stick representation of
C6H5(CH2)5CH3 guest. Carbon: Gray; Hydrogen: White; Oxygen: Red.
64
2.10. Nonaromatic Guests
M-xylyl bridged cryptophanes also crystallize with a variety of nonaromatic
solvents, including THF, CH2Cl2, CH2BrCl, CH3Cl, DMF, DMSO, NO2Me, Et2O and
acetone. Note that the chemical
nature of these molecules is quite
varied, in terms of size, shape and
polarity. It is quite surprising that
chemically similar hosts can bind
these very different guests. We
observe many interesting features in
these crystals, including guest
disorder resultant from host-guest
size mismatch, encapsulation of two molecules, high symmetry structures, and host
conformational changes.
2.10.1. Encapsulation of two guests
Aromatic guests are comparatively large when looking at the cryptophane host
molecule; one molecule fits inside the pore with no chance to fit a second guest inside.
However, just as the hexylbenzene guest was too large to fit entirely inside of the
cryptophane container, very small organic species are too small to effectively solvate
Figure 2.12. Left: Two encapsulated NO2Me
molecules as packed within (±)-anti-42NO2Me.
Right: Two encapsulated CH2Cl2 molecules as packed
within (±)-anti-42CH2Cl2.
65
the cavity. As a result, m-xylyl
bridged cryptophanes are forced
to bind two small guests rather
than the one large molecule
previously noted (Figure 2.12).
Table 2.4 delineates which
guests induce coencapsulation
with relation to the overall guest
volume.
Coencapsulated guests,
including NO2Me, CH2Cl2,
CH2BrCl DMSO, and acetone, have several common structural features. The guests
are all small, with molecular volumes ranging from 50Å3 to 68 Å
3; larger guests have
been found to only encapsulate one guest molecule. Also, these guests have a
generally pyramidal or triangular shape, which may allow for a more effective packing
and coencapsulation inside of the cryptophane. The pyramidal bases reside in the
larger equatorial region, while the point resides in the [1.1.1]orthocyclophane cap. On
the other hand, the triangular guests basically stack upon one another (Figure 2.12).
Due to the constrictive nature of the container, the guests are in close contact with one
another and are generally well ordered, as one might expect considering that two
molecules are being held in a relatively small pocket inside the cryptophane.
Table 2.5. Encapsulated guest volume in various
cryptophane host molecule materials.
Host Guest
Guest
Volume
(Å3)
Dielectric
Constant
(±)-anti-4 2 NO2Me 50 35.9
(±)-anti-6 2 NO2Me 50 35.9
(±)-anti-4 2 CH2Cl2 58 9.1
(±)-anti-H39 2 acetone 61 20.7
(±)-anti-4 2 DMSO 68 47
(±)-anti-4 THF 711
7.6
Syn-5 THF 711
7.6
(±)-anti-6 THF 711 7.6
(±)-anti-8 THF 711 7.6
(±)-anti-4 DMF 731 36.7
(±)-anti-4 CHCl3 741
4.8
Syn-7 Et2O 75 4.3
1 Guest exhibits disorder in structure.
66
The coencapsulated guests
are disparate in terms of their
electronic nature (polarity,
dielectric); however, these guests
generally orient themselves inside of
the cryptophane the same way. The
guests point their C-H groups toward the polar region of the CTB cone, while the
heteroatom region of these guests point toward the equatorial region of the
cryptophane. The guests do this for at least two reasons. First, the guests align
themselves to minimize or completely cancel their electronic dipole. This behavior
lowers the overall energy of the system. Secondly, the electronically “soft” alkyl
region of the guests better match the soft CTB cone than the harder equatorial region.
2.10.2 Guest Disorder in Cryptophane Structures
Employing nonaromatic guest probes allows one to assess guest binding with
guests of a variety of sizes and shapes, rather than the roughly disc shape of substituted
benzenes. It is because of this fact that we observe coencapsulation in the solid state.
However, some guests are too large to have two guests inside of the cryptophane, and
too small to have one guest that fits well inside of the cryptophane cavity. The result is
a guest-host mismatch, which leads to a disordered solvent molecule, residing within
the host. Guest disorder at low temperature is uncommon, in part because
Figure 2.13. Left: Model of disordered,
encapsulated DMF. Right: Model of disordered,
encapsulated CHCl3.
67
small guests will encapsulate a second molecule and because the cryptophane has the
ability to adapt to its guests. The crystal structure of (±)-anti-4DMF3DMF,
however, exhibited a (presumably dynamically) disordered encapsulated DMF
molecule. DMF has a molecular volume of 73Å3, which is slightly larger than the
largest coencapsulated guest, DMSO (68Å3). The final refinement for the encapsulated
DMF consisted of two half-occupancy DMF molecules that share full occupancy
nitrogen and oxygen heteroatoms (Figure 2.13). The movement of the encapsulated
DMF in the solid state (even at -100C) makes it difficult to determine the ideal
orientation of the guest; ironically, two of the three lattice-included DMF molecules
were well ordered. Similarly, (±)-anti-4CHCl3 complex in crystals of (±)-anti-
4CHCl3·CHCl3·C4H10O displays a spinning CHCl3 molecule (74Å3 volume), in four
orientations.
2.10.3. Host Conformation Changes of Cryptophanes Binding Nonaromatic
Guests
The m-xylyl bridged cryptophanes have so far been shown to adapt to the
guests that they bind. Aromatic guests have been shown to induce changes in the
cryptophanes’ ArCTB-O-CH2-Arbridge (Figures 2.8-2.9), so as to improve CH-
interactions between guest and host. Nonaromatic guests, unlike aromatic guests, do
68
not have a single energetically favored interaction to influence host-guest binding.
However, cryptophanes preferentially bind one guest or two guests based on their
relative sizes. These m-xylyl bridged cryptophanes obviously bind two small guests
(NO2Me) to best solvate the interior of the cryptophane pore, and bind one slightly
larger guest (CHCl3) because binding two of these guests cannot be accommodated by
the cryptophane host.
Experimentally, we have explored the size of the cryptophane cavity
crystallographically. It is evident that the cryptophane can adapt to relatively large
guests (1,2,4 trimethylbenzene, 9 heavy atoms) and relatively small guests (CH2Cl2, 3
heavy atoms). However, we wanted to quantify how the cryptophanes adapted to
nonaromatic guests. Again, the CCTB-O-C-CAr torsion angles were measured for each
cryptophaneguest structure obtained (Table 2.6), and the host molecule
conformations were separated by coencapsulated guest structures (two guests) and
singly encapsulated guest structures.
The distributions of CCTB-O-C-CAr torsion angles for the 12 crystal structures were
once again bimodal (Figure 2.14), and the ranges of each distribution were similar to
those observed for arene guest (70-120, 140-180). This reinforces the hypothesis
that these are the two lowest energy conformations for the m-xylyl bridges of these
cryptophanes. A comparison of the torsion angle histograms for crypto-
69
Table 2.6. X-Ray data for CryptophaneNon-Aromatic Guest materials.
Host Guest
Lattice
Solvent Sqz?1
S. G.2
a (Å)
b (Å)
c (Å)
α (°)
β (°)
γ (°)
Vol3
(Å3) R1 wR2 GOF
(±)-
anti-4
THF 3 THF No P21/n
20.233
18.070
23.638
90
108.47
90
8197 0.065 0.179 0.966
(±)-
anti-4
2
NO2Me
2
NO2Me
Yes P21/c
24.936
12.225
25.771
90
103.82
90
7629 0.085 0.243 0.943
(±)-
anti-4
2
CH2Cl2
0.5
CH2Cl2 +
0.6 Et2O
Yes (0.6
Et2O)
P21/c
24.569
12.432
25.777
90
102.98
90
7672 0.085 0.281 1.094
(±)-
anti-4
2
DMSO
4.6
DMSO
Yes (4.6
DMSO)
P-1
13.750
15.962
21.657
76.38
87.95
82.34
4578 0.078 0.213 0.940
(±)-
anti-4
CHCl3
CHCl3 +
Et2O
Yes
(CHCl3 +
Et2O)
P21/n
20.368
17.492
23.115
90
106.04
90
7915 0.069 0.217 1.087
1 SQUEEZE subroutine.
2 Space Group.
3 Unit Cell Volume.
70
Table 2.6. cont.. X-Ray data for CryptophaneNon-Aromatic Guest materials
Host Guest
Lattice
Solvent Sqz?1 S. G.
2
a (Å)
b (Å)
c (Å)
α (°)
β (°)
γ (°)
Vol3
(Å3) R1 wR2 GOF
(±)-
anti-4
DMF
2 DMF +
Et2O
Yes
(Et2O)
P21/n
20.862
17.512
24.050
90
108.47
90
8334 0.077 0.247 0.994
syn-5 THF
THF +
Et2O
Yes
(THF +
Et2O)
P21/c
12.694
25.783
24.941
90
102.87
90
7958 0.080 0.260 1.077
(±)-
anti-6
THF THF No P-1
10.829
13.917
24.447
102.58
92.36
111.56
3306 0.084 0.231 0.819
(±)-
anti-6
2
NO2Me
4
NO2Me
Yes (2
NO2Me)
P-1
13.080
14.549
20.930
73.12
77.39
83.19
3713 0.069 0.163 0.826
syn-7 Et2O
2 m-
xylene +
0.5 Et2O
Yes(2 m-
xylene +
0.5 Et2O)
P63/m
13.786
13.786
23.058
90
90
120
3795 0.067 0.210 0.954
1 SQUEEZE subroutine.
2 Space Group.
3 Unit Cell Volume.
71
Table 2.6. cont. X-Ray data for CryptophaneNon-Aromatic Guest materials
Host Guest
Lattice
Solvent Sqz?1 S. G.
2
a (Å)
b (Å)
c (Å)
α (°)
β (°)
γ (°)
Vol3
(Å3) R1 wR2 GOF
(±)-
anti-8
THF n/a No P-1
10.830
13.053
23.711
86.93
89.12
73.30
3206 0.037 0.159 1.050
(±)-
anti-
H39
2
acetone
Acetone
+ Et2O
Yes P-1
11.917
13.012
29.570
90.16
96.84
107.56
4337 0.063 0.191 1.020
1 SQUEEZE subroutine.
2 Space Group.
3 Unit Cell Volume.
guest and cryptophane2guests shows a greater relative number of eclipsed torsion
angles (70-120) vs. anti torsion angles (140-180) when only one guest was
encapsulated. Where only one nonaromatic guest was encapsulated, 43% of the
torsion angles (18 of 42) were eclipsed whereas only 27% (8 of 30) were eclipsed in
cryptophanes where two nonaromatic guests were encapsulated. As noted before, the
container molecule adjusts these torsion angles to adjust to the encapsulated guests,
and does this in a fairly uniform fashion when only one small guest is encapsulated.
This makes intuitive sense, as the container molecule is attempting to maximize its van
der Waals contact with its relatively small guest. Adding a second guest requires an
increase in the cavity size, which is reflected in the data. Only one or two of six
72
torsion angles are below 120 when two guests have been encapsulated, as there is less
need to shrink the cryptophane’s cavity size.
Figure 2.14. ArCTB-O-CH2-Arbridge torsion angles.
2.10.4. Crystal Structures of Host 7: High Symmetry Structure
Crystal engineers attempt to empirically predict and design crystal structures by using
molecular symmetry and packing arguments. Though the anti and syn m-xylyl bridged
cryptophanes reported here possess high molecular symmetry in solution (D3, C3h), the
anti cryptophanes, as described in previous sections, exhibit substantially lower
symmetry (C1, pseudo-C2) in the solid state. The previous sections showed that hosts
4, 5, 6 and 8 were structurally influenced by their guests. Unlike its anti diastereomer
(±)-anti-6, syn-7 expressed its highest possible molecular symmetry (C3h, -6) in its
crystal structure. Syn-7Et2O2 m-xylene0.5 Et2O crystallized in the high symmetry
02468
10121416
Two Guests One Guest
73
space group P63/m, where molecules of syn-7 reside on crystallographic -6 positions.
The solvent molecules, being incapable of holding -6 (C3h) symmetry, are obviously
disordered in these structures. The encapsulated ether molecule is disordered over
three positions as a result of its position along the three-fold crystallographic axis
Table 2.7. Torsion angles found in cryptophanesnon-aromatic guest(s) structures.
Host Guest
Torsion Ar-O-CH2-Ar [d]
(||) Host Guest
Torsion Ar-O-CH2-Ar
[d] (||)
(±)-
anti-4
2 NO2Me
149.8, 171.3
146.1, 84.5
167.5, 151.3
(±)-
anti-6
2 NO2Me
90.9, 171.2
172.6, 87.3
161.8, 150.4
(±)-
anti-4
2 CH2Cl2
152.6, 168.3
165.3, 153.6
148.7, 78.3
(±)-
anti-H39
2 C3H6O
162.7, 94.0
148.6, 172.6
76.7, 172.3
(±)-
anti-4
2 DMSO
131.9, 158.3
88.4, 178.1
177.2, 84.2
(±)-
anti-4
THF
84.7, 170.5
164.4, 99.0
173.8, 86.1
syn-5 THF
164.1, 83.2
158.2, 91.3
164.1, 83.2
(±)-
anti-6
THF
161.8, 82.3
82.1, 176.1
156.2, 87.3
(±)-
anti-8 THF
76.9, 178.2
171.8, 85.4
78.1, 169.4
(±)-
anti-4
DMF
87.0, 170.5
168.7, 82.8
162.3, 97.4
(±)-
anti-4
CHCl3
169.6, 88.2
161.0, 100.1
86.5, 165.8
syn-7 Et2O
164.3
74
(Figure 2.15).
2.11. Conclusions
The two-step synthesis of
several cryptophanes was
described and several m-xylyl
bridged cryptophanes were
characterized in solution by
1H NMR and structurally by
single crystal X-Ray
diffraction. M-xylyl bridged cryptophane molecules were shown to exhibit a rich
binding chemistry in the solid state. A variety of aromatic guests were used as guests,
and a common binding motif was observed in which the guests tilted away from the
cryptophane’s idealized C3 axis. Guest-cryptophane CH- interactions were observed
in these complexes, and this interaction was used to explain guest orientation within
the host. Analysis of CCTB-O-C-CAr torsion angles in these complexes revealed that
cryptophane may adjust to increase CH- contact by decreasing these torsion angles.
This analysis was also performed on cryptophane-nonaromatic complexes, which
confirmed that cryptophanes could adjust to their guests’ based on their size as well.
Crystallization with guests of various size revealed that guests above nine
Figure 2.15. Spacefill packing of syn-7 as seen down c-axis.
Lattice solvent has been deleted to show the channels that
run between the cryptophane molecules.
75
heavy atoms would be partially encapsulated (with the guest arene preferentially
bound), while small guests (four heavy atoms, or less than 70Å3) are doubly
encapsulated. Guests of intermediate size (70-80Å3), while encapsulated, are often
disordered in the solid state; this suggests a host-guest mismatch with these guests.
Cryptophane syn-7 was found to crystallize in the high symmetry P63/m space group,
which corresponds exactly to syn-7’s C3h idealized molecular symmetry.
2.12. Experimental
2.12.1 General Methods
All reactions were carried out under nitrogen atmosphere. All solvents and
reagents were used without further purification. Flash chromatography was carried out
on silica gel (32-64μm). 1H (300MHz) and
13C (90MHz) NMR were recorded on
Varian Mercury 300NMR. Uncorrected melting points were performed on a Thomas
Hoover capillary melting point apparatus. Single crystal x-ray diffraction was
performed using a Bruker-AXIS SMART diffractometer with CCD area detector
(MoK radiation) at -100 ºC. Lattice parameters were determined from least-square
analysis and the reflection data was integrated using SAINT. Structures were solved
using direct methods and refined by full matrix least-squares based on F2 using X-
SEED.28
76
2.12.2. New Molecule Characterization
3,5-Bis-(4-hydroxymethyl-2-methoxy-phenoxymethyl)-benzoic acid methyl
ester (1). 3-methoxy-4-hydroxy benzyl alcohol (3.51g, 22.8 mmol) and K2CO3 (3.15
g, 22.8 mmol) were stirred in 50 mL acetone. 3,5-bis(bromomethyl)-benzoic acid
methyl ester (3.25g, 10.1 mmol) was added to the slurry. The mixture was stirred
under nitrogen at room temperature for 4 hours. H2O (500mL) was added and product
extracted with CH2Cl2 (3x40mL). The solution was dried over MgSO4 and filtered.
Solvent was removed en vacuo. The crude product was chromatographed on silica gel,
1.1 Et2O/acetone was used as eluent. The product was isolated as a white solid. The
product was also purified by sonication of crude oil in Et2O. Yield (3.49 g, 79%); m.p.
98C; Rf 0.76 (1:1 Acetone/Et2O); 1H NMR (CDCl3): δ8.00(s, br, 2H, Ar); δ7.69(s, br,
1H, Ar); δ6.89(s, 2H, Ar); δ6.74(s, 4H, Ar); δ5.13(s, 4H, ArCH2O); δ4.55(s, 4H,
CH2OH); δ3.87(s, 3H, COOCH3); δ3.84(s, 6H, OCH3). 13
C NMR (CDCl3): 52.18,
56.74, 63.32, 66.89, 115.01, 120.70, 127.06, 131.48, 132.61, 135.38, 140.61, 142.25,
159.09, 168.48. Anal. % Calcd for C26H28O8: C, 66.66; H, 6.02. Found: C, 66.42; H,
6.24.
{4-[3-(4-Hydroxymethyl-2methoxy-phenoxymethyl)-benzyloxy]-3-
methoxy-phenyl}-methanol (2). 3-methoxy-4-hydroxy benzyl alcohol (1.06g,
6.87mmol) and K2CO3 (1.08 g, 7.78 mmol) were stirred in 30mL MeOH.
,’dibromo-m-xylene (0.736g, 2.79 mmol) was added to the slurry. The mixture was
77
stirred under nitrogen at room temperature for 1.5 hours. H2O (100 mL) was added
and product extracted with CHCl3 (3 x 30 mL). Solution was dried over MgSO4 and
filtered. Solvent was removed under vacuum. Crude product was chromatographed on
silica gel, with ether as the initial eluent, followed by acetone. Product isolated as a
white solid. Yield (0.729g, 77%). MP=103˚C. 1H NMR (CDCl3): δ 3.88 (s, 6H,
OCH3), 4.60 (s, 4H, ArCH2OH), 5.15 (s, 4H, ArCH2OAr), 6.79 (s, 4H, Ar), 6.93 (s,
2H, Ar), 7.36 (s, 3H, Ar), 7.49 (s, 1H, Ar). Anal. % Calcd for C24H26O6, 70.23; H,
6.38. Found: C, 69.95; H, 6.58.
3,5-Bis-(4-hydroxymethyl-2-methoxy-phenoxymethyl)-bromobenzene (3).
3-methoxy-4-hydroxy benzyl alcohol (5.7 g, 30.9 mmol), 3,5-bis(bromomethyl)-
bromobenzene (3.25g, 10.1 mmol) and K2CO3 (5.1 g, 30.9 mmol) were added to 200
mL 1:1 CH2Cl2/methanol and stirred at room temperature for 24 hours. The reaction
was monitored by TLC in 1:5 hexanes/ ethyl acetate (Rf = 0.33). The solvent was
removed in vacuo and the crude product was extracted with CH2Cl2/H2O. The organic
layer was dried with MgSO4 and the CH2Cl2 was removed in vacuo. The product was
isolated as a white solid. Yield: (4.47 g, 59%). 1H NMR (CDCl3): δ 3.86 (s, 6H,
OCH3), 4.58 (s, 4H, CH2OH), 5.07 (s, 4H, OCH2Ar), 6.76 (s, 4H, Ar), 6.91 (s, 2H, Ar),
7.38 (s, 1H, Ar), 7.50 (s, 2H, Ar); 13
C NMR (CDCl3): δ 150.38, 147.75, 140.35,
135.27,130.20, 125.09, 123.50, 119.85, 114.82, 111.54, 70.87, 65.70, 56.52. Anal. %
Calcd for C24H25O6Br: C, 58.91; H, 5.15. Found: C, 59.11; H, 5.07.
78
Synthesis of cryptophane ((±)-anti-4 and syn-5). Diol (1) (4.02 g, 8.58
mmol) was dissolved in 75 mL CHCl3. The solution was added dropwise to 2 L
stirring HCOOH. The solution was stirred under nitrogen atmosphere and heated to
50˚C for 3 hours. The solvent was removed en vacuo, and distilled H2O was added to
crude solid. The solid was filtered and redissolved in CH2Cl2. The solution was dried
over MgSO4 and filtered. The solvent removed under reduced pressure. The crude
product was chromatographed on silica gel; 8:1 CH2Cl2/Et2O was used as the eluent.
The cryptophane diastereomers appear as white solid.
(±)-Anti-4. Yield (0.376 g, 10%); m.p. = 202C; Rf = 0.43; 1H NMR (300
MHz, CDCl3, 25C): δ8.07 (s, br, 6H, Ar); δ7.22 (s, br, 3H, Ar); δ6.60 (s, 6H, Ar);
δ6.40 (s, 6H, Ar); δ5.11 (d, 6H, ArCH2O, 2J (H,H) = 13.3Hz); δ4.94 (d, 6H, ArCH2O,
2J (H,H) = 13.0Hz); δ4.58 (d, 6H, ArCH2a,
2J (H,H) = 13.7Hz); δ3.95 (s, 9H, CO2CH3);
δ3.47 (s, 18H, OCH3); δ3.34 (d, 6H, ArCH2e, 2J (H,H) = 13.7Hz).
13C NMR (90MHz,
CDCl3, 25C): 36.27, 52.40, 70.25, 113.56, 114.68, 126.92, 128.85, 131.62, 132.62,
138.64, 146.45, 148.02, 166.76. Anal. % Calcd for C78H72O18 + 4C4H8O: C, 71.19; H,
6.61. Found: C, 70.85; H, 6.47.
Syn-5. Yield (0.361g, 10%); Rf = 0.35 (8:1 CH2Cl2/Et2O). m.p. = 202 C
79
(dec).. 1
H NMR (300MHz, CDCl3, 25C): δ7.96(s, br, 3H, Ar); δ7.89(s, br, 6H, Ar);
δ6.63 (s, 6H, Ar); δ6.38(s, 6H, Ar); δ5.30(d, 6H, ArCH2O, 2J(H,H) = 13.3Hz); δ4.82(d,
6H, ArCH2O, 2J(H,H) = 13.4Hz); δ4.58(d, 6H, ArCH2a,
2J(H,H) =13.7Hz); δ3.95(s,
9H, CO2CH3); δ3.42(s, 18H, OCH3); δ3.36(d, 6H, ArCH2e, 2J(H,H) = 13.8Hz).
13C
NMR (90MHz, CDCl3, 25C): 34.90, 54.18, 68.77, 115.92, 116.64, 123.13, 130.37,
132.55, 141.81, 154.25, 169.46. Anal. % Calcd for C78H72O18 + 5C6H5NO2: C, 67.81;
H, 5.11; N, 3.66. Found: C, 68.04; H, 4.94; N, 3.31.
Synthesis of cryptophane ((±)-anti-6 and syn-7). Diol (2) (4.13g, 10.0mmol)
was dissolved in 50 mL CHCl3. The solution was added dropwise to 4L stirring
HCOOH. The solution was stirred under a nitrogen atmosphere for 23 hours. The
solvent was removed en vacuo, and distilled H2O was added to crude solid. The solid
was filtered and redissolved in CH2Cl2. The solution was dried over MgSO4 and
filtered. The solvent removed under reduced pressure. The crude product was
chromatographed on silica gel; 10:1 CH2Cl2/Et2O was used as eluent. The cryptophane
diastereomers appear as white solid.
(±)-Anti-6. Yield (0.311g, 8%); Rf = 0.65 (10:1 CH2Cl2/Et2O); m.p. = 204˚C
(dec.). 1H NMR (300MHz, CDCl3, 25C): δ7.84 (d, 9H, Ar,
4J (H,H) = 1Hz); δ7.01
(s, br, Ar, 3H); δ6.62 (s, 6H, Ar); δ6.42 (s, 6H, Ar); δ5.10 (d, 6H, ArCH2O, 2J (H,H) =
12.9Hz); δ4.89 (d, 6H, ArCH2O, 2J (H,H) = 13.0Hz); δ4.58 (d, 6H, ArCH2a,
2J (H,H) =
80
13.7Hz); δ3.48 (s, 18H, OMe); δ3.34 (d, 6H, ArCH2e, 2J (H,H) = 13.8Hz).
13C NMR
(CDCl3): 36.21, 55.32, 64.48, 113.67, 115.03, 127.59, 128.20, 131.74, 138.07, 140.66,
141.71. Anal. % Calcd for C72H66O12 + 6 CH3NO2: C, 62.90; H, 5.68; N, 5.64.
Found: C, 62.47; H, 6.01; N, 5.27.
Syn-7. Yield (0.041g, 1%); Rf = 0.46 (10:1 CH2Cl2/Et2O); m.p. = 201C
(dec.); 1H NMR (300MHz, CDCl3, 25C): δ7.73(s, br, 3H, Ar); δ6.66 (s, 6H, Ar);
δ6.42(s, 6H, Ar); δ5.26(d, 6H, ArCH2O, 2J (H,H) = 13.0Hz); δ4.79(d, 6H, ArCH2O,
2J
(H,H) = 13.2Hz); δ4.58(d, 6H, ArCH2a, 2J (H,H) = 13.6Hz); δ3.44(s, 18H, OCH3);
δ3.35(d, 6H, ArCH2e, 2J (H,H) = 13.7Hz). Anal. % Calcd for C72H66O12 + C4H10O +
C8H10: C, 77.40; H, 6.65. Found: C, 77.66; H, 6.85.
Synthesis of cryptophane ((±)-anti-8). Diol (3) (6.10g, 12.4 mmol) was
dissolved in 400 mL CHCl3. The solution was added dropwise to 4L stirring HCOOH.
The solution was stirred under a nitrogen atmosphere for 24 hours at room temperature
and was montitored by TLC in 60:1 CH2Cl2/ ether. The formic acid was removed in
vacuo and solid product was dissolved in 100 ml 60:1 CH2Cl2/ ether to yield a dark
brown solution. 400 mL of ether was added to the solution and it turned yellow with a
white precipitate. The precipitate was filtered and dissolved in 100 mL CH2Cl2. The
solution was condensed by removing about 75 mL in vacuo. A pure precipitate formed
and was filtered.
81
(±)-Anti-8. Yield (0.170 g, 3 %); Rf = 0.72 (40:1 CH2Cl2/Et2O; m.p. = 218C
(dec.). 1H NMR (CDCl3): δ 7.55 (s, 2H, Ar), δ 6.94 (s, 1H, Ar), δ 6.58 (s, 4H, Ar), δ
6.43 (s, 2H, Ar), δ 5.05 ((d, 6H, ArCH2O, 2J (H,H) = 13.1Hz), δ 4.84 (d, 6H, ArCH2O,
2J (H,H) = 13.1Hz), δ 4.58 (d, 6H, ArCH2a,
2J(H,H) = 13.7Hz), δ 3.53 (s, 6H, OCH3), δ
3.35 (d, 6H, ArCH2e, 2J (H,H) = 13.7Hz);
13C NMR (CDCl3): δ 148.21, 146.51,
140.44, 132.85, 131.73, 128.82, 123.11, 122.98, 114.86, 113.64, 70.13, 56.49, 36.51.
Anal. % Calcd for C72H63O12Br3 + C4H8O: C, 68.32 ;H, 5.36. Found: C, 68.68; H,
5.31.
(±)-Anti-H39: Compound (±)-Anti-4 (289 mg, 0.223 mmol) was dissolved in
22 mL DMF. 10 % NMe4OH in H2O (4.1 mL, 5.5 mmol) was added in one portion.
The solution was heated to 80C for 2.5 hours, and reaction was monitored by TLC
(8:1 CH2Cl2/Et2O). The solvent was removed under reduced pressure and the
remaining solid was dissolved in 30 mL of 1:1 H2O/acetone solution. 12M HCl was
added to the solution, and the resultant solid was filtered and washed with distilled
H2O. Crude (±)-Anti-H39 was recrystallized by dissolving in an acetone/methanol
solution and allowing the slow evaporation of acetone. Yield: (252 mg, 87%). M.P.
240C (dec). 1H NMR (300 MHz, DMSO[D6], 298K) 7.96 (s, 6H, Ar-H), 7.33 (s,
3H, Ar-H), 6.90 (s, 6H, Ar-H), 6.70 (s, 6H, Ar-H), 5.12 (d, 6H, Ar-CH2O,
2J(H,H) = 12.6 Hz), 5.02 (d, 6H, Ar-CH2O,
2J(H,H) = 12.6 Hz), 4.60 (d, 6H, , Ar-
82
CH2a, 2J(H,H) = 12.5 Hz), 3.39 (s, 18H, OCH3).
1H NMR (300 MHz, Acetone[D6],
298K) 8.12 (s, 6H, Ar-H), 7.54 (s, 3H, Ar-H), 7.02 (s, 6H, Ar-H), 6.82 (s, 6H,
Ar-H), 5.15 (s, 12H, Ar-CH2O), 4.73 (d, 6H, Ar-CH2a, 2J(H,H) = 13.3 Hz), 3.56
(s, 18H, OCH3), 3.51 (d, 6H, Ar-CH2e 2J(H,H) = 13.3 Hz). IR (cm
-1, selected bands)
3448, 2927, 1706, 1607, 1509, 1479, 1448, 1398, 1375, 1261, 1214, 1144, 1086, 1027,
948, 883, 852, 774, 740, 618, 530. Anal. calcd. for C75H66O18 + 2 C3H6O: C, 70.94; H,
5.73. Found: C, 70.89 H, 5.93.
Syn-H310: Compound Syn-5 (158 mg, 0.121 mmol) was heated and dissolved
in 11 mL DMF. 10 % NMe4OH in H2O (5.2 mL, 5.5 mmol) was added and solution
was heated for 5 minutes at 80°C. The solution was rotovapped to dryness and the
solid was dissolved in a minimal volume of 1:1 acetone/H2O solution. The solution
was acidified with several drops of 6M HCl, and the pH of the solution was monitored.
The solution was placed in the freezer, and the crystalline solid was filtered. Yield:
(136 mg, 91%). M.P. 240C (dec). 1H NMR (300 MHz, Acetone[D6], 298K) 8.04
(s, 9H, Ar-H), 7.08 (s, 6H, Ar-H), 6.87 (s, 6H, Ar-H), 5.23 (d, 6H, Ar-CH2O,
2J(H,H) = 13.3 Hz), 5.08 (d, 6H, Ar-CH2O,
2J(H,H) = 13.3 Hz), 4.74 (d, 6H, Ar-
CH2a, 2J(H,H) = 13.5 Hz), 3.55 (s, 18H, OCH3), 3.48 (d, 6H, Ar-CH2e
2J(H,H) =
13.5 Hz).
83
2.12.3. Crystal Structures
(±)-Anti-4THF3THF:
Newly purified (±)-anti-4 was dissolved in THF. After several minutes, colorless
crystals precipitated out of solution. A suitable crystal was analyzed by x-ray single
crystal diffraction. Single crystal structure of (±)-anti-4THF3THF: C94H104O22,
0.48 x 0.45 x 0.40 mm, monoclinic, space group P21/n, a = 20.233(2), b = 18.070(2), c
= 23.638(2) Å, = 108.474(2), V = 8196.6(14) Å3, Z = 4, calcd = 1.285g/cm
3, MoK
radiation, = 0.71073 Å, 2max = 50, scans, 173(2)K, 52817 total reflections, 14430
unique reflections, 7507 reflections with I>2(I) (Rint = 0.0753); absorption correction
SADABS (Tmin = 0.9577, Tmax = 0.9646, = 0.09 mm-1
), structure solution using
SHELX-S, refinement (against F2) with SHELX-97-2, 1090 parameters, 0 restraints,
H atoms placed in calculated positions and refined with a riding model, R1 = 0.0650
(I>2(I)) and wR2 = 0.1785 (all data), residual electron density max./min = 0.55/-0.35
e- Å3, GOF = 0.966.
(±)-Anti-42CH3NO2•2CH3NO2:
Crude (±)-anti-4 was dissolved in nitromethane and recrystallized by slow evaporation.
Single crystal structure of (±)-anti-42C3H6OC3H6O C4H10O: C88H84N4 O26, Mr =
1541.58, 0.30 x 0.20 x 0.10 mm, monoclinic, space group P21/c (no.14), a =
24.9356(16), b = 12.2250(8), c = 25.7708(16) Å, = 103.8210(10)°, V = 7628.5(8) Å3,
84
Z = 4, calc = 1.34g/cm3, MoK radiation, = 0.71073 Å, 2max = 50°, scans, 186(2)
K, 55552 total reflections, 13427 unique reflections, 6589 reflections with I>2(I)
(Rint = 0.090); absorption correction SADABS (Tmin = 0.8627, Tmax = 1.000, = 0.10
mm-1
), structure solution with SHELX-S, refinement (against F2) using SHELX-97-2,
935 parameters, 0 restraints, H atoms placed in calculated positions on ordered
moieties and refined with a riding model, R1 = 0.0849 (I>2(I)) and wR2 = 0.2432 (all
data), residual electron density min./max. – 0.46/ 1.10 e- /Å3, GOF = 0.943.
SQUEEZE analysis of the unmodeled solvent reveals the solvent-accessible volume to
be 741 Å3 per unit cell, which is occupied by 245 electrons (calculated. 2 NO2CH3 per
asymmetric unit).
Anti-4C6H5I•C6H5I:
Crude (±)-anti-4 was dissolved in iodobenzene and recrystallized by diffusion of ether
antisolvent. C85.2H80O18.6I, Mr = 1528.39, 0.55 x 0.50 x 0.38 mm, monoclinic, space
group P21 (no. 4), a = 14.1142(11), b = 17.3693(13), c = 17.8605(13) Å, =
101.3760(10)°, V = 4292.5(6) Å3, Z = 2, calc = 1.32 g/cm
3, MoK radiation, =
0.71073 Å, 2max = 52°, scans, 173(2) K, 45808 total reflections, 16829 unique
reflections, 14746 reflections with I>2(I) (Rint = 0.033); absorption correction
SADABS (Tmin/Tmax = 0.8415, = 0.80 mm-1
), structure solution with SHELX-S,
refinement (against F2) using SHELX-97-2, 937 parameters, 1 restraints, H atoms
85
placed in calculated positions on ordered moieties and refined with a riding model, R1
= 0.044 (I>2(I)) and wR2 = 0.1145 (all data), residual electron density min./max. –
0.29/ 0.46 e- /Å3, GOF = 1.043. SQUEEZE analysis of the unmodeled solvent reveals
the solvent-accessible volume to be 984 Å3 per unit cell, which is occupied by 163
electrons (calculated. C6H5I per asymmetric unit).
(±)-Anti-42CH2Cl2•0.5CH2Cl2•0.6C4H10O:
Crude (±)-anti-4 was dissolved in dichloromethane and recrystallized by diffusion of
ether antisolvent. C82.9H83O18.6Cl5, Mr = 1554.14, 0.50 x 0.46 x 0.16 mm, monoclinic,
space group P21/c (no. 14), a = 24.5688(19), b = 12.4315(9), c = 25.7768(19) Å, =
102.9790(10)°, V = 7671.8(10) Å3, Z = 2, calc = 1.35g/cm
3, MoK radiation, =
0.71073 Å, 2max = 56°, scans, 173(2) K, 90988 total reflections, 18410 unique
reflections, 12242 reflections with I>2(I) (Rint = 0.039); absorption correction
SADABS (Tmin = 0.8807, Tmax = 0.9595, = 0.26 mm-1
), structure solution with
SHELX-S, refinement (against F2) using SHELX-97-2, 991 parameters, 0 restraints,
H atoms placed in calculated positions on ordered moieties and refined with a riding
model, R1 = 0.085 (I>2(I)) and wR2 = 0.2812 (all data), residual electron density
min./max. – 0.83/ 2.25 e- /Å3, GOF = 1.094. SQUEEZE analysis of the unmodeled
solvent reveals the solvent-accessible volume to be 590 Å3 per unit cell, which is
occupied by 108 electrons (calculated. 0.6 C4H10O per asymmetric unit).
86
(±)-Anti-4C6H5(CH2)5CH3 :
Crude (±)-anti-4 was dissolved in phenylhexane and recrystallized by diffusion of
ether antisolvent. C90H90O18, Mr = 1459.69, 0.12 x 0.12 x 0.08 mm, Monoclinic, space
group P21/n (no. 14), a = 16.503(10), b = 26.981(15), c = 16.729(9) Å, =
99.645(11)°, V = 7344(7) Å3, Z = 4, calc = 1.32 g/cm
3, MoK radiation, = 0.71073 Å,
2max = 47.14°, scans, 173(2) K, 45177 total reflections, 10213 unique reflections,
4081 reflections with I>2(I) (Rint = 0.243); absorption correction SADABS (ratio of
Tmin/Tmax = 0.005632, = 0.09 mm-1
), structure solution with SHELX-S, refinement
(against F2) using SHELX-97-2, 984 parameters, H atoms placed in calculated
positions on ordered moieties and refined with a riding model, R1 = 0.0721 (I>2(I))
and wR2 = 0.1769 (all data), residual electron density min./max. –0.35/0.36 e- /Å3,
GOF = 0.869.
(±)-Anti-42C3H6SO•4.6C3H6SO:
Crude (±)-anti-4 was dissolved in DMSO and recrystallized by diffusion of ether
antisolvent. C97.8H111.6O24.6S6.6, Mr = 1892.37, 0.41 x 0.33 x 0.25 mm, triclinic, space
group P-1 (no. 2), a = 13.750(2), b = 15.962(3), c = 21.657(4) Å, = 76.380(3), =
87.950(3), = 82.338(3)°, V = 4578(1) Å3, Z = 2, calc = 1.37g/cm
3, MoK radiation,
= 0.71073 Å, 2max = 50°, scans, 173(2) K, 34670 total reflections, 16019 unique
87
reflections, 7603 reflections with I>2(I) (Rint = 0.067); absorption correction
SADABS (Tmin = 0.9329, Tmax = 0.9583, = 0.13 mm-1
), structure solution with
SHELX-S, refinement (against F2) using SHELX-97-2, 938 parameters, 0 restraints,
H atoms placed in calculated positions on ordered moieties and refined with a riding
model, R1 = 0.0777 (I>2(I)) and wR2 = 0.2134 (all data), residual electron density
min./max. – 0.54/ 0.82 e- /Å3, GOF = 0.940. SQUEEZE analysis of the unmodeled
solvent reveals the solvent-accessible volume to be 1205 Å3 per unit cell, which is
occupied by 447 electrons (calculated. 4.6 C3H6SO per asymmetric unit).
(±)-Anti-4CHCl3•CHCl3•C4H10O:
Crude (±)-anti-4 was dissolved in chloroform and recrystallized by diffusion of ether
antisolvent. C84H84O19Cl6, Mr = 1610.30, 0.41 x 0.33 x 0.25 mm, monoclinic, space
group P21/n (no. 14), a = 20.368(2), b = 17.492(2), c = 23.115(3) Å, = 106.044(2), V
= 7914.6(16) Å3, Z = 4, calc = 1.29g/cm
3, MoK radiation, = 0.71073 Å, 2max = 50°,
scans, 173(2) K, 57942 total reflections, 13929 unique reflections, 8414 reflections
with I>2(I) (Rint = 0.047); absorption correction SADABS (ratio of Tmin/Tmax =
0.8823, = 0.13 mm-1
), structure solution with SHELX-S, refinement (against F2)
using SHELX-97-2, 927 parameters, 0 restraints, H atoms placed in calculated
positions on ordered moieties and refined with a riding model, R1 = 0.0690 (I>2(I))
and wR2 = 0.2171 (all data), residual electron density min./max. – 1.06/ 0.86 e- /Å3,
88
GOF = 1.087. SQUEEZE analysis of the unmodeled solvent reveals the solvent-
accessible volume to be 1432 Å3 per unit cell, which is occupied by 383 electrons
(calculated. 1 CHCl3 and 1 C4H10O per asymmetric unit).
(±)-Anti-4C3H7NO•2C3H7NO•C4H10O:
Crude (±)-anti-4 was dissolved in DMF and recrystallized by diffusion of ether
antisolvent. C91H103N3O22, Mr = 1590.83, 0.50 x 0.25 x 0.25 mm, monoclinic, space
group P21/n (no. 14), a = 20.862(4), b = 17.512(3), c = 24.050(4) Å, = 108.469(3)°,
V = 8334(2) Å3, Z = 4, calc = 1.27g/cm
3, MoK radiation, = 0.71073 Å, 2max = 50°,
scans, 173(2) K, 61494 total reflections, 14668 unique reflections, 7700 reflections
with I>2(I) (Rint = 0.069); absorption correction SADABS (Tmin = 0.9581, Tmax =
0.9787, = 0.09 mm-1
), structure solution with SHELX-S, refinement (against F2)
using SHELX-97-2, 980 parameters, 0 restraints, H atoms placed in calculated
positions on ordered moieties and refined with a riding model, R1 = 0.0774 (I>2(I))
and wR2 = 0.2465 (all data), residual electron density min./max. – 0.57/ 1.81 e- /Å3,
GOF = 0.994. The two lattice DMF molecules were modeled; however, the disordered
ether molecule required a SQUEEZE analysis, which revealed the solvent-accessible
volume to be 674 Å3 per unit cell, which is occupied by 181 electrons (calculated. 1
C4H10O per asymmetric unit).
89
(±)-Anti-4C6H5NO2•0.3C6H5NO2•0.7C4H10O:
Crude (±)-anti-4 was dissolved in nitrobenzene and recrystallized by diffusion of ether
antisolvent. C87.7H83.2N1.3O21.3, Mr = 1496.22, 0.20 x 0.14 x 0.10 mm, monoclinic,
space group P21/c (no. 14), a = 24.793(2), b = 12.4495(11), c = 25.788(2) Å, =
104.130(2)°, V = 7718.7(12) Å3, Z = 4, calc = 1.29g/cm
3, MoK radiation, = 0.71073
Å, 2max = 50°, scans, 173(2) K, 69117 total reflections, 13574 unique reflections,
6188 reflections with I>2(I) (Rint = 0.116); absorption correction SADABS (ratio of
Tmin/Tmax = 0.8729, = 0.09 mm-1
), structure solution with SHELX-S, refinement
(against F2) using SHELX-97-2, 952 parameters, 0 restraints, H atoms placed in
calculated positions on ordered moieties and refined with a riding model, R1 = 0.1030
(I>2(I)) and wR2 = 0.3209 (all data), residual electron density min./max. – 0.56/ 0.80
e- /Å3, GOF = 0.991.
(±)-Anti-4C6H5CN•0.5C6H5CN•C4H10O:
Crude (±)-anti-4 was dissolved in benzonitrile and recrystallized by diffusion of ether
antisolvent. C92.5H89.5N1.5O19, Mr = 1526.23, 0.65 x 0.25 x 0.15 mm, monoclinic, space
group P21/c (no. 14), a = 24.834(3), b = 12.5378(14), c = 25.847(3) Å, =
104.530(2)°, V = 7790.4(15) Å3, Z = 4, calc = 1.30g/cm
3, MoK radiation, = 0.71073
Å, 2max = 50°, scans, 173(2) K, 40701 total reflections, 13700 unique reflections,
4609 reflections with I>2(I) (Rint = 0.095); absorption correction SADABS (Tmin =
90
0.9435, Tmax = 0.9865, = 0.09 mm-1
), structure solution with SHELX-S, refinement
(against F2) using SHELX-97-2, 946 parameters, 0 restraints, H atoms placed in
calculated positions on ordered moieties and refined with a riding model, R1 = 0.0649
(I>2(I)) and wR2 = 0.1748 (all data), residual electron density min./max. – 0.30/ 0.24
e- /Å3, GOF = 0.787. SQUEEZE analysis of the unmodeled solvent reveals the
solvent-accessible volume to be 961 Å3 per unit cell, which is occupied by 268
electrons (calculated. 0.5 C6H5CN and 1 C4H10O per asymmetric unit).
Anti-4C6H5Br•2C6H5Br:
Crude (±)-anti-4 was dissolved in bromobenzene and recrystallized by diffusion of
ether antisolvent. C96H87O18Br3, Mr = 1768.45, 0.40 x 0.40 x 0.10 mm, monoclinic,
space group P21 (no. 4), a = 14.133(5), b = 17.466(7), c = 17.844(7) Å, =
101.710(7)°, V = 4313(3) Å3, Z = 2, calc = 1.36 g/cm
3, MoK radiation, = 0.71073 Å,
2max = 52°, scans, 173(2) K, 45808 total reflections, 16892 unique reflections,
14746 reflections with I>2(I) (Rint = 0.033); absorption correction SADABS (Tmin =
0.6889, Tmax = 0.9060, = 0.44 mm-1
), structure solution with SHELX-S, refinement
(against F2) using SHELX-97-2, 922 parameters, 1 restraints, H atoms placed in
calculated positions on ordered moieties and refined with a riding model, R1 = 0.071
(I>2(I)) and wR2 = 0.1746 (all data), residual electron density min./max. – 0.32/ 0.47
e- /Å3, GOF = 0.831. SQUEEZE analysis of the unmodeled solvent reveals the
91
solvent-accessible volume to be 949 Å3 per unit cell, which is occupied by 319
electrons (calculated. 2 C6H5Br per asymmetric unit).
(±)-Anti-4C6H5(CH2)2CH3• C6H5(CH2)2CH3•1.5CH2Cl2:
Crude (±)-anti-4 was dissolved in n-propylbenzene and dichloromethane and
recrystallized by slow evaporation of dichloromethane. C97.5H99O18Cl3, Mr = 1665.21,
0.18 x 0.14 x 0.10 mm, triclinic, space group P-1 (no. 2), a = 13.829(3), b = 15.207(4),
c = 22.304(5) Å, = 74.599(4), = 73.373(5), = 81.353(4)°, V = 4319(2) Å3, Z = 2,
calc = 1.28g/cm3, MoK radiation, = 0.71073 Å, 2max = 50°, scans, 173(2) K,
22816 total reflections, 15122 unique reflections, 5369 reflections with I>2(I) (Rint =
0.086); absorption correction SADABS (ratio of Tmin/Tmax = 0.7833, = 0.18 mm-1
),
structure solution with SHELX-S, refinement (against F2) using SHELX-97-2, 1063
parameters, 0 restraints, H atoms placed in calculated positions on ordered moieties
and refined with a riding model, R1 = 0.1005 (I>2(I)) and wR2 = 0.2801 (all data),
residual electron density min./max. – 0.02/ 0.01 e- /Å3, GOF = 0.905.
(±)-Anti-4C6H5Cl•0.5C6H5Cl•C4H10O:
Crude (±)-anti-4 was dissolved in chlorobenzene and recrystallized by diffusion of
ether antisolvent. C91H89.5O19Cl1.5, Mr = 1540.38, 0.60 x 0.40 x 0.20 mm, monoclinic,
92
space group P21/c (no. 14), a = 24.890(2), b = 12.4526(11), c = 25.884(2) Å, =
104.519(2)°, V = 7766.4(12) Å3, Z = 4, calc = 1.32g/cm
3, MoK radiation, = 0.71073
Å, 2max = 50°, scans, 173(2) K, 56987 total reflections, 13657 unique reflections,
7777 reflections with I>2(I) (Rint = 0.073); absorption correction SADABS (Tmin =
0.9202, Tmax = 0.9724, = 1.41 mm-1
), structure solution with SHELX-S, refinement
(against F2) using SHELX-97-2, 1000 parameters, 0 restraints, H atoms placed in
calculated positions on ordered moieties and refined with a riding model, R1 = 0.0675
(I>2(I)) and wR2 = 0.1972 (all data), residual electron density min./max. – 0.74/ 0.55
e- /Å3, GOF = 1.018.
Syn-5C6H5NO2•4 C6H5NO2:
Crude syn-5 was dissolved in nitrobenzene and recrystallized by diffusion of ether
antisolvent. C108H97N5O28, Mr = 1912.98, 0.50 x 0.40 x 0.35 mm, triclinic, space group
P-1 (no. 2), a = 11.627(2), b = 14.792(3), c = 27.340(5) Å, = 87.835(4), =
85.537(4), = 82.665(4)°, V = 4647.7(14) Å3, Z = 2, calc = 1.37g/cm
3, MoK radiation,
= 0.71073 Å, 2max = 50°, scans, 173(2) K, 25010 total reflections, 16277 unique
reflections, 7603 reflections with I>2(I) (Rint = 0.041); absorption correction
SADABS (Tmin = 0.9520, Tmax = 0.9660, = 0.10 mm-1
), structure solution with
SHELX-S, refinement (against F2) using SHELX-97-2, 1279 parameters, 0 restraints,
H atoms placed in calculated positions on ordered moieties and refined with a riding
93
model, R1 = 0.0512 (I>2(I)) and wR2 = 0.1080 (all data), residual electron density
min./max. – 0.24/ 0.25 e- /Å3, GOF = 0.826.
Syn-5THF•THF•C4H10O:
Crude syn-5 was dissolved in THF and recrystallized by diffusion of ether antisolvent.
C90H98O21, Mr = 1515.68, 0.50 x 0.25 x 0.25 mm, monoclinic, space group P21/c
(no.14), a = 12.694(2), b = 25.783(5), c = 24.941(5) Å, = 102.866(4)°, V = 7958(3)
Å3, Z = 4, calc = 1.27g/cm
3, MoK radiation, = 0.71073 Å, 2max = 50°, scans,
173(2) K, 28256 total reflections, 13278 unique reflections, 4685 reflections with
I>2(I) (Rint = 0.070); absorption correction SADABS (Tmin = 0.9567, Tmax = 0.9780,
= 0.09 mm-1
), structure solution with SHELX-S, refinement (against F2) using
SHELX-97-2, 902 parameters, 0 restraints, H atoms placed in calculated positions on
ordered moieties and refined with a riding model, R1 = 0.0616 (I>2(I)) and wR2 =
0.1575 (all data), residual electron density min./max. – 0.41/ 0.55 e- /Å3, GOF = 0.754.
SQUEEZE analysis of the unmodeled solvent reveals the solvent-accessible volume to
be 1229 Å3 per unit cell, which is occupied by 313 electrons (calculated. 1 C4H8O and
1C4H10O per asymmetric unit).
(±)-Anti-6THF•THF:
Crude (±)-anti-6 was dissolved in THF and recrystallized by diffusion of ether
94
antisolvent. C80H82O14, Mr = 1267.46, 0.60 x 0.10 x 0.10 mm, triclinic, space group P-
1 (no.2), a = 10.8293(17), b = 13.917(2), c = 24.447(4) Å, = 102.578(3), =
92.363(3), = 111.561(3)°, V = 3306.0(9) Å3, Z = 2, calc = 1.27g/cm
3, MoK radiation,
= 0.71073 Å, 2max = 50°, scans, 173(2) K, 23510 total reflections, 11610 unique
reflections, 3697 reflections with I>2(I) (Rint = 0.108); absorption correction
SADABS (Tmin = 0.9501, Tmax = 0.9914, = 0.081 mm-1
), structure solution with
SHELX-S, refinement (against F2) using SHELX-97-2, 814 parameters, 0 restraints,
H atoms placed in calculated positions on ordered moieties and refined with a riding
model, R1 = 0.0836 (I>2(I)) and wR2 = 0.2308 (all data), residual electron density
min./max. – 0.39/ 0.84 e- /Å3, GOF = 0.819.
(±)-Anti-6C6H5Br•2.5C6H5Br:
Crude (±)-anti-6 was dissolved in bromobenzene and recrystallized by diffusion of
ether antisolvent. C87H78.5O12Br2.5, Mr = 1515.84, 0.65 x 0.35 x 0.20 mm, monoclinic,
space group C2/c (no. 15), a = 25.609(2), b = 12.1159(11), c = 47.281(4) Å, =
103.039(2)°, V = 14292(2) Å3, Z = 8, calc = 1.41g/cm
3, MoK radiation, = 0.71073
Å, 2max = 50°, scans, 188(2) K, 57338 total reflections, 12582 unique reflections,
7774 reflections with I>2(I) (Rint = 0.048); absorption correction SADABS (Tmin =
0.4463, Tmax = 0.7562, = 1.48 mm-1
), structure solution with SHELX-S, refinement
(against F2) using SHELX-97-2, 894 parameters, 0 restraints, H atoms placed in
95
calculated positions on ordered moieties and refined with a riding model, R1 = 0.0801
(I>2(I)) and wR2 = 0.2596 (all data), residual electron density min./max. – 2.20/ 0.80
e- /Å3, GOF = 1.077.
2_(±)-Anti-61,3-C6H4(CH3)2•2-1,3-C6H4(CH3)2:
Crude (±)-anti-6 was dissolved in m-xylene and recrystallized by diffusion of ether
antisolvent. C176H172O24, Mr = 2671.14, 0.60 x 0.45 x 0.20 mm, monoclinic, space
group P21/n (no. 14), a = 22.306(2), b = 25.435(3), c = 26.475(3) Å, = 109.780(2)°,
V = 14134(3) Å3, Z = 4, calc = 1.26g/cm
3, MoK radiation, = 0.71073 Å, 2max = 50°,
scans, 173(2) K, 127872 total reflections, 24895 unique reflections, 7733
reflections with I>2(I) (Rint = 0.112); absorption correction SADABS (Tmin = 0.9522,
Tmax = 0.9837, = 0.08 mm-1
), structure solution with SHELX-S, refinement (against
F2) using SHELX-97-2, 1802 parameters, 0 restraints, H atoms placed in calculated
positions on ordered moieties and refined with a riding model, R1 = 0.0605 (I>2(I))
and wR2 = 0.1620 (all data), residual electron density min./max. – 0.43/ 1.11 e- /Å3,
GOF = 0.752.
(±)-Anti-61,2,4-C6H3(CH3)3•1,2,4C6H3(CH3)3:
Crude (±)-anti-6 was dissolved in warm 1,2,4 trimethylbenzene and recrystallized by
slow cooling. C90H90O12, Mr = 1363.62, 0.60 x 0.50 x 0.25 mm, monoclinic, space
96
group P21/n (no. 14), a = 23.323(2), b = 13.7672(13), c = 24.591(2) Å, =
112.890(2)°, V = 7274.3(12) Å3, Z = 4, calc = 1.25g/cm
3, MoK radiation, = 0.71073
Å, 2max = 50°, scans, 173(2) K, 52653 total reflections, 12815 unique reflections,
9060 reflections with I>2(I) (Rint = 0.040); absorption correction SADABS (Tmin =
0.9528, Tmax = 0.9799, = 0.08 mm-1
), structure solution with SHELX-S, refinement
(against F2) using SHELX-97-2, 977 parameters, 0 restraints, H atoms placed in
calculated positions on ordered moieties and refined with a riding model, R1 = 0.0597
(I>2(I)) and wR2 = 0.1796 (all data), residual electron density min./max. – 0.38/ 0.74
e- /Å3, GOF = 1.078.
(±)-Anti-61,2 C6H4(CH3)2•1,2 C6H4(CH3)2:
Crude (±)-anti-6 was dissolved in o-xylene and recrystallized by diffusion of ether
antisolvent. C88H86O12, Mr = 1335.65, 0.50 x 0.45 x 0.22 mm, monoclinic, space
group P21/n (no. 14), a = 23.8309(18), b = 13.5043(10), c = 24.0631(18) Å, =
112.8090(10)°, V = 7138.4(9) Å3, Z = 4, calc = 1.24g/cm
3, MoK radiation, =
0.71073 Å, 2max = 50°, scans, 186(2) K, 52178 total reflections, 12562 unique
reflections, 7546 reflections with I>2(I) (Rint = 0.040); absorption correction
SADABS (Tmin = 0.9604, Tmax = 0.9823, = 0.08 mm-1
), structure solution with
SHELX-S, refinement (against F2) using SHELX-97-2, 942 parameters, 0 restraints,
H atoms placed in calculated positions on ordered moieties and refined with a riding
97
model, R1 = 0.0699 (I>2(I)) and wR2 = 0.2327 (all data), residual electron density
min./max. – 0.33/ 0.504 e- /Å3, GOF = 0.978.
(±)-Anti-62CH3NO2•4CH3NO2:
Crude (±)-anti-6 was dissolved in nitromethane and recrystallized by diffusion of ether
antisolvent. C78H84N6O24, Mr = 1489.51, 0.50 x 0.50 x 0.50 mm, triclinic, space group
P-1 (no.2), a = 13.080(2), b = 14.549(2), c = 20.930(3) Å, = 73.116(2), =
77.392(3), = 83.188(3)°, V = 3712.8(10) Å3, Z = 2, calc = 1.33g/cm
3, MoK radiation,
= 0.71073 Å, 2max = 50°, scans, 173(2) K, 33714 total reflections, 13063 unique
reflections, 5909 reflections with I>2(I) (Rint = 0.070); absorption correction
SADABS (ratio of Tmin/Tmax = 0.7614, = 0.10 mm-1
), structure solution with
SHELX-S, refinement (against F2) using SHELX-97-2, 934 parameters, 0 restraints,
H atoms placed in calculated positions on ordered moieties and refined with a riding
model, R1 = 0.0595 (I>2(I)) and wR2 = 0.1625 (all data), residual electron density
min./max. – 0.25/ 0.41 e- /Å3, GOF = 0.826. Two lattice NO2CH3 molecules per ASU
were modeled as disordered solvent. SQUEEZE analysis of the remaining solvent
reveals the solvent-accessible volume to be 423 Å3 per unit cell, which is occupied by
136 electrons (calculated. 2 NO2CH3 molecules per asymmetric unit).
Syn-7C4H10O•2C8H10•0.5C4H10O:
98
Crude syn-7 was dissolved in m-xylene and recrystallized by diffusion of ether
antisolvent. C94H101O13.5, Mr =1446.82, 0.50 x 0.50 x 0.20 mm, hexagonal, space
group P63/m (no.), a = 13.786(2), b = 13.786(2), c = 23.058(4) Å, = 90, = 90, =
120°, V = 3795.2(11) Å3, Z = 12, calc = 1.33g/cm
3, MoK radiation, = 0.71073 Å,
2max = 54.16°, scans, 178(2) K, 12264 total reflections, 2293 unique reflections,
1300 reflections with I>2(I) (Rint = 0.062; absorption correction SADABS (Tmin =
0.9609, Tmax = 0.9841, = 0.08 mm-1
), structure solution with SHELX-S, refinement
(against F2) using SHELX-97-2, 166 parameters, 0 restraints, H atoms placed in
calculated positions on ordered moieties and refined with a riding model, R1 = 0.0671
(I>2(I)) and wR2 = 0.2100 (all data), residual electron density min./max. – 0.24/ 0.42
e- /Å3, GOF = 0.954. SQUEEZE analysis reveals the solvent-accessible volume to be
619Å3 per unit cell, which is occupied by 139 electrons (calculated. 2 C8H10 and 0.5
C4H10O molecules per asymmetric unit).
(±)-Anti-8C6H5NO2•2.4C6H5NO2:
Crude (±)-anti-8 was dissolved in nitrobenzene and recrystallized by diffusion of ether
antisolvent. C92.4H83N3.4O18.8Br3, Mr = 1781.60, 0.18 x 0.28 x 0.80 mm, triclinic, space
group P-1 (no. 2), a = 13.9075(10), b = 14.6595(10), c = 23.3456(16) Å, =
82.227(1), = 78.335(1), = 64.221(1)°, V = 4191.4(5) Å3, Z = 2, calc = 1.45g/cm
3,
MoK radiation, = 0.71073 Å, 2max = 56°, scans, 173(2) K, 38413 total
99
reflections, 19271 unique reflections, 12870 reflections with I>2(I) (Rint = 0.033);
absorption correction SADABS (Tmin = 0.3757, Tmax = 0.7713, = 1.52 mm-1
),
structure solution with SHELX-S, refinement (against F2) using SHELX-97-2, 1033
parameters, 0 restraints, H atoms placed in calculated positions on ordered moieties
and refined with a riding model, R1 = 0.0488 (I>2(I)) and wR2 = 0.1401 (all data),
residual electron density min./max. – 0.99/ 1.83 e- /Å3, GOF = 1.005. SQUEEZE
analysis of the unmodeled solvent reveals the solvent-accessible volume to be 441 Å3
per unit cell, which is occupied by 55 electrons (calculated. 0.4 C6H5NO2 per
asymmetric unit).
(±)-Anti-8THF:
Crude (±)-anti-8 was dissolved in THF and recrystallized by evaporation.
C76H71N3.4O13Br3, Mr = 1432.06, 0.18 x 0.28 x 0.80 mm, triclinic, space group P-1 (no.
2), a = 10.8295(17), b = 13.053(2), c = 23.711(4) Å, = 86.932(2), = 89.123(2), =
73.302(2)°, V = 3205.9(9) Å3, Z = 2, calc = 1.484g/cm
3, MoK radiation, = 0.71073
Å, 2max = 50°, scans, 173(2) K, 23181 total reflections, 11140 unique reflections,
9310 reflections with I>2(I) (Rint = 0.033); absorption correction SADABS (Tmin =
0.6174, Tmax = 1.0000, = 1.96 mm-1
), structure solution with SHELX-S, refinement
(against F2) using SHELX-97-2, 880 parameters, 0 restraints, H atoms placed in
calculated positions on ordered moieties and refined with a riding model, R1 = 0.0367
100
(I>2(I)) and wR2 = 0.1589 (all data), residual electron density min./max. – 0.34/ 0.49
e- /Å3, GOF = 1.050.
(±)-Anti-H392C3H6OC3H6OC4H10O:
Crude (±)-anti-H39 was dissolved in an acetone/methanol mixture, and recrystallized
by slow evaporation of acetone. Single crystal structure of (±)-anti-
H392C3H6OC3H6O C4H10O: C88H94O23, 0.75 x 0.30 x 0.28 mm, triclinic, space
group P-1, a = 11.9169(13), b = 13.0118(15), c = 29.570(3) Å, = 90.160(2), =
96.840(2), γ = 107.562(2), V = 4336.7(8) Å3, Z = 2, calcd = 1.164g/cm
3, MoK
radiation, = 0.71073 Å, 2max = 56, scans, 173(2)K, 39222 total reflections, 19863
unique reflections, 12374 reflections with I>2(I) (Rint = 0.0325); absorption
correction SADABS (Tmin = 0.9398, Tmax = 0.9769, = 0.084 mm-1
), structure solution
using SHELX-S, refinement (against F2) with SHELX-97-2, 920 parameters, 0
restraints, H atoms placed in calculated positions and refined with a riding model, R1 =
0.0631 (I>2(I)) and wR2 = 0.1912 (all data), residual electron density max./min =
0.376/-0.316 e- Å3, GOF = 1.020. SQUEEZE analysis of the unmodeled solvent
reveals the solvent-accessible volume to be 1232 Å3 per unit cell, which is occupied by
146 electrons (calculated. 2 C3H6O and 1 C4H10O per asymmetric unit).
101
2.13 References
1. Canceill, J.; Collet, A., J. Chem Soc., Chem. Commun. 1988, 582-584.
2. (a) Gabard, J.; Collet, A., J. Chem. Soc., Chem. Commun. 1981, 1137-1139;
(b) Canceill, J.; Collet, A.; Gottarelli, G.; Palmieri, P., J. Am. Chem. Soc. 1987,
109, 6454-6464; (c) Brotin, T.; Devic, T.; Lesage, A.; Emsley, L.; Collet, A.,
Chem. Eur. J. 2001, 7, 1561-1573.
3. Holman, K. T., unpublished results.
4. (a) Brotin, T.; Dutasta, J.-P., Eur. J. Org. Chem. 2003, 2003, 973-984; (b)
Darzac, M.; Brotin, T.; Rousset-Arzel, L.; Bouchu, D.; Dutasta, J.-P., New J.
Chem. 2004, 28, 502-512; (c) Huber, G.; Brotin, T.; Dubois, L.; Desvaux, H.;
Dutasta, J.-P.; Berthault, P., J. Am. Chem. Soc. 2006, 128, 6239-6246.
5. Zhong, Z.; Ikeda, A.; Shinkai, S.; Sakamoto, S.; Yamaguchi, K., Org. Lett.
2001, 3, 1085-1087.
6. (a) Manville, J. F.; Troughton, G. E., J. Org. Chem. 1973, 38, 4278-4281; (b)
Lesot, P.; Merlet, D.; Sarfati, M.; Courtieu, J.; Zimmermann, H.; Luz, Z., J.
Am. Chem. Soc. 2002, 124, 10071-10082.
7. Canceill, J.; Lacombe, L.; Collet, A., ibid.1986, 108, 4230-4232.
8. (a) Kerckhoffs, J. M. C. A.; ten Cate, M. G. J.; Mateos-Timoneda, M. A.; van
Leeuwen, F. W. B.; Snellink-Ruël, B.; Spek, A. L.; Kooijman, H.; Crego-
Calama, M.; Reinhoudt, D. N., ibid.2005, 127, 12697-12708; (b) Sambrook,
M. R.; Beer, P. D.; Wisner, J. A.; Paul, R. L.; Cowley, A. R.; Szemes, F.; Drew,
102
M. G. B., J. Am. Chem. Soc. 2005, 127, 2292-2302; (c) Braunschweig, A. B.;
Ronconi, C. M.; Han, J.-Y.; Aricó, F.; Cantrill, S. J.; Stoddart, J. F.; Khan, S. I.;
White, A. J. P.; Williams, D. J., Eur. J. Org. Chem. 2006, 2006, 1857-1866.
9. (a) Zyryanov, G. V.; Rudkevich, D. M., J. Am. Chem. Soc. 2004, 126, 4264-
4270; (b) Zhang, S.; Echegoyen, L., J. Am. Chem. Soc. 2005, 127, 2006-2011;
(c) Nielsen, K. A.; Cho, W.-S.; Lyskawa, J.; Levillain, E.; Lynch, V. M.;
Sessler, J. L.; Jeppesen, J. O., J. Am. Chem. Soc. 2006, 128, 2444-2451.
10. (a) Park, S. J.; Lee, J. W.; Sakamoto, S.; Yamaguchi, K.; Hong, J.-I., Chem.--
Eur. J. 2003, 9, 1768-1774; (b) Corbellini, F.; Mulder, A.; Sartori, A.; Ludden,
M. J. W.; Casnati, A.; Ungaro, R.; Huskens, J.; Crego-Calama, M.; Reinhoudt,
D. N., J. Am. Chem. Soc. 2004, 126, 17050-17058; (c) Sessler, J. L.; Gross, D.
E.; Cho, W.-S.; Lynch, V. M.; Schmidtchen, F. P.; Bates, G. W.; Light, M. E.;
Gale, P. A., J. Am. Chem. Soc. 2006, 128, 12281-12288.
11. (a) Tobey, S. L.; Anslyn, E. V., ibid.2003, 125, 14807-14815; (b) Paisey, S. J.;
Sadler, P. J., Chem. Commun. 2004, 306-307; (c) Correia, I.; Dornyei, A.;
Jakusch, T.; Avecilla, F.; Kiss, T.; Costa Pessoa, J., Eur. J. Inorg. Chem. 2006,
2006, 2819-2830.
12. (a) Mansikkamaki, H.; Nissinen, M.; Schalley, C. A.; Rissanen, K., New J.
Chem. 2003, 27, 88-97; (b) Liu, Y.; Guo, D.-S.; Yang, E.-C.; Zhang, H.-Y.;
Zhao, Y.-L., Eur. J. Org. Chem. 2005, 2005, 162-170; (c) Clark, T. E.; Makha,
M.; Raston, C. L.; Sobolev, A. N., Dalton Trans. 2006, 5449-5453.
103
13. CCDC Structure Codes, B., BIMXUR (Mough et. al. Angew. Chem. Int. Ed.
2004, 43, 5631-5635), CUSCEY (Canceill et. al. J. Chem. Soc., Chem
Commun. 1985, 361), DIJJUB (Canceill et. al. J. Chem. Soc., Chem. Commun.
1986, 339), IYETUB, IYEVAJ, IYEVEN (Cavagnat et. al. J. Phys. Chem. B.
2004, 108, 5572), JOHGAO, JOHGES (Cram et. al. J. Am. Chem. Soc. 1991,
113, 8909), PICKUH, PICLAO (Renault et. al. Bull. Soc. Chim. Fr. 1993 130,
740), SEDPOG (Canceill et. al. Angew. Chem. Int. Ed. Engl. 1989, 28, 1246),
TUHDAB, TUHDAB01 (Garcia et. al. Bull. Soc. Chim. Fr. 1996, 133, 853),
XABDOU (Roesky et. al. Chem. Eur. J. 2003, 9, 1104.
14. CCDC Structure Codes, G. C. e. a. T. L., 41, 19465), KEHDAC, KEHDAC10
(Tanner et. al. J. Am. Chem. Soc. 1990, 112, 1659), KIRRIM (Quan et. al. J.
Chem. Soc., Chem. Commun. 1991, 660), JILZIN (Sherman et. al. J. Am.
Chem. Soc. 1991, 113, 2194), JUMZAS (Choi et. al. J. Chem. Soc., Chem.
Commun. 1992, 1733), LUXVAB, LUXVEF, LUXVIS (Warmuth et. al. J.
Org. Chem. 2003, 68, 2077), MALHAI (Gibb et. al. Chem. Commun. 2000,
363), NERYIS (Yoon et. al. Chem Commun 1997, 1303), PAQFES (Park et. al.
Chem Commun 1998, 55), PIHZAH, PIHZEL, PIHYEK, PIHYOU, PIHYIO,
PIHYUA (Robbins et. al. J. Am. Chem. Soc. 1994, 116, 111), TENLON,
TENLUT (Helgeson et. al. J. Am. Chem. Soc. 1996, 118, 5590), TUCKUX,
TUCLAE (Yoon et. al. J. Org. Chem. 1996, 61, 9323), VURBUF (Cram et. al.
J. Am. Chem. Soc. 1992, 114, 7765), YETKAJ, YETKEN (Eid Jr. et. al. J.
104
Am. Chem. Soc. 1994, 116, 8506), YOCRAJ (Helgeson et. al. J. Chem. Soc.,
Chem. Commun. 1995, 307), ZAQMIN (Fraser et. al. J. Org. Chem. 1995, 60,
1207), ZELDID (Byun et. al. J. Chem. Soc., Chem. Commun. 1995, 1825),
ZUFVEB (Byun et. al. J. Chem. Soc., Chem. Commun. 1995, 1947). .
15. Helgeson, R. C.; Knobler, C. B.; Cram, D. J., J. Am. Chem. Soc. 1997, 119,
3229-3244.
16. Takahashi, S.; Miura, H.; Kasai, H.; Okada, S.; Oikawa, H.; Nakanishi, H.,
ibid.2002, 124, 10944-10945.
17. (a) Miura, H.; Yuzawa, S.; Takeda, M.; Takeda, M.; Yoichi, H.; Tomoaki, T.;
Akabori, S., Supramol. Chem. 1996, 8, 53-65; (b) Roesky, C. E. O.; Weber, E.;
Rambusch, T.; Stephan, H.; Gloe, K.; Czugler, M., Chem.– Eur. J. 2003, 9,
1104-1112.
18. (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J. Eds.;
Wiley-VCH: New York, 1998; (b) Tsuji, J. Palladium Reagents and Catalysts,
Innovations in Organic Synthesis; Wiley: New York, 1995.
19. (a) Kurz, K.; Goebel, M. W., Helv. Chim. Acta 1996, 1967-1979; (b) Guldi, D.
M.; Swartz, A.; Luo, C.; Gómez, R.; Segura, J. L.; Martín, N., J. Am. Chem.
Soc. 2002, 124, 10875-10886.
20. Van Der Sluis, P.; Spek, A. L., Acta Crystallogr. Sect. A: Found. Crystallogr.
1990, 46, 194-201.
105
21. Garel, L.; Lozach, B.; Dutasta, J. P.; Collet, A., J. Am. Chem. Soc. 1993, 115,
11652-11653.
22. (a) Giacovazzo, C., Fundamentals of crystallography. International Union of
Crystallography, Chester, 1992. (b) Braga, D.; Grepioni, F.; Desiraju, G. R.,
Chem. Rev. 1998, 98, 1375-1406.
23. Nishio, M., Tetrahedron 2005, 61, 6923-6950.
24. (a) Hancock, K. S. B., Chem. Commun. 1998, 1409-1410; (b) Nagahama, S.;
Inoue, K.; Sada, K.; Miyata, M.; Matsumoto, A., Cryst. Growth Des. 2003, 3,
247-256; (c) Nishio, M., CrystEngComm 2004, 6, 130-158; (d) Manimaran,
B.; Lai, L.-J.; Thanasekaran, P.; Wu, J.-Y.; Liao, R.-T.; Tseng, T.-W.; Liu, Y.-
H.; Lee, G.-H.; Peng, S.-M.; Lu, K.-L., Inorg. Chem. 2006, 45, 8070-8077.
25. (a) Brandl, M.; Weiss, M. S.; Jabs, A.; Suhnel, J.; Hilgenfeld, R., J. Mol. Biol.
2001, 307, 357-377; (b) Kinoshita, T.; Miyake, H.; Fujii, T.; Shoji, T.; Goto,
T., Acta Crystallogr. Sect. D: Biol. Crystallogr. 2002, 58, 622-626; (c)
Umezawa, Y.; Nishio, M., Nucleic Acids Res. 2002, 30, 2183-2192.
26. Hyperchem 7.5 was used to estimate energy for a simplified model, which
neglected the CTB groups. MM+ molecular dynamics was performed,
followed by geometry optimization. The model is admittedly crude, but
repeatedly demonstrated that the energy difference between the staggered and
eclipsed conformation was 0.5-1.0 kcal/mol, which is reasonable based on the
functional groups. .
106
27. Collet, A.; Brienne, M. J.; Jacques, J., Chem. Rev. 1980, 80, 215-230.
28. Barbour, L. J., J. Supramol. Chem. 1, 189-191.
107
CHAPTER 3: SYNTHESIS AND CHARACTERIZATION OF AN
“IMPLODED” CRYPTOPHANE ATROPISOMER
3.1. Introduction to CTB “cup” inversion
The CTB cups that constitute the cryptophanes are C3 symmetric and axially
chiral when A ≠ Z (Figure 3.1). In CTB molecules, the cup-shaped molecules can
invert and racemize when A ≠ Z (Figure 3.1).1 This racemization has been well
studied in this class of molecules, and kinetic data has been obtained for a variety of C3
symmetric CTB derivatives (Figure 3.1, A ≠ Z).2 It has been observed that molecular
derivation at the A and Z positions has little effect on the racemization kinetics.3 A
common mechanistic pathway has been identified for the conformation change, as seen
in Figure 3.1. The CTB first undergoes a partial inversion to a “saddle-twist”
intermediate, in which one methylene group inverts.4 The “saddle-twist” intermediate
is almost as stable as the cup form of the molecule, with a difference of approximately
12-16 kJ/mol between the two.3,4
The overall activation energy barrier to
atropisomerization is 110-115 kJ//mol,4,5
while the barrier from the saddle-twist
conformer to the cup conformer is 94-102 kJ/mol.4
The saddle-twist CTB conformation has characteristic NMR spectral features
that are dramatically different from the cup conformation. The metastable saddle-twist
conformer undergoes a low-energy rotation, which is shown in Figure 3.2. In the
saddle-twist CTB conformation, one methylene group points in the opposite direction
from the other two. However, the inverted methylene group rotates “up” while the
108
next methylene group rotates “down” or inverts. This saddle-twist rotation (Figure
3.2) occurs very quickly, such that the rate of rotation at 120K is at least 106
s-1
(and
possibly much greater).4 As a result, the saddle-twist form of an A,Z substituted CTB
displays its time-averaged C3h symmetry on the NMR timescale. The unique doublet
splitting of the axial and equatorial methylene groups in cup-shaped CTB molecules is
not observed in the NMR spectra of saddle-twist CTB molecules and this behavior has
been used to monitor the kinetics and thermodynamic behavior of the saddle-twist/cup
atropisomerization.
The crown form of most CTB molecules is typically the thermodynamically
stable form, and very little or no saddle-twist CTB atropisomer is observed due to its
(±)-anti-4THF·3THF
(±)-anti-4THF
Figure 3.1. Crown inversion of CTBs. Note that the saddle-twist intermediate is close in
energy to the crown conformation (ΔΔG298 = ~12-16 kJ/mol higher for saddle-twist
intermediate).3,4
109
relative thermodynamic instability. However, one can functionalize the CTB molecule
to destabilize the crown CTB atropisomer, and the result is the observation of both
crown and saddle-twist CTB atropisomers in equilibrium. Changes to the methylene
linkages (functionalization, oxidation, heteroatom substitution) or ortho substitution
with bulky constituents (Figure 3.3) have been found to produce significant saddle-
twist CTB atropisomers.3,6
Figure 3.2. Saddle-twist rotation of CTBs. Arrows show one direction of rotation,
but rotation could occur in the other direction.
110
3.2. Thermal Analysis of (±)-Anti-
4THF3THF
The material (±)-anti-4THF3THF,
reported formally and completely in Chapter 2,
desolvates spontaneously under ambient
conditions, and single crystals of this material eventually become opaque after being
removed from the mother liquor. Thermogravimetric analysis (TGA) of this material
reveals two distinct but partially overlapping weight losses, which we tentatively
assigned to desolvation of lattice-included THFs followed by desolvation of the
encapsulated THF species (Figure 3.4). Maintaining (±)-anti-4THF3THF at 85C
for fifteen hours allows the mass loss to stabilize, and it corresponds approximately to
the loss of 2 equivalents of THF (calculated: 3 equivalents). The discrepancy between
the calculated and actual mass loss is likely a result of THF loss prior to TGA heating.
The 85-equilibrated material was then heated to 200C, and lost 5.2% of its original
mass (calcd. 5.3%), corresponding to 1 equivalent of THF. This series of experiments
strongly suggests the following: 1. It is possible to completely remove the lattice-
included THF molecules without removing encapsulated THF molecules. 2.
Encapsulated THF molecules are retained more strongly than the lattice-included THF,
suggesting that constrictive binding properties of the cryptophane convey to the solid
Figure 3.3. CTB oxide molecule in
saddle-twist formation.
111
state, as the encapsulated THF is removed
upon heating to >130C while the lattice
THFs are slowly removed at room
temperature over several days, or over
several hours at 85C (THF boiling point =
65C).7 3. Heating to ~210C results in the
removal of all THF, leaving guest-free
cryptophane material.
3.3. Consequences of Desolvation:
Atropisomerization of (±)-anti-4
3.3.1. 1H NMR of desolvated (±)-anti-4
material
1H NMR analysis was performed on
anti-(±)-4 that had been heated to 210C to confirm that the material had completely
desolvated and to verify the integrity of the compound after TGA analysis. 1H NMR
clearly revealed changes as the spectrum displayed several new peaks in addition to the
peaks corresponding to anti-(±)-4 (Figure 3.5). A careful examination of the new
NMR spectrum revealed that the number of new peaks was approximately twice the
number of peaks in (±)-anti-4. Fortunately, the new species, hereafter (±)-imp-4, could
Figure 3.4. TGA of cryptophane materials.
Top: Thermograms of (±)-anti-4THF3THF
and (±)-anti-4THF as a function of
temperature. Note that the THF molecules in
the lattice can be separated from the
encapsulated THF molecule. Bottom:
Isothermal thermogram of (±)-anti-
4THF3THF at 85C. This heating profile
allows for removal of only lattice THF
molecules.
(±)-anti-4THF
(±)-anti-4THF3THF
112
be separated from (±)-anti-4 by
preparative TLC (eluent 8:1
CH2Cl2/Et2O), allowing for a 1H
NMR analysis of the new species
without the interference of (±)-
anti-4. Spectroscopic analysis of
this new species is consistent with
a reduction in molecular
symmetry from D3 in (±)-anti-4 to
C3 in (±)-imp-4. Notably, over a
period of several days in solution,
(±)-imp-4 reverts entrirely back
into (±)-anti-4 and the original
spectrum of (±)-anti-4 results (Figure 3.4). From this, we concluded that ()-imp-4
was actually an atropisomer of ()-anti-4, and not a decomposition product. Also, the
atropisomerization was occurring in the solid-state after the cavity had been emptied at
high temperature. The new atropisomer could be separated from the starting material,
allowing for characterization of the new material. However, ()-imp-4 was unstable in
solution and converted completely to (presumably solvent-occupied) ()-anti-4 when
the material was dissolved in an appropriate solvent.
Figure 3.5. 1H NMR of atropisomerization of (±)-anti-4
over time.
113
Collet described similar behavior after thermal treatment of other
cryptophanes,5b
in which cryptophanes having bridges longer than three carbon units.
Collet observed similar 1H NMR behavior, and described these cryptophanes as being
“in-out” cryptophanes, although it is not entirely clear whether he believes these
cryptophanes exist in a cup-in-cup form or in a saddle-twist-cup form (see Figure 3.6).3
3.3.2. 2D NMR of (±)-imp-4: COSY and ROESY
The reversion of (±)-imp-4 to (±)-anti-4 was monitored over time by 1H NMR.
However, there were several unanswered questions concerning the 1H NMR spectrum
of the C3 symmetric (±)-imp-4 species. First, there appeared to be missing peaks in the
CDCl3 NMR spectrum, corresponding to the methylenic protons of one of the CTB
moieties. The D3 symmetric (±)-anti-4 has four sets of doublets, therefore, the
symmetry reduced C3 symmetric (±)-imp-4 should have eight doublets. However, the
1H NMR spectrum of (±)-imp-4 contained only seven clearly defined doublets in the
CDCl3 spectrum of (±)-imp-4. The
peak integrations and peak shapes in
the 4.5-5.5 ppm region of the NMR
indicated that there was significant
peak overlap. Two dimensional
NMR techniques were therefore
employed to understand the details of
Figure 3.6. Left: Model of a “cup-in-cup”
cryptophane. Right: Model of a “saddle-twist-cup”
cryptophane.
114
(±)-imp-4’s 1H NMR spectrum. Since COSY (Correlated Overhauser Spectroscopy)
NMR yields information about the coupling connectivity of a species,8 it was
performed on (±)-imp-4 to clarify the position of the overlapped peaks and to provide
information about the coupling found within the (±)-imp-4 spectrum. COSY of (±)-
imp-4 in CDCl3 revealed four coupled sets between the observed seven doublets, which
confirmed that one doublet was hidden in the 1H NMR spectrum of (±)-imp-4 in CDCl3
(Figure 3.7). The COSY spectrum revealed two couplets (9, 5.05 ppm and 10, 4.99
ppm; 8, 5.11 ppm and 11, 4.88 ppm), which are consistent with the coupling between
the diastereotopic benzyl protons of the m-xylyl cryptophane bridge. A third COSY
couplet (16-17, 3.45 ppm and 12, 4.67 ppm), is consistent with coupling between
equatorial and axial CTB methylene protons for a cup-shaped CTB unit. The fourth
COSY couplet, (16-17, 3.45 ppm and 14, 3.58 ppm) revealed the position of the eighth
doublet at 3.58 ppm. This coupled pair must be between equatorial and axial CTB
methylene protons; however, an axial CTB proton had moved significantly upfield
from approximately 4.68 ppm to 3.58 ppm. The interpreted COSY spectrum
confirmed that the 1H NMR spectrum of (±)-imp-4 (Figure 3.7) corresponds to a C3
symmetric atropisomer of (±)-anti-4.
The upfield shift of the axial CTB proton is significant, as this behavior is
observed in the NMR spectra of saddle-twist CTB molecules.4 However, upfield
chemical shifts have also been noted in cryptophane guest molecules, as shown in
Figure 2.3. The close proximity of the CTB arene rings effectively shields the guest
115
Figure 3.7. COSY of (±)-imp-4 in CDCl3 at 25°C. Top: Full spectrum. Bottom:
Expanded spectrum.
116
Figure 3.8. COSY of (±)-imp-4 in acetone-d6 at 25°C.
molecules. A CPK model of a cup-in-cup (±)-imp-4 shows that the axial protons of
one cup reside neatly within the second cup, which may also explain the observed
upfield chemical shift.
The proton NMR spectrum of (±)-imp-4 was also acquired in acetone-d6. In
acetone, only six doublets were clearly observed. However, the COSY spectrum of
(±)-imp-4 in acetone-d6 clearly revealed four couplets, revealing the position of the two
missing doublets in the 1H NMR spectrum (Figure 3.8). The COSY coupling between
H8 (5.21 ppm) and H10 (5.05 ppm) and H9 (5.09 ppm) and H11 (5.00 ppm) described
117
the coupling between the diastereotopic protons on the m-xylyl bridge, while the
coupling between H12 (4.80 ppm) and H14 (3.60 ppm) and H14 and H16 (3.45 ppm)
describe the COSY coupling between axial and equatorial protons on the
cryptophane’s two CTB subunits. Again, one axial proton has shifted significantly
upfield (H14, 3.60 ppm). This spectrum helped to confirm the data acquired in the
CDCl3 COSY analysis. From these experiments, it was concluded that the
atropisomerization seriously affected one set of the CTB axial protons, shifting them
significantly upfield.9 The NMR experiments also confirmed the expected coupling
for the C3 symmetry of (±)-imp-4.
ROESY (Rotating Frame Overhauser Effect Spectroscopy) yields information
about the distance between protons in space,8,10
and ROESY experiments were carried
out to understand the spatial relationships of the protons in (±)-imp-4 in CDCl3. The
goals were to assign the entire NMR spectrum and to determine the structure of (±)-
imp-4 in solution. There were two plausible structures for the imploded conformer
(Figure 3.6): a fully imploded, cup-in-cup cryptophane with molecular symmetry of
C3, or a saddle-twist conformer with a molecular symmetry of C1 (but a time-averaged
C3 symmetry).
The ROESY spectrum of (±)-imp-4 taken in CDCl3 provided a wealth of
information concerning the through-space relationship of (±)-imp-4’s protons. Several
through-space interactions were found, and have been highlighted in Figure 3.9. An
118
oval shows the cross-peaks between a bridge aromatic peak (1) and two diastereotopic
Figure 3.9. ROESY of (±)-imp-4 in CDCl3 at 25°C.
119
bridging protons (9-10). Another oval reveals cross-peaks between the same two
diastereotopic bridging protons (9-10) and one CTB peak (4). A third oval shows a
cross-peak between the CTB peaks (4 and 5) and a fourth identifies the cross-peaks
between CTB peak (5) and the unshifted OMe peak (15). The ROESY spectrum
relates all of these peaks in space, and likely corresponds to the unchanged, cup-like
CTB moiety. Two additional cross-peaks are of interest: ovals relate aromatic peaks
(1 and 4) and aromatic peaks (2 and 6). This confirms that CTB peaks 4 and 6 are
nearer to the bridge while CTB peaks are nearer to the methoxy peaks. Unfortunately,
no concrete information concerning the overall structure of (±)-imp-4 could be
obtained.
While the time-averaged C3 symmetry characteristic of saddle-twist rotation in
CTB moieties have been observed as low as 100K, it was hoped that the energy barrier
to saddle-twist rotation would be larger in (±)-imp-4, which would increase the
temperature at which the C1 species would be observed by NMR . A low temperature
1H NMR spectrum of (±)-imp-4 was obtained at -55C in CDCl3 (Figure 3.10). While
Figure 3.10. 1H NMR of (±)-imp-4 at -55C.
120
no C1 species were observed by NMR, very significant spectral broadening was
observed. Since spectral broadening can occur as a process slows to near the NMR
timescale, this low temperature NMR was evidence that a CTB saddle-twist rotation
was occurring, and that the spectrum was broadening in response to the reduced energy
in the solution.
The NMR experiments (ROESY, COSY, and 1-D 1
H NMR at varied
temperatures) in total strongly suggested that (±)-imp-4 was a time-averaged C3
symmetric conformer of (±)-anti-4. The data, particularly the collapse of the Ha and He
signals for one of the CTB moieties, suggested that the saddle-twist model of (±)-imp-
4, a molecule with an instantaneous C1 symmetry, was the more appropriate model.
The broadening of one methoxy peak and the two Ar-H associated with the
unconventional CTB suggested dynamic behavior on the 1H NMR time scale, while the
upfield shift of one methoxy peak (Δ -0.65 ppm) also indicated some shielding, which
could occur if the methoxy pointed into the cone of a CTB. However, the NMR data is
merely suggestive, but not conclusive, of a cup-saddle-twist conformation for (±)-imp-
4 as opposed to the cup-in-cup structure proposed by Collet for their cryptophanes
exhibiting similar behavior.
3.4. Kinetics of atropisomerization by 1H
NMR
As stated previously, NMR has been used successfully to monitor the
conversion of (±)-imp-4 to (±)-anti-4. A series of experiments were prepared, such
121
that (±)-imp-4 was purified and dissolved in CDCl3 and the solutions were monitored
by 1H NMR over time at a number of different temperatures. Since the concentration
of the solution is directly proportional to the peak integration, the changes in
concentration were monitored by following the peak area of (±)-imp-4 over time. The
kinetics of atropisomerization at 298K are shown in Figure 3.11. The data reveals a
(pseudo)first order process with respect to (±)-imp-4. At room temperature (298K), the
rate constant for the atropisomerization of (±)-imp-4 to (±)-anti-4 was determined to be
2.3x10-5
sec-1
, which corresponds to a half-life of approximately 8.3 hours (t1/2 = 500
minutes). The rate constant was determined at multiple temperatures (298K to 323K at
5 degree intervals) and this data used to generate an Eyring plot.11
The Eyring plot,
shown in Figure 3.12, was used to calculate the activation parameters for the
conversion of (±)-imp-4 to (±)-anti-4.
Figure 3.11. Kinetics of inflation of (±)-imp-4 to (±)-anti-4 by 1H NMR integration at
298 K.
122
For comparison, the
experimentally determined
activation parameters for the
crown-to-crown inversion of
CTBs6,7,12
and for the
“explosion” of the pentyl
bridged cryptophane
(Cryptophane “O”)13
are listed alongside the isomerization of (±)-imp-4 in Table 3.1.
The measured for ∆G‡ (±)-imp-4 is much lower than the activation energy barrier
corresponding to the known crown-to-crown atropisomerizations; in fact, the barrier is
much closer to the saddle-to-crown conformational change. Also note that the crown-
to-saddle transformation has a highly negative ΔS‡ value, as do both implosions
studied, while the crown-to-crown transformation has ΔS‡ value near zero. The
kinetics data and derived activation parameters support the saddle-twist model for (±)-
imp-4.
Table 3.1. Comparison of activation parameters for CTB conformers.
ΔG298‡
(kJ/mol)
ΔH‡
(kJ/mol)
ΔS‡
(J/mol K)
(±)-Imp-4 99(3) 70(3)
-98(5)
Implosion:
Cryptophane O13
97 86 -36
CTB crown-to-saddle
atropisomerization3,4
108 95
-44
CTB crown-to-crown
atropisomerization6,7,12
110-115 108-119 -13-(+13)
Figure 3.12. Eyring plot derived from isothermal kinetic data.
123
3.5. Single crystal structure of (±)-imp-411CHCl3
The results of NMR analysis and kinetic studies strongly suggested that the
structure of (±)-imp-4 contains one cup-shaped CTB and one saddle-twist CTB, and
that the atropisomerization to (±)-anti-4 corresponds to a saddle-twist to cone CTB
transition. However, a crystal structure would supply concrete proof of (±)-imp-4
structure, and provide an explanation for the NMR and kinetics data. Unfortunately,
growing an X-ray diffraction quality crystal of such a molecule would prove to be very
difficult, as the half-life of (±)-imp-4 in solution at 298K was a mere eight hours. In
spite of this, attempts were begun to grow a suitable crystal, as crystals were observed
when chloroform solutions of (±)-imp-4 were quickly evaporated to dryness in vacuo.
Instead of growing crystals at room temperature, attempts were made to grow (±)-imp-
4 crystals in the freezer, as this would dramatically increase the half-life of the unstable
atropisomer.
Single crystals of (±)-imp-411CHCl3 were obtained by vapor diffusion of n-
pentane into a purified solution of (±)-imp-4 in CHCl3 at 253K, where the half-life was
estimated to be ~56 days.14
The X-ray structure indeed confirms that the structure of
(±)-imp-4 corresponds to the saddle-twist within cup conformation, as seen in Figure
3.13. The saddle-twist conformation had historically been difficult to crystallize, and
(±)-imp-4 was the first example of a saddle-twist CTB structure that has not been
124
Figure 3.13. Single crystal structure of (±)-imp-4. The 11 CHCl3 molecules in the ASU have been
removed for clarity. Left: Stick structure of (±)-imp-4. Note that the saddle-twist CTB points a
methoxy group into the cup-shaped CTB. CTB arene rings are highlighted in blue. Right: (±)-
imp-4 in which the cup-shaped CTB unit is shown in CPK form, and the saddle-twist CTB unit is
shown in stick form. The saddle-twist CTB arene rings are highlighted in blue.
Figure 3.14. Assigned 1H NMR of (±)-imp-4.
125
destabilized intentionally.8,15
The structure also revealed that the methoxy group of the
saddle-twist CTB subunit points directly into the cavity of the cone CTB subunit.
The structure of (±)-imp-4 helps to explain the anomalous upfield (∆δ~0.65
ppm) shielding of one OMe, which was observed in the 1H NMR spectrum. The
structure of (±)-imp-4 in the crystal structure is C1; in solution, fast saddle-twist
rotation on the NMR timescale gave a C3 averaged spectrum. However, cooling the
solution caused peak broadening to occur, as the saddle-twist rotation was slowed
down to approach the NMR timescale. With the crystal structure in hand, a complete
assignment of the 1H NMR spectrum was completed, and is shown in Figure 3.14.
3.6. Conclusions
The thermal properties of (±)-anti-4THF3THF were studied, and the material
was found to lose THF in two distinct but partially overlapping, separable transitions.
The deconvolution of these mass losses revealed that the THF molecules encapsulated
within the cryptophanes were more thermally stable than the lattice-included THF
molecules. A 1H NMR of the completely guest free material revealed that an
atropisomerization had occurred in the solid-state, yielding an imploded cryptophane
(±)-imp-4. NMR studies and kinetics analyses suggested that the structure of (±)-imp-4
consisted of one cone-shaped CTB subunit and one saddle-twisted subunit, whereas
(±)-anti-4 possess two CTB cone subunits. The saddle-twist structure of the
thermodynamically unstable (±)-imp-4 was confirmed by single-crystal X-ray
126
crystallography. From the NMR (1D and 2D) data and the crystal structure, the 1H
NMR spectrum for (±)-imp-4 was completely assigned and the anomalous spectral
features were explained.
3.7. Experimental
3.7.1. General Methods
All reactions were carried out under nitrogen atmosphere. All solvents and
reagents were used without further purification. Flash chromatography was carried out
on silica gel (32-64μm). 1H (300MHz) NMR was recorded on Varian Mercury
300NMR. Thermogravimetric analyses were performed using a TA Instruments TGA
2050 under a constant stream of nitrogen gas. Single crystal x-ray diffraction was
performed using a Bruker-AXIS SMART diffractometer with CCD area detector
(MoK radiation) at -100 ºC. Lattice parameters were determined from least-square
analysis and the reflection data was integrated using SAINT. Structures were solved
using direct methods and refined by full matrix least-squares based on F2 using X-
SEED.
3.7.2. New Molecule Characterization
(±)-imp-4. (±)-Anti-4THF, earlier prepared from (±)-Anti-4THF3THF by
heating to 85C for fifteen hours, was heated in a vacuum oven at 180˚C for 16 hours,
either under positive N2 pressure or under vacuum. The material was air cooled
127
immediately after removal from the oven. (±)-Imp-4 was separated from residual (±)-
anti-4 on Whatman 150Å 1000m thickness silica gel preparatory TLC plates, using
8:1 CH2Cl2/Et2O as eluent. The separation was performed in the freezer to prevent
reconversion during separation. (±)-Imp-4 was desorbed from silica gel with acetone-
d6, which was removed under reduced pressure. (±)-Imp-4 was recrystallized by vapor
diffusion of pentane into a CHCl3 solution at 253K. (±)-Imp-4 appears as a white solid.
Rf = 0.36; 1H NMR(300MHz, CDCl3, 25C): δ8.02 (s, br, 3H, Ar); δ7.94 (s, br, 3H,
Ar); δ7.25 (s, br, 3H, Ar); δ6.83 (s, 3H, Ar); δ6.61 (s, 3H, Ar); δ6.34 (s, 3H, Ar); δ6.07
(s, br, 3H, Ar); δ5.11 (d, 3H, ArCH2O, 2J (H,H) = 13.9Hz); δ5.05 (d, 3H, ArCH2O,
2J
(H,H) = 13.5Hz); δ4.99 (d, 3H, ArCH2O, 2J (H,H) = 13.5Hz); δ4.88 (d, 3H, ArCH2O,
2J (H,H) = 13.9Hz); δ4.67 (d, 3H, ArCH2,
2J (H,H) = 13.5Hz); δ3.95 (s, 9H, CO2CH3);
δ3.58 (d, 3H, ArCH2, 2J (H,H) = 15.8Hz); δ3.52 (s, 9H, OCH3); δ3.48 (d, 6H, ArCH2,
2J (H,H) = 15.7Hz)); δ2.82 (s, 9H, OCH3).
3.7.3 Kinetics Experiments
Mixtures of (±)-anti-4 and (±)-imp-4 were dissolved in CDCl3 and the
concentration of both species was monitored by 1H NMR at five degree intervals from
25 to 50C. Six peaks identified as (±)-imp-4 were monitored over time, and the
change in integrated area was followed. The instrument was locked and shimmed at
the experimental temperature, and the sample was analyzed using a time-sequence
macro. The macro programs the instrument to obtain a 1H NMR spectrum at a given
128
time interval. The peak corresponding to 2.82 ppm is shown for each experiment.
Experiments were monitored for 1-3 half-lives. The corresponding rate constant
values were calculated from the slope, and used to derive the Eyring plot. The Eyring
plot in Figure 3.12 was used to derive the activation parameters for the reversion from
(±)-imp-4 to (±)-anti-4.
3.7.4 Crystal Structure
(±)-Imp411CHCl3:
Newly purified (±)-imp-4 was dissolved in CHCl3. Diffusion of n-pentane into
the CHCl3 solution was performed at -30C; large single crystals were formed. Single
crystal structure of racemic (±)-imp-411CHCl3: C89H83O36Cl33, 0.56 x 0.32 x 0.12
mm, triclinic, space group P-1, a = 14.094(5), b = 16.361(5), c = 26.247(8) Å, =
103.372(5), = 101.191(5), = 104.318(5), V = 5499(3) Å3, Z = 22, calcd = 1.577
g/cm3, MoK radiation, = 0.71073 Å, 2max = 45, scans, 183(2) K, 31876 total
reflections, 14293 unique reflections, 7834 reflections with I>2(I) (Rint = 0.0835);
absorption correction SADABS (Tmin = 0.6403, Tmax = 0.9024, = 0.874 mm-1
),
structure solution with SHELX-S, refinement (against F2) using SHELX-97-2, 1419
parameters, 0 restraints, H atoms placed in calculated positions on ordered moieties
and refined with a riding model, R1 = 0.1309 (I>2(I)) and wR2 = 0.3400 (all data),
residual electron density max./min. 0.76/ -0.93 e- /Å3, GOF = 1.060. The relatively
high values of the merging and final R factors are directly attributed to the presence of
129
a large number of highly disordered chloroform molecules and crystal decomposition
of the sample on transfer to the low-temperature stream. Disordered chloroform
molecules are modeled as partial occupancy carbon and chlorine atoms. The
stoichiometry of the crystal was estimated by using the SQUEEZE subroutine of the
program PLATON,16
which estimates the solvent-accessible volume of 2738Å3 (50%
of the unit cell) to be occupied by 1239 electrons (calcd. 10.7 equivalents CHCl3).
130
3.8 References
1. Lüttringhaus, A.; Peters, K. C., Angew. Chem., Int. Ed. Engl. 1966, 5, 593-594.
2. (a) Collet, A.; Gabard, J., J. Org. Chem. 1980, 45, 5400-5401; (b) Canceill, J.;
Collet, A.; Gottarelli, G., J. Am. Chem. Soc. 1984, 106, 5997-6003; (c)
Canceill, J.; Collet, A.; Gottarelli, G.; Palmieri, P., J. Am. Chem. Soc. 1987,
109, 6454-6464; (d) Malthete, J.; Collet, A., J. Am. Chem. Soc. 1987, 109,
7544-7545.
3. Collet, A., Tetrahedron 1987, 43, 5725-5759.
4. Zimmermann, H.; Tolstoy, P.; Limbach, H.-H.; Poupko, R.; Luz, Z., J. Phys.
Chem. B 2004, 108, 18772-18778.
5. (a) Collet, A.; Jacques, J., Tetrahedron Lett. 1978, 19, 1265-1268; (b) Garcia,
C.; Collet, A., Bull. Chim. Soc. Fr. 1995, 132, 52-58.
6. (a) Anand, N. K.; Cookson, R. C.; Halton, B.; Stevens, I. D. R., J. Am. Chem.
Soc. 1966, 88, 370-371; (b) Cookson, R. C.; Halton, B.; Stevens, I. D. R., J.
Chem. Soc. B. 1968, 767-774; (c) Staffilani, M.; Bonvicini, G.; Steed, J. W.;
Holman, K. T.; Atwood, J. L.; Elsegood, M. R. J., Organometallics 1998, 17,
1732-1740; (d) Lindsay, A. S., J. Chem. Soc. 1965, 1685.
7. Handbook of chemistry and physics online. 89th ed.; CRC Press: Boca Raton,
Fla., 2009.
8. Friebolin, H., Basic one- and two-dimensional NMR spectroscopy. 4th ed.;
WILEY-VCH: Weinheim ;, 2005; p 1-406.
131
9. Garcia, C.; Aubry, A.; Collet, A., Bull. Chim. Soc. Fr. 1996, 133, 853-867
10. Huber, J. G.; Dubois, L.; Desvaux, H.; Dutasta, J.-P.; Brotin, T.; Berthault, P.,
J. Phys. Chem. A. 2004, 108, 9608-9615.
11. Lente, G.; Fabian, I.; Poe, A. J., New J. Chem. 2005, 29, 759-760.
12. Sato, T.; Uno, K., J. Chem. Soc., Perkin Trans. 1 1973, 895-900.
13. Lozach, B. D. T., Univerite’ Claude Bernard, Lyon, 1991. Garel, L. Doctoral
Thesis, Universite’ Claude Bernard, Lyon, 1995.
14. Mough, S. T.; Goeltz, J. C.; Holman, K. T. Angew. Chem. Int. Ed. 2004, 43,
5631-5635.
15. Guy, A.; Doussot, J.; Falguieres, A.; Prieur, B.; Baclet, B., Bull. Chim. Soc. Fr.
1996, 133, 1009.
16. Van Der Sluis, P.; Spek, A. L., Acta Crystallogr. Sect. A: Found. Crystallogr.
1990, 46, 194-201.
132
CHAPTER 4: SYNTHESIS AND CHARACTERIZATION OF
CRYPTOPHANE-BASED METAL-ORGANIC POLYMER (CBMOP):
SINGLE CRYSTAL TO SINGLE CRYSTAL PARTIAL DESOLVATION
4.1. Introduction: Single Crystal to Single Crystal Processes
In many ways, the crystalline solid state has been considered a static system.
The classic model of a molecular crystal has been that its molecular components are
held rigidly in space through various intermolecular and intramolecular forces.
Furthermore, it was believed that the close-packed nature of the crystalline solid
prevents significant molecular movement within the crystal. Consequently,
significant molecular egress from a crystal (e.g. desolvation), ingress into the crystal
(e.g. sorption), or movement within the crystal commonly results in the degradation
and collapse of the single crystal into a powder. This behavior has been observed
frequently; for example, desolvation of all of the cryptophane inclusion compounds
reported in Chapter 2 result in fracture of the crystal. The breakdown of the single
crystal was often believed to be required for exogenous molecular species to react
with single crystals, as the reactions were thought to occur at or very near the
crystal‟s surface. The resulting cracks increased the accessible surface area for the
reaction and decrease the need for diffusion through the crystal bulk.
There has been an increased focus on research that looks at molecular crystals
that are capable of sustaining movement within the crystal and/or diffusion of small
exogenous molecules through the bulk of the crystal. In such instances, the diffusion
133
exogenous molecules
through the bulk of the
crystal.1 In such
instances, the diffusion
does not necessarily
result in the destruction
of the single crystal, as
the changes may occur
in a single crystal to
single crystal fashion.
This phenomenon was
recently highlighted in
an issue of Australian
Journal of Chemistry.2
There are four major types of single crystal to single crystal processes: absorption,3
desolvation,4 guest exchange,
5 and polymerization
6 (or other reactions
7), as shown in
Figure 4.1. Adsorption involves the addition of small atomic or molecular guests to a
single-crystal, while desolvation involves the removal of volatile guests from the
crystal bulk.
Single-crystal to single-crystal desolvation has been known to produce dramatic
changes in the structural features of the crystal. For example, Suh and coworkers
Figure 4.1. Single-crystal to single-crystal processes.
134
were able to drive off six pyridine molecules and 26 H2O molecules per asymmetric
unit in a single-crystal to single-crystal fashion, resulting in an incredible 35%
reduction in unit cell volume as well as a dramatic decrease of 5.1Å in bilayer
thickness8 (Figure 4.2)! Exposure to water-pyridine solvent vapor or immersion
within water-pyridine resulted in a complete reversion to the initial structure,
although the guest readsorption was not in a single-crystal to single-crystal fashion.
This is merely one exceptional example of many for single-crystal to single crystal
desolvation recently reported in the literature recently.5,9
Guest exchange is another single-crystal to single-crystal process, where
crystallized molecules are replaced by other molecules. To affect such an exchange,
Figure 4.2. a) [Ni2(C26H52N10)]3[BTC]46C5H5N36H2O bilayer viewed in stick form (left) and
spacefill (right). b) [Ni2(C26H52N10)]3[BTC]44H2O bilayer viewed in stick form (left) and
spacefill (right).
135
a single crystal is submersed in a solution. The new guest molecules diffuse through
the existing crystal lattice, and replace the initially crystallized guests. Frequently,
the new guest molecules move through available channels. Saied and Wuest
described guest exchange in
“Deformation of Porous
Molecular Networks Induced by
the Exchange of Guests in Single
Crystals”9 (Figure 4.3). This
study examined the effect of
changing one molecular
component (carboxylic acids) in a
two-component molecular crystal
(tetrapyridone and carboxylic
acid). Submersion of a crystal in
a liquid does not result in dissolution and recrystallization, but rather in guest
exchange if the new carboxylic acid is smaller than the cocrystallized carboxylic acid.
In general, networks are capable of shrinkage and expansion; however network
shrinkage is more facile.10
While most single-crystal to single-crystal processes involve the removal,
addition or exchange of molecules from the molecular crystal, one class involves the
reactivity of the components of the crystal. Schmidt and coworkers first reported the
Figure 4.3. a) Structure of tetrapyridone crystallized
with isovaleric acid. b) Structure of tetrapyridone after
guest exchange with propionic acid. Note the decrease
in the c-axis with the smaller propionic acid.
136
Figure 4.4. Single-crystal to single-crystal syntheses. Top left: Crystal structure of 1,6 triene.
Top Right: Crystal structure of photo-polymerized 1,6 triene. Bottom left: Hydrogen bond
mediated assembly of 4,4’ bipyridyl ethylene. Bottom right: [2+2] Photochemical synthesis of
[2.2]paracyclophane.
[2+2] photodimerization of cinnamic acids,11
and defined the experimental conditions
that are necessary for a successful reaction. Schmidt‟s so-called „Topochemical
Postulate‟ states that a “reaction in the solid state occurs with a minimum amount of
atomic or molecular movement.”12
Observations of photoreactions in crystallized
olefins have been shown to occur if the olefins are in parallel alignment and lie within
4.2Å of one another.13
Since Schmidt‟s initial finding, chemists have used the
topochemical postulate and principles of crystal engineering to design materials that
137
Figure 4.5. One dimensional chain of CBMOP-solvent as viewed down the b-axis. Chain
propagates along the [1 0 1] direction. Hydrogen atoms, encapsulated DMF molecules, and
solvent molecules omitted for clarity. CTB arenes have been filled in.
will successfully photochemically react in a predictable fashion.14
In some cases,
these reactions may occur in a single-crystal to single-crystal fashion: two examples
include the polymerization of a 1,6 triene15
and the synthesis of a [2.2]
paracyclophane3d
(Figure 4.4).
The field of single-crystal to single-crystal transformations has only recently
gained significant attention in the literature. The increase in reported single-crystal to
single-crystal processes reflects several recent advances. The advent of the area
(CCD) detector in X-ray crystallography has increased the number of crystals
analyzed in a given period of time, allowing for more detailed analysis of molecular
crystal dynamics.16
Also, the increase in reported single-crystal to single-crystal phe-
138
nomena has encouraged further research in the field, as the previous paradigm of the
“chemical cemetery”17
continues to give way to a more dynamic view of crystalline
solids. While it remains impossible to predict if a crystal will undergo a single-
crystal to single-crystal transformation, it is evident that dynamic behavior in the
crystalline solid will continue to be studied.
4.2. A 1-D Cryptophane-Derived Coordination Polymer
The solvothermal reaction of ligand anti-(±)-H39 with Cu(NO3)2 2.5 H2O and
pyridine in 2:1 DMF/MeOH yielded dark blue prismatic crystals. The low
temperature X-ray single crystal structure of these crystals (immediately transferred
to the low temperature stream after removal from the mother liquor) revealed a one-
dimensional polymeric material comprised of anti-(±)-93-
ligands that are linked by
coordination to copper(II) ions; the single crystals have a composition of [Cu1.5((±)-
9DMF)(C6H5N)3(MeOH)]∙xDMF∙yMe OH (ca. x = 1, y = 2, vide infra) hereafter
CBMOP∙solvent (Figure 4.5). This structure‟s asymmetric unit consists of one
cryptophane and 1.5 crystallographically distinct copper ions, and the coordination
about the copper ions is given in Figure 4.6. The coordination about Cu(1) has a
Jahn-Teller distorted octahedral coordination consisted of two crystallographically
equivalent trans carboxylates (Cu1-O3 = 1.925(4)Å; Cu1-O2 = 1.960(4), two trans
pyridine ligands (Cu1-N13S = 2.040(6)Å; Cu1-N17S = 2.010(6)Å) and two weakly
coordinating, crystallographically equivalent carbonyl oxygen atoms (Cu1-O1,4 =
139
Figure 4.6. Coordination environment about metal centers.
2.519 Å). Two Cu(1) atoms link cryptophane molecules; one cryptophane molecule
is found within the asymmetric unit and one at (1/2-x, 5/2-y, -z).
Cu(2) has two trans carboxylates (Cu2-O6,6‟ = 1.963(3)Å), two pyridines (Cu2-
N13S = 2.040(6)Å; Cu2-N17S = 2.010(6)Å), and two axially coordinated MeOH
molecules (Cu2-O7, Cu2-O7‟; = 2.518(5)Å). The two carboxylate ligands are not
coplanar; the dihedral angle of O(5)-O(6)-O(6‟)-C(5‟) is 142. Cu(2) falls on a
Wykoff crystallographic position (0, y. ¼), which is a glide plane, and the two
cryptophane molecules that link through Cu(2) are in the related symmetrically
through the glide plane. One cryptophane linked through Cu(2) has atoms found in
the asymmetric unit and one at (-x, y, ½-z).
The one-dimensional polymer can be described as cryptophane dimers that are
linked to one another through the third m-xylyl bridge, similar to (±)-anti-
H39·(2C3H6O). While (±)-anti-H39 links cryptophanes to form a linear polymer,
CBMOP forms a one-dimensional bent polymer (Figure 4.5). Cu(1) linked two
cryptophanes to form a dimeric structure, which is analogous to the dimeric structure
140
of anti-H39. Cu(2) linked the dimers to one another, such that the polymer
propagated along the [101] direction. The polymer‟s “kink” or bend can be attributed
to the m-xylyl bridge linked to Cu(2), which is rotated approximately 60 from that of
(±)-anti-H39 linearity (Figure 4.7). The stereochemistry of the cryptophanes along
the polymer was [{(+)-9-(-)-9}-{(-)-9-(+)-9}], where (+) and (-) indicate the helicity
of the cryptophanes within the chain .
Determining the composition
of CBMOPsolvent was complicated
by significant disorder of lattice-
solvent. This is an unfortunate
consequence of using bulky, elliptical
ligands since they pack inefficiently
in the solid-state. Though the
polymeric region of the structure was
generally well ordered, the lattice
solvent was not well-ordered. One DMF and two MeOH were assigned to this
electron density. A SQUEEZE18
analysis of CBMOP-solvent was performed, and
determined the solvent accessible volume of 3880 Å3
per asymmetric unit (485Å3/unit
cell, 20.2% of the unit cell volume), with 573 unmodeled e-s per unit cell (72 per
ASU). The formulation defined earlier for the lattice solvent (1DMF, 2MeOH) has a
total of 76e-s per ASU.
Figure 4.7. Overlay of cryptophane in anti-(±)-H39
and CBMOPsolvent viewed from top of
cryptophane. Note the difference in the
cryptophane bridges on the left. While (±)-anti-
H39 continues in a nearly straight path, CBMOP-
solvent is rotated approximately 60°.
141
Thermogravimetric analysis of CBMOP-solvent was employed to confirm
the stoichiometry of the material. Subjecting CBMOP-solvent to a 10C/min
heating ramp, and monitoring mass as a function of temperature revealed a
continuous mass loss upon heating. One mass loss occurs between 50 and 100C, a
second apparent mass loss between 130C and 220C and a third, more steep mass
loss is found above 250C (Figure 4.8 Bottom). The highest temperature mass loss
corresponds with the decomposition of the material; however, the two lower
temperature mass losses likely correspond to the desolvation of the CBMOP-solvent
material. The lowest temperature mass loss most likely corresponds to the removal of
included lattice solvent molecules, especially considering that those solvent
molecules are highly disordered even at low temperatures. Furthermore, the forces
that are containing these molecules within the lattice are weak (van der Waals) and a
path exists to allow their release. The “second” mass loss likely corresponds to the
removal of coordinated solvent molecules, and possibly the encapsulated DMF
solvent molecule, which are held by stronger intermolecular forces (coordination
bonds, constrictive binding). An isothermal TGA experiment (Figure 4.8 Top) was
performed to quantify and possibly separate the two early mass losses so as to
understand the desolvation process. A very slow heating ramp followed by an
isotherm (0.2C/min up to 160C, isothermed for ~800 minutes) revealed three
discernable but still convoluted mass losses: a low temperature mass loss occurring
very near 30C, a transition occurring between 40C and 80C, and a higher
142
temperature transition occurring between 100C and 150C. The first transition
Figure 4.8. Thermogravimetric analysis of CBMOP-solvent. Top: CBMOP mass as a function
of heating at 0.2°C/min from room temperature to 160°C followed by an isothermal hold at
160°C for ~ 800 minutes. Bottom: CBMOP mass as a function of heating at 10°C/min from
room temperature to 380°C.
143
likely corresponds to surface-bound solvent molecules, as the solvent was removed
immediately, while the second and third transitions more likely correspond to lattice
desolvation and metal coordinated solvent loss of CBMOP. The temperatures are
lower in the second experiment; however, the heating ramp is much slower as well
(0.2C/min vs. 10C/min). This phenomenon is commonly observed in
thermogravimetric (and calorimetric) studies at various rates of heating.
4 mg). The second and third mass losses were calculated to be 11.7% and
12.0% respectively; the theoretical mass losses were calculated to be 7.5% for the
loss of lattice solvent and 14.7% for the loss of coordinated solvent (18.7% for loss
of coordinated solvent and encapsulated solvent). The experimental mass loss total
of 23.7% is intermediate between the theoretical mass loss total of 22.2% for loss of
coordinated and lattice solvent and 26.2% for loss of coordinated, lattice and
encapsulated solvent. It is quite possible that some, but not all encapsulated DMF
molecules have been driven from the cryptophanes‟ pores.
4.3. Unit Cell Changes in CBMOP
It was observed that single crystals of this material retained their single crystal
features long after their removal from the mother liquor. Several crystals (5+
crystals) of CBMOP-solvent were removed from the mother liquor, immediately
mounted, and placed in the low temperature nitrogen stream (173±2K) of the X-ray
single crystal diffractometer, and an orientation matrix and unit cell was obtained for
144
Table 4.1. Unit Cell data for CBMOP∙solvent and CBMOP∙desolvated at RT and 173K.
CBMOP∙solvent @ 173K
[a]
CBMOP∙desolvated @ 173K
[b]
CBMOP∙solvent @ RT
[c]
CBMOP∙desolvated @ RT
[c]
a (Å) 53.0(1) 53.3(2) 53.28(7) 53.40(3)
b (Å) 16.09(2) 15.89(4) 16.26(2) 16.15(1)
c (Å) 23.13(3) 22.43(8) 23.40(4) 22.70(1)
Volume
(Å3)
19249(26) 18534(87) 19784(57) 19162(24)
[a] Average of seven crystals. [b] Average of six crystals. [c] Result from one crystal.
each crystal. The averaged initial unit cell parameters from these experiments are
given in Table 4.1. Each crystal was removed from the cold temperature stream, and
exposed to ambient conditions for a period of at least two hours. The single crystals
were then remounted on the diffractometer, and a second orientation matrix and unit
cell was obtained for each crystal at 173K. Though, the crystals‟ quality had
diminished somewhat after being exposed to ambient conditions, each crystal yielded
a similar, but statistically smaller unit cell, as shown in Table 4.1 (Monoclinic C,
19249(26)Å3 vs. Monoclinic C, 18534(87)Å
3). The total unit cell volume change
measured 715Å3 per unit cell, which corresponds to a volume decrease of 3.7%; this
change is statistically significant. This behavior implied that a single-crystal to
single-crystal desolvation process was occurring in this system.
The unit cell volume shrinkage was also monitored in real time by tracking
the cell volume of two crystals as a function of time that the crystals were exposed to
ambient conditions (Figure 4.9). The volume change occurred rapidly at room
145
temperature, but the solvated crystals were stable indefinitely at 173K. It is
interesting to note that the rate of volume change occurs rapidly (completed in ca. 1
hour); however, the rate is deceleratory in nature, which is commonly observed in
solid-state desolvation.19
Figure 4.9. Unit cell change of CBMOP as a function of time at 25C. Data points consist of
individual unit cell matrices collected over time.
4.3.1. X-Ray Single Crystal Structure of CBMOP-desolvated
Despite the decrease in quality of CBMOP crystals upon desolvation, a
dataset of desolvated CBMOP, hereafter CBMOP-desolvated, was collected and the
structure solved. Not surprisingly, the single crystal structure of CBMOP-
desolvated was very similar to that of CBMOP-solvent; however, several notable
differences were observed beyond the unit cell volume change. There were
significant changes about the metal centers: Cu(1) lost approximately 0.4 pyridine
18400
18500
18600
18700
18800
18900
19000
19100
19200
19300
0 20 40 60 80 100 120 140
time (min)
Vo
lum
e (
Å3)
146
molecules and 0.5 MeOH molecules while Cu(2) appeared to lose 0.4 pyridines.
Furthermore, the carboxylate-copper O-Cu-O angles changed from 169.1(2)˚ to
160.9(4)˚ about Cu1 and 178.8(1)˚ to 174.0(5)˚ about Cu2 respectively. The
reduction of the angles had the net effect of contracting the b- and c-axes. The unit
cell changes in the single crystal of CBMOP-desolvated were similar to those
observed in the unit cells of CBMOP-solvent that had been exposed to ambient
conditions for 2+ hours (Table 4.1). Furthermore, the number of unit cell electrons
that were not modeled in the single crystal structure, as determined by SQUEEZE,
was reduced from 573 in CBMOP-solvent to 397 in CBMOP-desolvated, which
corresponds to a loss of approximately 1.5 MeOH per asymmetric unit.
4.3.2. Explanation of Single Crystal Desolvation
As observed in Figure 4.10, the unit cell dimensions in the b- and c- axes
statistically decrease upon partial desolvation of the crystals. Since the crystal shrunk
as a result of single-crystal to single-crystal desolvation, a structural analysis was
performed to determine how the crystal desolvated. Examination of the global
structure of CBMOP revealed that solvent-filled channels exist along the c-axis, and
the included solvent has access to the surface of the crystal via these channels. The
channels are two-dimensional with a ladder-like structure, and the infinite chains that
extend along the c-direction are also connected to one another by short channels that
147
roughly run parallel to the a-axis.
These channels, shown in Figure 4.12,
were observed to be larger in the
CBMOP-solvent structure relative to
the CBMOP-desolvated structure.
Face indexing of a CBMOP-solvent
crystal was performed to determine
what faces were expressed. Figure
4.11 is a schematic representation of
the crystal habit of CBMOP; it
revealed that the (0 0 1) face was the
predominant crystal face. As shown in
Figure 4.12, the solvent channels run
roughly normal to this face. The solvent,
therefore, is likely to leave the crystal
through its largest face.
4.4. Desolvation/Resolvation of Bulk CBMOP Observed by Powder X-ray
Diffraction
Powder X-ray diffraction (PXRD) was employed to confirm that the desolvation
behavior occurred in the bulk material, and to determine if one could regenerate the
Figure 4.10. Changes in c-axis (top) and b-axis
(bottom) before and after desolvation. Green
points represent individual CBMOP∙solvent
crystals, except for labeled spot. The orange
points below the green points represent
CBMOP∙solvent crystals after desolvation
(CBMOP∙desolvated.
148
original CBMOP-solvent material by
resolvating the CBMOP-desolvated
material (i.e. suspend the material in
mother liquor). It was necessary to
calculate powder X-ray patterns from the
room temperature unit cell data for CBMOP-solvent (Figure 4.13 a-b) and CBMOP-
desolvated, (Figure 4.13 c); LAZY-PULVERIX,20
an X-SEED program interface,
was used to calculate the powder X-ray diffraction patterns. LAZY-PULVERIX was
also employed to broaden the narrow peaks in the calculated powder X-ray
diffraction patterns, to better match the broad peaks observed in powder X-ray
diffraction.
CBMOP-solvent was packed into an open capillary tube and allowed to
desolvate over a period of weeks. The PXRD patterns were obtained over time and
the resulting patterns were compared to the calculated powder patterns for CBMOP-
solvent and CBMOP-desolvated. The broadened theoretical pattern for CBMOP-
solvent (Figure 4.13.b) matched well with the experimental pattern for bulk
CBMOP-solvent (Figure 4.13.d), confirming that the bulk crystalline material
possesses the same structure as the single crystals. Furthermore, three reflections, the
(110), (220) and (221), could be uniquely assigned in the experimental pattern, as
Figure 4.11. Faces of crystal CBMOP.
149
Figure 4.12. Top: Spacefill representations of the single crystal structures of CBMOPsolvent
(top) and CBMOPdesolvated (bottom) as viewed down the [001] direction. The lattice solvent
molecules have been removed for clarity. Note that the channels collapse upon desolvation.
Bottom: Connolly surface plot of CBMOP-solvent as viewed normal to the [010] direction. The
dark blue highlighted areas are the channels observed above. The channels form a ladder-like
structure extending along the c-axis, and having rungs that run roughly along the a-axis.
150
these reflections were sufficiently distant from neighboring peaks to prevent
significant overlapping.
The calculated powder patterns for CBMOP-solvent and CBMOP-
desolvated predicted that the (110) and (220) reflections, as well as the diffraction
peak near 6.8 2θ, would shift to slightly lower 2θ values upon desolvation.
Experimentally this was confirmed, as seen in Figure 4.13.d-f, which showed that the
bulk material converted from CBMOP-solvent to CBMOP-desolvated over about 1
week in the capillary tube. However, after 22 days (Figure 4.13.h), the powder
pattern of the CBMOP-based material had broadened significantly, while
maintaining the same general features. This suggests that the material changes
beyond the single-crystal to single-crystal structural changes observed, but that the
same polymeric structure likely remains. Also, broadening of crystalline peaks may
indicate a reduction in crystallite size as a result of desolvation. The addition of
mother liquor to the highly desolvated material led to a complete restoration of the
solvated material, as evidenced by the powder diffraction pattern (Figure 4.13.j).
Thus, it appears that the initial stages of desolvation occur in a single crystal to single
crystal fashion, and this has been successfully characterized; however, the powder
diffraction data imply that even further desolvation occurs over the time frame of
days to weeks, resulting in fracture of the single crystals (See Figure 4.14 for model).
Though we were unable to structurally characterize the highly desolvated material,
the reversion to CBMOP-solvent upon addition of mother liquor after three weeks
151
suggests that the highly desolvated CBMOP structure is similar to CBMOP-
desolvated.
Figure 4.13. Calculated powder X-ray diffractograms were determined using the program
LAZY-PULVERIX and the single-crystal x-ray diffraction data for CBMOP-solvent and
CBMOP-desolvated. The room temperature unit cells for each material were used to more
accurately match the experimental data, which were collected at room temperature. The
powder x-ray diffraction (PXRD) experiment was performed on one open capillary tube of
CBMOP collected over time. Experimental partial powder X-ray diffractograms (PXRD) of
the desolvation process of CBMOP∙solvent. a) Calculated PXRD pattern using the unit cell
CBMOP∙solvent obtained at room temperature. b) Calculated PXRD pattern of
CBMOP∙solvent that has been arbitrarily broadened to more accurately reflect the peaks widths.
c) Calculated PXRD of CBMOP∙desolvated at room temperature. d) Experimental PXRD
pattern of CBMOP at t = 0. e) PXRD pattern of CBMOP at t = 1 day. f) PXRD pattern of
CBMOP at t = 6 days. g) PXRD pattern of CBMOP at t = 8 days. h) PXRD pattern of CBMOP
at t = 14 days. i) PXRD pattern of CBMOP at t = 22 days. j) Experimental PXRD pattern of the
material in (i) after moistening the material with mother liquor.
4.5. Gas Sorption Study on CBMOP-desolvated
Many coordination polymer-based materials have been shown to successfully
absorb gases21
due to their permanent porosity. We wanted to examine the
152
structurally flexible CBMOP-desolvated material to determine if this material would
exhibit some porous behavior and thus
adsorb gases.
In a collaborative effort with Robert
Fairchild and Susumu Kitagawa, synthesized
CBMOP-desolvated was tested for porosity
at Kyoto University using the FMS-BG (Bel
Inc.) automatic gravimetric absorption
measurement system.22
The CBMOP
material was heated to 80C for 5 hours
under high vacuum. The „empty‟ material was cooled to 77K and nitrogen gas
sorption was monitored gravimetrically. The data reveal a so-called Type X sorption
isotherm, indicating that the material does not possess permanent pores.
4.6. Synthesis of a Cryptophane-Dimer
Having found a synthetic protocol that successfully produced a single crystal of
a cryptophane-based MOF, attempts were made to modify this synthesis to produce a
multi-dimensional material. One modification included the addition of HNO3 to the
solution mixture. The result of acidification of the reaction medium was the slow
growth of dark blue crystals. X-ray analysis of these crystals revealed a metal-
organic cryptophane dimer, which was the first example of a metal-organic container
Figure 4.14. Proposed model of
desolvation of CBMOF over time.
153
molecule dimer with formula [Cu(H9py)(py)3]9DMF, hereafter CBD or container-
based dimer. The quality of this structure was relatively poor, but the data was
sufficient to locate the atoms of the cryptophane, as well as the metal cations and its
corresponding ligands. The cryptophane dimer can be described as an “incomplete
polymerization” in that one carboxylic acid remains protonated while two carboxylic
acids have been deprotonated and have coordinated with copper(II) cations. The
structure of this material explained the crystal‟s softness and instability in air (and in
heated mother liquor), as the material was molecular, not an infinite polymeric
material. Unlike the polymer CBMOF, CBD exhibits no single-crystal-to single-
crystal behavior.
While the dimeric CBD appears to be similar to that of polymer CBMOF, there
are significant differences in the coordination and in the connectivity about the
copper cations. The copper metal center in CBD was five-coordinate (T-Shaped),
with three ancillary pyridine ligands, rather than four and six-coordinate metal centers
of CBMOF (square planar and Jahn-Teller distorted octahedral), with two ancillary
pyridines (Figure 4.15). The carboxylates are also syn to one another (O4C-O3C-
O4A-O3A = 7.3), rather than anti or gauche as in CBMOF. The unreacted
protonated carboxylic acid groups hydrogen bond to a DMF lattice solvent molecule
(O3B-O12X = 2.56Å).
154
4.7. Conclusions
The first container-based polymers were synthesized and characterized
structurally. (±)-anti-H39 formed a linear 1-D polymer comprised of cryptophane
molecules that hydrogen bond to one another, while CBMOF was a bent 1-D
polymer comprised of cryptophane molecules that link through coordination via their
carboxylate moieties. CBMOF was found to retain its crystallinity upon partial
desolvation, and this single-crystal to single-crystal process was monitored by X-ray
crystallography (single crystal and powder). The unit cell shrinkage was monitored
in real time, revealing a deceleratory rate of cell shrinkage. The unit cell was found
to decrease by nearly 4% in volume, with minimal structural rearrangement. The
faces of the crystal were indexed, and solvent channels that lie perpendicular to the (0
0 1) face were shown to shrink upon desolvation. Both single crystal and powder x-
ray crystallography revealed that the single crystal to single crystal desolvation
observed is not complete; however, the completely desolvated CBMOF material
could not be structurally defined. The powder x-ray diffraction pattern taken after
several weeks suggested that the basic structural features remained intact at greater
levels of desolvation. Furthermore, the introduction of the highly desolvated powder
yielded an immediate return to the completely solvated CBMOF material. The
resolvation of a single crystal of CBMOF-desolvated caused the single crystal to
occlude and crack, meaning that while the resolvation was a bulk property, it was not
a single crystal to single crystal property.
155
4.8. Experimental
4.8.1. General Methods
All solvents and reagents were used without further purification. Uncorrected
melting points were performed on a Thomas Hoover capillary melting point
apparatus. Elemental analysis data were collected using a Perkin Elmer 2400 CHN
microanalyzer. Infrared spectroscopy was performed using a Perkin-Elmer Spectrum
One FTIR, scanning from 4500 cm-1
to 500 cm-1
. Powder X-ray diffraction was
obtained on a Rigaku RAPID powder diffractometer (CuKα) equipped with a curved
image plate area detector. Single crystal X-ray diffraction data was obtained on a
Bruker-AXIS SMART diffractometer (MoKα) at -100ºC unless explicitly stated.
Lattice parameters were determined from least-square analysis and the reflection data
was integrated using SAINT. Structures were solved using direct methods and
refined by full matrix least-squares based on F2 using X-SEED.
4.8.2. Synthesis of New Materials
CBMOP: (±)-Anti-H39 (103 mg, 0.082mmol) and Cu(NO3)22.5H2O (72 mg,
0.31mmol) were dissolved in 2:1DMF/MeOH (36mL) and pyridine (3.6mL). The
solution was heated to 110˚C for 13 hours in a Parr bomb. The solution was
subsequently cooled at 0.1˚C/min to 90˚C, and held at 90˚C for 1 hour. The solution
was further cooled at 0.1 ˚C/min to 60˚C, isothermed at 60˚C for 1 hour, then cooled
156
at 0.1˚C/min to 40˚C. Dark blue crystals were filtered and weighed (129 mg, yield =
90% (yield based on [Cu1.5((±)-9DMF)(C6H5N)3(MeOH)]∙2MeOH∙DMF per ASU
as estimated by SQUEEZE). Melting point and elemental analysis unable to be
determined due to the highly variable nature of the crystalline material. Powder X-
Ray diffraction of the bulk material possesses the same structure as that confirmed in
the single crystal determination.
CBD: (±)-Anti-H39 (1.5 mg, 0.0012 mmol) and Cu(NO3)22.5H2O (30.7 mg,
0.13 mmol) were dissolved in 2:1DMF/MeOH (1 mL) and pyridine (1 mL). After 11
days, an additional 0.6 mL of MeOH and 3 drops (0.1 mL) conc. HNO3 were added.
The solution was evaporated and dark blue crystals were observed. Mass, melting
point and elemental analysis were not determined due to the highly variable nature of
the crystalline material.
4.8.3. Crystal Structures
CBMOP-solvent: C94H89N6O20Cu1.5, Mr = 1690.08, 0.44 x 0.24 x 0.18 mm,
monoclinic, space group C2/c (no. 15), a = 52.87(1)Å, b = 16.102(3)Å, c =
23.170(4)Å, = 102.582(3). V = 19250(6)Å3, T = 173(2)K, Z = 8, calcd = 1.17
gcm3, Mo-K radiation, = 0.71073Å, 2max = 46, scans, 173(2)K, 38123 total
reflections, 13381 unique reflections, 8119 reflections with I2(I) (Rint = 0.062);
absorption correction SADABS (Tmin = 0.8435, Tmax = 0.9314, = 0.40 mm-1
),
157
structure solution using SHELXS, refinement (against F2) with SHELX-97-2,
1107 parameters, 0 restraints, H atoms placed in calculated positions and refined with
a riding model, R1 = 0.0692 (I2(I)) and wR2 = 0.2037 (all data), residual electron
density max/min = 0.69/-0.66 e-/Å
3, GOF = 0.971. Disordered solvent molecules
were modeled using the SQUEEZE subroutine of the program PLATON,[1]
which
estimates the solvent accessible volume is 3880 Å3
to be occupied by 573 electrons
per unit cell (calculated 2 MeOH molecules and 1 DMF molecule).
CBMOP-desolvated: C94H89N4O24Cu1.5, Mr = 1712.08, 0.36 x 0.18 x 0.14
mm, monoclinic, space group C2/c (no.15), a = 53.319(6)Å, b = 15.912(2)Å, c =
22.444(2)Å, = 102.719(2). V = 18574(3) Å3, T = 173(2)K, Z = 8, calcd = 1.22
gcm-3
, Mo-K radiation, = 0.71073Å, 2max = 44.2, scans, 173(2)K, 51526 total
reflections, 11482 unique reflections, 4551 reflections with I2(I) (Rint = 0.1090);
absorption correction SADABS (Tmin = 0.8647, Tmax = 0.9441, = 0.42 mm-1
),
structure solution using SHELXS, refinement (against F2) with SHELX-97-2, 977
parameters, 4 restraints, H atoms placed in calculated positions and refined with a
riding model, R1 = 0.1090 (I2(I)) and wR2 = 0.3301 (all data), residual electron
density max/min = 0.75/-0.42 e-/Å
3, GOF = 0.938. The high values of the merging
and final R factor values are attributed to the degradation of the crystal as a result of
the desolvation process, or as a result of greater molecular motion as the remaining
species attempt to fill space. It was impossible to model the remaining disordered
158
solvent; SQUEEZE analysis reveals the solvent-accessible volume to be 2994 Å3
which is occupied by 397 electrons (calculated. 1DMF and 0.5 MeOH molecules).
The program X-SEED[2]
was used as a graphical interface to SHELX and for the
generation of figures.
CBD: C94H89N6O20Cu1.5, Mr = 1690.08, 0.44 x 0.24 x 0.18 mm, triclinic,
space group P-1 (no. 2), a = 14.03(1)Å, b = 16.42(1)Å, c = 26.75(2)Å, = 99.90(2),
= 92.40(2), = 108.54(2). V = 5726()Å3, T = 173(2)K, Z = 2, calcd = 1.28 gcm
-3,
Mo-K radiation, = 0.71073Å, 2max = 44, scans, 173(2)K, ___ total reflections,
13799 unique reflections, 4031 reflections with I2(I) (Rint = 0.115); absorption
correction SADABS (Tmin = ___, Tmax = ___, = 0.27 mm-1
), structure solution using
SHELXS, refinement (against F2) with SHELX-97-2, 512 parameters, 0 restraints,
H atoms placed in calculated positions and refined with a riding model, R1 = 0.118
(I2(I)) and wR2 = 0.300 (all data), residual electron density max/min = 1.36/-1.28e
-
/Å3, GOF = ___. Disordered solvent molecules were modeled using the SQUEEZE
subroutine of the program PLATON,[1]
which estimates the solvent accessible
volume is 2170 Å3
to be occupied by 708 electrons per unit cell (calculated 18 DMF
molecules per unit cell). The poor quality of this dataset was a consequence of the
large number of lattice solvent molecules, which comprise approximately 23% of the
crystal‟s mass. This crystal is relatively unstable, even to temperature increases in
the mother liquor, which cause the crystals to crack and blacken.
159
4.8.4. Unit Cell Analysis over time
Crystals were removed from the mother liquor and quickly placed into the
cold temperature stream (-100C) and centered. The crystals were indexed at the low
temperature, and then removed from the cold temperature stream for a period of time.
The crystals were then reintroduced to the cold temperature stream, recentered and
reindexed. The total unit cell volumes are plotted with respect to the total amount of
time that the crystals were exposed to room temperature conditions. Note that the
rate of volume change is greatest initially; this deceleratory rate change is common in
solid-state desolvation processes.
160
4.9 References
1. (a) Atwood, J. L.; Barbour, L. J.; Jerga, A.; Schottel, B. L. Science, 2002,
298, 1000-1002. (b) Dobrzanska, L.; Lloyd, G. O.; Raubenheimer, H. G.;
Barbour, L. J. J. Am. Chem. Soc. 2006, 128, 698-699.
2. (a) Barbour, L, J. Aust. J. Chem. 2006, 59, 595-596. (b) Halder, G. J.;
Kepert, C. J. Aust. J. Chem. 2006, 59, 597-604. (c) Suh, M. P.; Cheon, Y.
E. Aust. J. Chem. 2006, 59, 605-612. (d) Friscic, T.; MacGillivray, L. R.
Aust. J. Chem. 2006, 59, 613-616. Wang, Z.; Zhang, Y.; Kurmoo, M.; Liu,
T.; Vilminot, S.; Zhao, B.; Gao, S. Aust. J. Chem. 2006, 59, 617-628.
3. (a) Matsuda, R.; Kitaura, R.; Kitagawa, S.; Kubota, Y.; Belosludov, R. V.;
Kobayashi, T. C.; Sakamoto, H.; Chiba, T.; Takata, M.; Kawazoe, Y.; Mita,
Y. Nature, 2005, 436, 238-241.
4. (a) Te, R. L.; Griesser, U. J.; Morris, K. R.; Byrn, S. R.; Stowell, J. G. Cryst.
Growth. Des. 2003, 3, 997-1004. (b) Wei, Q.; Nieuwenhuyzen, M.; Meunier,
F.; Hardacre, C.; James, S. L. Dalton Trans. 2004, 1807-1811.
5. (a) Zhang, J.-P.; Lin, Y.-Y.; Zhang, W.-X.; Chen, X.-M. J. Am. Chem. Soc.
2005, 127, 14162-14163. (b) Maji, T. K.; Mostafa, G.; Matsuda, R.;
Kitagawa, S. J. Am. Chem. Soc. 2005, 127, 17152-17153.
6. Irngartinger, H.; Skipinski, M. Tetrahedron, 2000, 56, 6781-6794.
161
7 . (a) Kim, J. H.; Lindeman, S. V.; Kochi, J. K. J. Am. Chem. Soc. 2001, 123,
4951-4959. (b) Toh, N. L.; Nagarathinam, M.; Vittal, J. J. Angew. Chem.,
Int. Ed. 2005, 44, 2237-2241. (c) Devic, T.; Batail, P.; Avarari, N. Chem.
Commun. 2004, 1538-1539. (d) Armentano, D.; De Munno, G.;
Mastropietro, T. F.; Julve, M.; Lloret, F. J. Am. Chem. Soc. 2005, 127,
10778-10779.
8. Suh, M. P.; Ko, J. W.; Choi, H. J. J. Am. Chem. Soc. 2002, 124, 10976-
10977.
9. Saied, O.; Maris, T.; Wuest, J. D. J. Am. Chem. Soc. 2003, 125, 14956-
14957.
10. (a) Biradha, K.; Fujita, M. Angew. Chem., Int. Ed. 2002, 41, 3392-3394. (b)
Biradha, K.; Hongo, Y.; Fujita, M. Angew. Chem., Int. Ed. 2002, 41, 3395-
3398. (c) Ananchenko, G. S.; Udachin, K. A.; Dubes, A.; Ripmeester, J. A.;
Perrier, T.; Coleman, A. W. Angew. Chem., Int. Ed. 2006, 45, 1585-1588.
(d) Ohmori, O.; Kawano, M.; Fujita, M. J. Am. Chem. Soc. 2004, 126,
16292-16293.
11. Schmidt, G. M. J. Pure Appl. Chem. 1971, 27, 647-678.
12. Schmidt, G. M. J.; Cohen, M. D. J. Chem. Soc. 1964, 1996.
13. (a) Ramamurthy, V.; Venkatesan, K. Chem. Rev. 1987, 87, 433-481. (b)
Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025-1074.
162
14. (a) Suzuki, T.; Fukushima, T.; Yamashita, Y.; Miyashi, T. J. Am. Chem. Soc.
1994, 116, 2793-2803. (b) Varshney, D. B.; Papaefstathiou, G. S.;
MacGillivray, L. R. Chem. Commun. 2002, 1964-1965. (c) Takahashi, S.;
Miura, H.; Kasai, H.; Okada, S.; Oikawa, H.; Nakanishi, H. J. Am. Chem.
Soc. 2002, 124, 10944-10945.
15. Hoang, T.; Lauher, J. W.; Fowler, F. W. J. Am. Chem. Soc. 2002, 124,
10656-10657.
16. An ISI Web of Knowledge search for “single-crystal to single-crystal”
processes yielded 4 matches between 1980 and 1990, and 59 matches in 2010
alone.
17. Dunitz, J. D.; Schomaker, V.; Trueblood, K. N. J. Phys. Chem. 1988, 92,
856.
18. Van Der Sluis, P.; Spek, A. L. Acta Crystallogr. Sect. A. 1990, 46, 194-201.
19. Brown, M. E. Introduction to Thermal Analysis: Techniques and
Applications, Chapman and Hall, London, 1988.
20. LAZY PULVERIX is a computer program designed to calculate x-ray and
neutron powder diffraction patterns from single-crystal x-ray and neutron
data. Yvon, K.; Jeitschko, W.; Parthe‟, E. J. Appl. Cryst. 1977, 10, 73-74.
21. (a) Rowsell, J. L. C.; Spencer, E. C.; Eckert, J.; Howard, J. A. K.; Yaghi, O.
M. Science, 2005, 305, 1350-1354. (b) Kepert, C. J.; Rosseinsky, M. J.
163
Chem. Commun. 1999, 375-376. (c) Li, H.; Eddaoudi, M.; O‟Keeffe, M.;
Yaghi, O. M. Nature, 1999, 402, 276-279.
22. Kitaura, R.; Seki, K.; Akiyama, G.; Kitagawa, S. Angew. Chem., Int. Ed.
2003, 42, 428-431.
164
CHAPTER 5: SOLID-STATE KINETICS OF SUPRAMOLECULAR HOST-
GUEST CLATHRATES
5.1. Introduction: Solid-State Kinetics
The concept of solid-state kinetics seems to be a contradiction in terms. Most
chemists are accustomed to thinking about kinetics in the gas-phase or in solution;
this can be attributed to several factors. First, the Arrhenius equation (k = Aexp(-Ea/
RT) was derived empirically, and found to best fit reactions occurring in the gas
phase and in solution.1 Even today, the Arrhenius equation is often used to report
kinetic data in terms of activation energy (Ea) and frequency factor (log A). Henry
Eyring expounded upon Arrhenius’s work, and found a relation between Arrhenius’
empirical variables and more meaningful thermodynamic quantities (Ea = ΔH‡
+ RT;
ln A ΔS‡).2 The Eyring equation (k = (kBT/h)*exp(-∆H
‡/RT)*exp(-∆S
‡/R)) allows
for direct calculation of these useful parameters, which consequently allows for the
determination of ΔG‡ at any temperature.
3 Furthermore, Eyring related these kinetic
parameters to transition state theory, meaning that the Eyring equation is a theoretical
construct rather than and not an empirical model. The Eyring equation is the
accepted means to study gas, solution-based, and mixed-phase reactions. It is crucial
to note that neither of these theories describes kinetics specifically in the solid-state,
and that both models are geared toward systems with far more mobile reactants that
are not limited in their ability to achieve a specific transition state. The Arrhenius
and Eyring models are often taught to students in General Chemistry or Physical
165
Chemistry; however, kinetic study of solid-state processes is rarely discussed, even in
graduate level study.
Nonetheless, solid-state reactions and thermal processes can and do occur; a
single-crystal to single-crystal desolvation was described in Chapter 4. Reactions
also occur in polycrystalline and amorphous solids. Several important nonacademic
examples of solid state reactions include the dehydration of important materials such
as borax4 and carbamazepine dehydrate,
5 determining the activation energy to the
reactions of high energy materials,6 solid state polymerization,
7 and even cooking.
8
These reactions occur in a fairly reproducible fashion which implies that they are
following a reaction coordinate that is similar to reactions in solution. It is this belief
that has led solid-state scientists to study solid-state kinetics; however, there is a great
deal of debate in the literature as to the applicability of activation energy (and by
association ΔH‡
and ΔS‡) to solid state reactions,
9 because conditions in the solid
state do not allow reaction collisions to occur as in solution or in the gas phase.
Unlike solution kinetic studies, which often rely on spectroscopic methods,
reactions in the solid state are often monitored using either calorimetric or
gravimetric instrumentation.10
Thermogravimetric analysis (TGA) is an attractive
instrument for monitoring all processes that involve a mass change (dehydration,
desolvation), while differential scanning calorimetry (DSC) can be used to evaluate
and quantitate the heat-flow associated with solid-state processes. These instruments
measure changes in mass (TGA) and heat flow (DSC) as a function of temperature
166
and time.11
In these experiments, the fractional extent of a solid state reaction () can
be measured against both variables, which has consequences on the kinetic
experiments performed. Two main approaches have been developed to deal with
these three variable experiments: isothermal and nonisothermal (or dynamic)
methods.12
In isothermal kinetics, various techniques are used to measure the variable ,
which is defined as the extent of the reaction and varies from 0 to 1. In isothermal
TGA experiments, one initially calculates in gravimetric experiments by
determining the mass change at time n and dividing by the total mass change. Alpha,
in turn, is fitted to various models (Table 5.1) that have been derived from observed
crystallization processes.13
The experimentally determined alpha is inserted into the
integral form of the equations given in Table 5.1, and each equation is plotted as a
function of time. The best-fit line is calculated for each model, and the linearity of
Table 5.1. Solid-state rate expressions for several reaction models.
Model Integral Form
g(α) = kt
Differential Form
f(α) = 1/k dα/dt
Zero-Order (R1) α 1
Contracting Area (R2) [1-(1- α)1/2
] 2(1- α)1/2
Contracting Volume (R3) [1-(1- α)1/3
] 3(1- α)2/3
1-D Diffusion (D1) α 2
1/2α
2-D Diffusion (D2) [(1- α)ln(1- α)] + α [-ln(1- α)]-1
3-D Diffusion-Jander (D3) [1-[(1- α)1/3
]2 [3(1- α)
2/3]/
[2(1-(1- α)1/3
)]
3-D Diffusion-Ginstiling-Brounshtein (D4) 1-(2α/3)-(1-α)2/3
3/[2((1-α)-1/3
-1)]
Avarami-Erofeyev (A2) [-ln(1-α)]1/2
2(1-α)[-ln(1-α)]1/2
Avarami-Erofeyev (A3) [-ln(1-α)]1/3
3(1-α)[-ln(1-α)] 2/3
Avarami-Erofeyev (A4) [-ln(1-α)]1/4
4(1-α)[-ln(1-α)]3/4
First-order (F1) [-ln(1-α)] (1-α)]
167
each plot is statistically evaluated. The model that gives the most linear curve is
detetrmined to be the most appropriate kinetic model, and the slope of its best-fit line
represents the rate constant k. The determination of the rate constant at several
temperatures allows for the calculation of Arrhenius or Eyring activation parameters,
by plotting ln k vs. 1/T or ln (k/T) vs. 1/T respectively. This type of experiment is
more familiar to scientists, as solution kinetics studies are usually performed as a
series of isothermal experiments. Isothermal kinetics studies are considered to be
more accurate, but are often time-consuming.14
Nonisothermal kinetics experiments measure as a function of time and
temperature in a single experiment by heating the sample. The most common
nonisothermal kinetic experiments are performed at a constant rate, and
nonisothermal experiments have the general advantage of short experiment time as
compared to isothermal experiments. Nonisothermal experiments may use the
differential form of the models given in Table 5.1 to calculate the rate constant k.
There are additional nonisothermal models (Ozawa (OFW)15
, Kissinger,16
and Coats
and Redfern17
) given in Table 5.2, which monitor the rate of change of alpha or peak
temperature as a function of heating rate.18
Table 5.2. Nonisothermal kinetic models
β = heating rate. α = extent of reaction. Tmax = peak temperature.
Model Plot Slope
Ozawa ln β vs. 1/Tmax Ea/R
Kissinger ln( β/T2
max) vs. 1/Tmax Ea/R
Coats and Redfern ln[1-(1-α)1-n
/T2(1-n)] vs. 1/T -Ea/R
168
5.2. Desolvation of Host-Guest Systems
Supramolecular chemists, in general, have a keen interest in identifying and
quantifying intermolecular interactions. The crystalline solid state, due to its close
packed nature, can be viewed as a supramolecular entity.19
Molecular crystals offer
an interesting environment in which to study the interplay of intermolecular
interactions. One means to study this is through the examination of host-guest
structures, where the host is defined as a large, stable organic molecule which has
functionality that allows for intermolecular interaction. In these systems, the guest is
usually a small molecule, normally a solvent molecule or other volatile species,
which cocrystallizes with the host molecule. While stable at low temperatures, the
guest molecules can be driven off at higher temperatures.
Constrictive binding in container molecules has been established in solution
studies; however, constrictive binding kinetic studies in the solid-state have not been
reported for this class of host-guest crystalline molecular materials. However, there
have been studies on related clathrate inclusion materials. Luigi Nassembini has
studied the desolvation kinetics in a number of simple host-guest inclusion
compounds, as described in “Physicochemical Aspects of Host-Guest Compounds.”20
In one example, Nassembini described the removal of volatiles, including THF,
DMSO, and acetone, from binapthol-solvent clathrate materials.21
In another paper,
Nassembini compared and contrasted the structures and activation parameters of
xanthenol clathrates (Figure 5.1).22
Similarly, this chapter explores the desolvation
169
kinetics of THF in a
simple host-guest
clathrate system, in
which the host
(cyclotriveratrylene, or
CTV) is structurally
similar to a
cryptophane CTB
subunit. The kinetics of CTVTHF0.5 is examined and compared to the desolvation
kinetics of a cryptophane inclusion material (±)-anti-8THF. This specific
cryptophane inclusion material was chosen because it contained no THF in the lattice,
which could convolute the data interpretation.
5.3. Isothermal TGA Analysis of CTVTHF0.5
Cyclotriveratrylene (CTV) is a C3v symmetric cavitand derived from the acid
condensation of veratrole (1,2 dimethoxybenzene) and formaldehyde.23
The CTV
molecular scaffold has been modified by chemists to form pyramidic liquid crystals,24
larger molecular polyhedra25
and CTV coordination polymers,26
neutral molecule and
anion inclusion complexes,27
hemicryptophanes28
and cryptophanes by metal
coordination,29
iron-sulfur clusters,30
and amino acid glycoconjugates.31
CTV is a
classic inclusion host that forms stoichiometric clathrates when crystallized with
Figure 5.1. Series of xanthenol clathrates studied to relate structure
and desolvation kinetics.
170
many small molecules, including
water,32
benzene and water,33
THF,
ethyl acetate, benzene, and other
small molecules.34
This behavior has
been well characterized by single
crystal diffraction. It was found that
CTV packing was influenced by the
nature of the included solvent
molecules. Solvents that are hydrogen bond donor induced CTV to pack in
columnar, cup-in-cup stacks in which the donor hydrogen bonds to CTV oxygens.
This is the so-called α-phase. (Figure 5.2).35
The β-phase is induced by
crystallization of CTV with solvents that do not have hydrogen bond donor functional
groups. The most important structural feature that results from the differing α and β
forms is that the β form shows out-of-plane methoxy groups, while the α form has in-
plane methoxy groups.
CTV(THF)0.5 crystallizes in the β form, as THF has no hydrogen bond donors.
The structure of this clathrate is given in Figure 5.2. The oxygen atom of the THF
guest molecule appears to weakly hydrogen bond with a CTV methoxy substituent,
with a C-H…
O = 3.55 and 3.69Å. As a consequence of the structure, it was expected
that the THF molecules would be somewhat stable to desolvation.
Figure 5.2. Crystal structure of CTV0.5THF.
CTV molecules shown in stick, THF molecules
shown in spacefill form.
171
Figure 5.3. Nonisothermal TGA experiments of CTVTHF0.5 as a function of alpha (extent of
desolvation) at 5C/min and 10/min.
Initially, nonisothermal TGA experiments on CTV(THF)0.5 were performed to
determine the temperature range over which desolvation typically occurs. Figure 5.3
shows the results of two experiments, performed at 5 and 10C/min respectively.
There appears to be a two stage diffusion mechanism: an early stage desolvation that
is first observed at approximately 50C and a late stage desolvation that begins at
approximately 115C. Nonisothermal TGA of the CTV(THF)0.5 sample shows that a
gradual mass loss corresponding to the early stage desolvation was observed over a
50-60C (320K-380K) temperature range. However, the nonisothermal TGA of the
late stage desolvation was completed over a range of approximately 20C (380K-
400K). The early stage was not investigated with regard to desolvation
172
kinetics, as it only represented a small fraction of the entire thermal event, as
evidenced by the TGA and DSC data (α range <0.25). The later stage desolvation,
which was also monitored by DSC data, was thoroughly studied by isothermal TGA.
Freshly filtered and air dried
samples were crushed lightly
(particle size ~ 0.3-0.7 mm) and
placed on the TGA pan, and
isothermally heated at appropriate
temperatures. As the
CTV(THF)0.5 sample reached the
isothermal temperature, the
material progressed through the
early stage desolvation transition.
Once the isothermal temperature
had been achieved, the material
was held at the prescribed
temperature overnight or until the
mass loss was complete. Figure
5.4 (top) shows the isothermal
mass losses over time for a sample of CTVTHF0.5 held at various temperatures
Figure 5.4. Top: Plot of alpha vs. time for an isothermal
TGA experiment for the desolvation of CTVTHF0.5 at
96.2 C. Bottom: Isothermal TGA data after application
of the three-dimensional diffusion model for the
desolvation of CTVTHF0.5C.
173
(86C-106C), in which the mass loss data is converted to alpha, and plotted vs. time.
Alpha is also fit to the major functions described in Table 5.1, and plotted in Figure
5.4 (bottom). Analysis of each of these functions revealed that the isothermal kinetic
data best fit with the D3 model, which is the three-dimensional diffusion model for
desolvation (Figure 5.4, bottom). The rate
constant derived from the isothermal
experiments was calculated at various
temperatures, and both the Arrhenius and
the Eyring equations were plotted, and the
Eyring plot is given in Figure 5.5. From
the Arrhenius plot, the experimentally
derived activation energy was found to be
62 kcal/mol and the experimentally
derived frequency factor was 2.3 x 1033
. The values for these data were rather large,
and seemed to indicate an unfathomably high barrier to activation. When these
numbers were converted to enthalpy, entropy and free energy of activation, the
corresponding activation enthalpy and entropy were still very large (∆H‡
= 61(2)
kcal/mol, ∆S‡ = 84(6) cal/molK); however, the Gibbs free energy of activation for the
desolvation was determined to be 36 kcal/mol at 298K and 28 kcal/mol at 398K. The
free energy of activation revealed that the large enthalpic contribution to the
activation barrier was tempered by the highly positive activation entropy.
Figure 5.5. Eyring plot of desolvation of
CTVTHF0.5 derived from isothermal TGA
data.
174
5.4. Nonisothermal Kinetic Analysis of CTVTHF0.5
One goal of this study was to compare isothermal and nonisothermal
methodology to determine if they give similar values. Two major instruments are
used in nonisothermal solid-state kinetics: DSC and TGA. Since nonisothermal
TGA of CTVTHF0.5 appeared to have two distinct mass losses, this method was not
chosen. Nonisothermal calorimetric analyses of CTVTHF0.5 were simpler to
interpret, as only one endothermic peak was found. Varying the heating rate from
1C/min to 20C/min resulted in maxima in endothermic heat flow ranging from
96C to 112C, respectively. Figure 5.6 reveals an overlay of DSC traces for
CTVTHF0.5 for all temperature ramps (1, 2.5, 5, 10, and 20C/min). As
expected, the desolvation temperature increases with increasing heating rate
(hereafter ). An Ozawa plot was generated (ln vs. 1/T) to analyze the DSC data
(Figure 5.7). The derived slope is defined as -Ea/R; the corresponding activation
energy was calculated to be 58 kcal/mol. The intercept of the Ozawa plot
corresponds to lnA, such that the frequency factor A = 1.7 x 1034
. Since the
Arrhenius parameters are related mathematically to the Eyring parameters, we can
calculate ∆H‡ and ∆S
‡. (∆H
‡ = 57(2) kcal/mol; ∆S‡ = 96(6) cal/molK) Statistically,
the experimentally determined values were similar in the isothermal and
175
Figure 5.6. DSC overlay of desolvation of CTVTHF0.5 at varying heating rates.
nonisothermal experimental determinations of ∆H‡
(57(2) kcal/mol vs. 61(2) kcal/mol
respectively)
and ∆S‡
(96(6) cal/molK vs. 84(6)cal/molK respectively). The
agreement between the two sets of data lends credibility to the experimentally
determined values.
5.5. Nonisothermal DSC Analysis of (±)-anti-8THF
One goal of this experiment was to compare the desolvation kinetics of a
container-based material (cryptophanes) wherein the guest in encapsulated with a
176
simple clathrate (CTV).
However, study of most
cryptophane materials was
complicated by the fact that
most cryptophane-based
materials possess both lattice-
included and encapsulated
solvents, which severely
complicate the desolvation kinetics. In fact, this behavior was clearly observed and
reported in Chapter 3, Figure 3.3 for (±)-anti-4THF3THF, where it was observed
that the 1st three THF equivalents are lost from the material at a much lower
temperature (<120C) than the last equivalent (>120C). Fortunately, cryptophane
(±)-anti-8THF was found to form a 1:1 complex with THF (Figure 5.8). The
structure clearly shows
encapsulation of THF within the
cryptophane cavity.
Since isothermal and
nonisothermal results for the
CTVTHF0.5 clathrate were
statistically identical,
Figure 5.7. Ozawa plot derived from nonisothermal DSC
experiments for the desolvation of CTVTHF0.5 at various
heating rates (1-20C/min).
Figure 5.8. Stucture of (±)-anti-8THF. Left: Side
view of complex. Right: Top view of complex.
Carbon: Gray; Oxygen: Red; Hydrogen: White.
177
nonisothermal desolvation kinetics for (±)-anti-8THF were performed by DSC.
Figure 5.9 shows the overlay of DSC endotherms at a wide range of heating ramps
(1, 2.5, 5, 10, 20C/min). A comparison of the DSC desolvation endotherms for
the CTVTHF0.5 (Figure 5.6) and (±)-anti-8THF (Figure 5.9) shows significant
differences upon examination. The shapes of the endothermic peaks are quite
symmetric and sharp in the CTV desolvation, while the peaks are broad and
asymmetric in the cryptophane desolvation. In general, the shape of the DSC
endothermic peak may be a consequence of the “order” of the reaction, according to
Kissinger.16
Certainly, the shape of the curve has consequences in data analysis, as it
can be difficult to identify the temperature of maximum endothermic heat flow.
Also, the range of temperatures associated with desolvation is much larger in the
cryptophane (84C-
135C) as compared to
the CTV (96C-112C).
An Ozawa plot
was generated from the
DSC data for
desolvation of (±)-anti-
8THF (Figure 5.10).
It became immediately Figure 5.9. DSC overlay of desolvation of (±)-anti-8THF at
varying heating rates.
178
apparent that the slope and intercept of this Ozawa curve were much smaller than in
Ozawa plot for CTVTHF0.5 (Figure 5.5). The calculated activation energy, Ea, was
15(2) kcal/mol and the frequency factor log A is 9(1). This result was surprising, as it
indicates that the kinetic
barrier to desolvation was
larger in the CTV inclusion
compound of THF as
compared to the (±)-anti-
8THF encapsulation
complex. When the data for
(±)-anti-8 was converted to
∆H‡
and ∆S‡, we found that ∆S
‡ was negative (-17 cal/molK). This implies that the
rate limiting step is the squeezing of the guest from the cryptophane. Also, as the
temperature increases, the barrier to desolvation also increases. In fact, the seemingly
disparate activation parameters result in statistically identical ∆G‡
at 100C when
comparing the two DSC experiments (Table 5.3).
Table 5.3 Activation parameters for desolvation of CTV·THF0.5 and (±)-anti-8THF.
∆H
‡
(kcal/mol)
∆S‡
(cal/molK)
∆G‡
298
(kcal/mol)
∆G‡
373
(kcal/mol)
CTV (TGA) 61(2) 84(6) 36(3) 30(3)
CTV (DSC) 57(2) 96(6) 28(3) 21(3)
(±)-anti-8 (DSC) 14(1) -17(4) 19(2) 20(2)
Figure 5.10. Ozawa plot derived from nonisothermal DSC
data for the desolvation of (±)-anti-8THF.
179
5.6. Discussion of Activation Parameters
CTVTHF0.5 desolvation is characterized by a very large activation enthalpy,
as well as a largely positive activation entropy. This data suggests that the transition
state is highly disordered with respect to the ground state, while (±)-anti-8THF
desolvation has a relatively small activation enthalpy, but a negative activation
entropy. The transition state for (±)-anti-8THF is more ordered than the ground
state, which may be explained in this system as a disordered guest squeezing through
a highly oriented host molecule to exit. Despite these differences, the two materials
have similar activation free energy of desolvation (∆G‡). We were surprised that the
container effect did not seem to have a significant effect on the activation free energy
of the desolvation of the cryptophane material. One explanation might be that the
encapsulated THF molecules can exit the molecule easily, as seen from the side view
in Figure 5.8. Compare that with the structure of (±)-anti-4THF, in which the
cryptophane appears to more effectively encapsulate the guest (Figure 5.11). Another
explanation may be that molecular
implosion described in Chapter 3 is the
rate-limiting step, and that this perturbation
in the solid-state causes the crystal to
degrade and desolvate. A more
comprehensive study of CTV and Figure 5.11. Side view of (±)-anti-4THF
complex.
180
cryptophane clathrates may be useful in determining if there is a single rate-limiting
step that defines the desolvation of these materials.
5.7. Conclusions
The solid-state kinetics of desolvation were studied in two systems:
CTVTHF0.5 and (±)-anti-8THF. CTVTHF0.5 was analyzed using both isothermal
TGA as well as nonisothermal DSC techniques. The results for ∆H‡
and ∆S‡ were
statistically the same for the two different techniques. (±)-anti-8THF was analyzed
using nonisothermal DSC as well. While the values of ∆H‡
and ∆S‡
were very
different for the two systems, their values for ∆G‡
373 calculated from the DSC
experiments were statistically similar. The so-called “container effect” did not
seemingly enhance the stability of (±)-anti-8THF in the solid-state; however, its
structure may be sufficiently open to allow egress of the THF moiety. Another
theory is that the conversion of CTB to saddle twist in the solid-state is the rate-
limiting step in desolvation of these materials. Further study may help elucidate if
there is a common mechanism to desolvation.
5.8. Experimental
5.8.1. General Methods
All solvents and reagents were used without further purification
181
Thermogravimetric analyses were performed using a TA Instruments TGA 2050
under a constant stream of nitrogen gas. Differential Scanning Calorimetry was
performed using a TA Instruments DSC
5.8.2. Sample Preparation
Clathrate samples (CTVTHF0.5, 8THF) were prepared by dissolving
material in THF and placing in the freezer. The materials were removed from the
freezer and the crystals were vacuum filtered before thermal analysis. The crystals
were air dried for approximately 5 minutes before thermal analysis to remove surface
solvent molecules.
For DSC experiments, between 1 mg and 10 mg of material were weighed in
a DSC pan, which was immediately sealed and vented with a pinhole through the lid.
The material was immediately run on the DSC instrument at heating rates ranging
from 1C to 20C/min. The endothermic transition was plotted, and the temperature
corresponding to the maximum endothermic heat flow was recorded.
For isothermal TGA experiments, between 1 mg and 10 mg of material was
placed on a tared TGA pan. The material was ramped to the appropriate temperature
and held isothermally. The mass loss was plotted relative to time at a given
temperature, which was used to generate an alpha vs. time plot.
182
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