m.sc. thesis mk - november 15, 2011
TRANSCRIPT
Sterically Demanding Ethylenediamines and Polyamines for theStabilization of Main Group Elements in Low Coordination Numbers
by
Michael Krause
A Thesispresented to
The University of Guelph
In partial fulfillment of requirementsfor the degree of
Master of Sciencein
Chemistry
Guelph, Ontario, Canada
! Michael Krause, November, 2011
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ABSTRACT
STERICALLY DEMANDING ETHYLENEDIAMINES AND POLYAMINES FOR THESTABILIZATION OF MAIN GROUP ELEMENTS IN LOW COORDINATION NUMBERS
Michael KrauseUniversity of Guelph, 2011
Advisor:Prof. Dr. Michael K. Denk
This thesis explores the reaction of primary amines with 1,2-dibromoethane and
1,3-dibromopropane as a one step synthesis of N,N"-disubstituted ethylenediamines, R-
NH-CH2CH2-NH-R, N,N"-disubstituted propanediamines, R-NH-CH2CH2CH2-NH-R and
N-substituted azetidines RN[(CH2)3]. Unlike earlier approaches in the literature, this
method circumvents the use of the highly toxic #-haloamines.
The reaction can also be a convenient approach to N,N",N""-trisubstituted
diethylenetriamines which form as byproducts in the synthesis of the ethylenediamines
and are readily separated by distillation. The respective propylenetriamines were
obtained in analogous fashion from 1,3-dibromopropane. The use of N,Nʼ,N”-
trisubstituted triamines for the stabilization of low valent main group compounds was
exemplified through the synthesis and structural characterization of a phosphenium salt.
N,N'-disubstituted ethylenediamines, R-NH-CH2CH2-NH-R" bearing different
substituents R are difficult to obtain and require multi-step protocols. This thesis
describes their one step synthesis from aziridines and primary amines. The analogous
1,3-propandiamines were obtained from primary amines and azetidines.
N- tert-Butylimidazol was obtained through thermolysis of 1,3-di-tert-
butylimidazolium chloride and used as precursor for bis carbenes.
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Acknowledgements
I have been very fortunate to have had the opportunity to study chemistry
under the supervision of Dr. Michael K. Denk during my graduate years at
University of Guelph. My studies explored the art of inert atmosphere chemistry,
synthesis, and distillation of air and moisture sensitive compounds. Through his
inspiration I expanded my enthusiasm and knowledge for chemistry and owe Dr.
Denk my gratitude and highest respect.
Dr. Kathryn Preuss, Dr. Marcel Schlaf, Dr. Adrian Schwan, Dr. Dmitriy
Soldatov, and Dr. Dan Thomas also deserve a word of thanks for their guidance
and helpful advice throughout my chemistry training.
I want to acknowledge all of my lab mates past and present, who made
every day in the lab a rewarding experience through the many challenging
discussions we held. I especially need to recognize Jeff Hastie and Feng Lan
Zheng for the exciting experiments we conducted, and Dr. Debyani Niyogi for
teaching me the operation of the NMR and GC-MS equipment.
Case Gielen and Yves Savoret, the most talented machinist and
glassblower I know, respectively, deserve my gratitude for not only keeping our
lab running efficiently, but for expanding my knowledge about their fields.
My family has been amazing; without them I wouldnʼt have made it this far.
My mother and father have been such an inspiration to me; I canʼt thank them
enough for all the support they have shown me. That will be with me for the rest
of my life.
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Table of Contents
Chapter 1 – Introduction and Background … … … … … … … … … … … 1
1.1. Synthetic Overview … … … … … … … … … … … … … … … … … 2
1.2. Motivation … … … … … … … … … … … … … … … … … … … … … 5
1.3. Carbenes … … … … … … … … … … … … … … … … … … … … … 6
1.3.1. Singlet and Triplet Carbenes … … … … … … … … … … … 8
1.3.2. Stabilization of Carbenes … … … … … … … … … … … … … 11
1.3.2.1. Steric Effects … … … … … … … … … … … … … … 11
1.3.2.2. Electronic Effects … … … … … … … … … … … … 14
1.3.3. Synthesis of Diaminocarbenes … … … … … … … … … … … 18
1.3.3.1. Deprotonation of Imidazolium Salts … … … … … … 18
1.3.3.2. Reduction of Thioureas … … … … … … … … … … 22
1.3.3.3. Diaminocarbenes from Thermal Elimination ... ... ... … 23
1.3.4. Reactivity of Diaminocarbenes … … … … … … … … … … … 24
1.3.4.1. Dimerization … … … … … … … … … … … … … … 24
1.3.4.2. Reactions with Common Molecules … … … … … … 28
1.4. Ethylenediamine … … … … … … … … … … … … … … … … … … 29
1.5. Polyamines … … … … … … … … … … … … … … … … … … … … 32
1.5.1. Substituted Ethylenediamines and Polyamines … … … … … 32
1.5.2. Aziridines … … … … … … … … … … … … … … … … … … 43
1.5.3. Piperazines … … … … … … … … … … … … … … … … … 45
1.5.4. Haloamines … … … … … … … … … … … … … … … … … 48
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Chapter 2 – Results and Discussion … … … … … … … … … … … … … 52
2.1. Reaction of 1,2-Dibromoethane with Primary Amines … … … … … … 53
2.2. Reaction of 1,3-Dibromopropane with Primary Amines … … … … … 62
2.3. Phosphenium Cation Stabilization with Triamine Ligands ... ... … … … 67
2.4. Synthesis of N,N",N""-tri-tert-butyl-1,4,7-triazaheptane ... ... ... ... … … 72
2.5. Salts as Carbene Precursors … … … … … … … … … … … … … … 78
2.6. Outlook and Future Experiments … … … … … … … … … … … … … 81
Chapter 3 – Experimental Procedures … … … … … … … … … … … … 85
3.1. Reaction of 1,2-Dibromoethane with Primary Amines … … … … … … 87
3.1.1. N,N"-Dimethylethylenediamine (1a) … … … … … … … … … 89
3.1.2. N,N"-Dimethylpiperazine (2a) … … … … … … … … … … … 89
3.1.3. 1,4,7-Trimethyl-1,4,7-triazaheptane (3a) … … … … … … … 89
3.1.4. 1,4,7,10-Tetramethyl-1,4,7,10-tetraazadecane (4a) … … … 90
3.1.5. N,N"-Diethylethylenediamine (1b) … … … … … … … … … … 90
3.1.6. N,N"-Diethylpiperazine (2b) … … … … … … … … … … … … 91
3.1.7. 1,4,7-Triethyl-1,4,7-triazaheptane (3b) … … … … … … … … 91
3.1.8. 1,4,7,10-Tetraethyl-1,4,7,10-tetraazadecane (4b) … … … … 92
3.1.9. N,N"-Di-iso-propylethylenediamine (1c) … … … … … … … … 92
3.1.10. N,N"-Di-iso-propylpiperazine (2c) … … … … … … … … … … 93
3.1.11. 1,4,7-Tri-iso-propyl-1,4,7-triazaheptane (3c) … … … … … … 93
3.1.12. 1,4,7,10-Tetra-iso-propyl-1,4,7,10-tetraazadecane (4c) … … 94
3.1.13. 1,4,7,10,13-Penta-iso-propyl-1,4,7,10,13-pentaazatridecane(5c) … … … … … … … … … … … … … … … … … … … … 94
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3.1.14. N,N"-Di-tert-butylethylenediamine (1d) … … … … … … … … 95
3.1.15. N,N"-Di-tert-butylpiperazine (2d) … … … … … … … … … … 95
3.1.16. 1,4,7-Tri-tert-Butyl-1,4,7-triazaheptane (3d) … … … … … … 96
3.1.17. N,N"-Diphenylethylenediamine (1e) … … … … … … … … … 96
3.1.18. N,N"-Diphenylpiperazine (2e) … … … … … … … … … … … 97
3.1.19. 1,4,7-Triphenyl-1,4,7-triazaheptane (3e) … … … … … … … 97
3.2. Reaction of 1,3-Dibromopropane with Primary Amines … … … … … 98
3.2.1. N,N"-Dimethyl-1,3-propanediamine (7a) … … … … … … … 99
3.2.2. 1,5,9-Trimethyl-1,5,9-triazanonane (9a) … … … … … … … 99
3.2.3. N,N"-Diethyl-1,3-propanediamine (7b) … … … … … … … … 100
3.2.4. 1,5,9-Triethyl-1,5,9-triazanonane (9b) … … … … … … … … 100
3.2.5. N,N"-Di-iso-propyl-1,3-propanediamine (7c) … … … … … … 101
3.2.6. 1,5,9-Tri-iso-propyl-1,5,9-triazanonane (9c) … … … … … … 101
3.2.7. N,N"-Di-tert-butyl-1,3-propanediamine (7d) … … … … … … 102
3.2.8. N,N"-Diphenyl-1,3-propanediamine (7e) … … … … … … … … 102
3.2.9. 1,5,9-Triphenyl-1,5,9-triazanonane (9e) … … … … … … … 103
3.3. Asymmetric Diamines: Ring Opening Reactions of Arizidines andAzetidines … … … … … … … … … … … … … … … … … … … … … 104
3.3.1. N,N"-Disubstituted Ethylenediamines with DifferentSubstituents: N,N"-Diphenylethylenediamine (10) … … … … 104
3.3.2. N-tert-Butyl-azetidine (6d) … … … … … … … … … … … … 105
3.3.3. N-tert-Butyl-N"-phenyl-1,3-propanediamine (11) … … … … … 106
3.4. Triamine Ligand Building Blocks: R-NH2X-CH2CH2-X … … … … … … 108
3.4.1. 2-(tert-Butylamino)ethylchloride hydrochloride (12d) … … … 108
3.4.2. 2-(tert-Butylamino)ethylbromide hydrobromide (13d) … … … 109
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3.4.3. 3-(Methyl)-aza-1,5-dichloropentane hydrochloride (14) … … 110
3.4.4. 3-(Ethyl)-aza-1,5-dichloropentane hydrochloride (15) … … … 111
3.4.5. 3-(tert-Butyl)-aza-1,5-dichloropentane hydrochloride (16) … 112
3.5. Dicarbene Precursors from 1-tert-Butyl-Imidazol … … … … … … … 113
3.5.1. tert-Butylimidazol hydrochloride (19) … … … … … … … … 113
3.5.2. tert-Butylimidazol (20) (source: tert-Butylimidazolhydrochloride) … … … … … … … … … … … … … … … … 114
3.5.3. tert-Butylimidazol (20) (source: 1,3-di-tert-butylimidazol-2-ylidene) … … … … … … … … … … … … … … … … … … 115
3.5.4. 1-tert-Butyl-3-methylimidazol-2-ylidene hydroiodide (21) … … 116
3.5.5. Bis-(1-tert-butylimidazol-2-ylidene)-1,1-methylenedihydrobromide (22) … … … … … … … … … … … … … … 117
3.5.6. Bis-(1-tert-butylimidazol-2-ylidene)-1,2-ethanedihydrobromide (23) … … … … … … … … … … … … … … 118
3.5.7. Bis-(1-tert-butylimidazol-2-ylidene)-1,3-propanedihydrobromide (24) … … … … … … … … … … … … … … 119
3.6. Stabilization of Reactive Centers Using Intramolecular Dative Bonds … 120
3.6.1. [N3P]+Cl- (25) … … … … … … … … … … … … … … … … … 120
References … … … … … … … … … … … … … … … … … … … … … … 122
Appendix … … … … … … … … … … … … … … … … … … … … … … … 130
A.1. NMR Data of Commercially Available Starting Materials … … … … … 131
A.1.1. 1,2-Dibromoethane … … … … … … … … … … … … … … … 131
A.1.2. Methyliodide … … … … … … … … … … … … … … … … … 131
A.1.3. [(CH3CH2-)3NH]+Cl- … … … … … … … … … … … … … … … 131
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A.1.4. tBu-N(-CH2CH2-)2O … … … … … … … … … … … … … … … 132
A.1.5. N,N"-Di-para-tolylethylenediamine (1f) … … … … … … … … 132
A.2. X-Ray Data … … … … … … … … … … … … … … … … … … … … 133
A.2.1. Phosphenium Cation (25) … … … … … … … … … … … … 133
A.2.2. 2-(tert-Butylamino)ethylchloride hydrochloride (12d) … … … 138
A.2.3. 2-(tert-Butylamino)ethylbromide hydrobromide (13d) … … 142
A.2.4. 1,3-Di-tert-butylimidazoliumbromide ... ... ... ... ... ... ... ... ... … 145
A.3. Solubility Data ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... … 149
A.3.1. 3-(Ethyl)-aza-1,5-dichloropentane hydrochloride (15) … … 149
A.3.2. 3-(tert-Butyl)-aza-1,5-dichloropentane hydrochloride (16) … 150
A.3.3. 1,3-Di-tert-butylimidazolium chloride … … … … … … … … … 151
List of Tables
Table 1: Computational bond angles and singlet / triplet energy gaps (Eg, inkcal•mol-1) of selected carbenes.
Table 2: Computational bond angles and singlet / triplet gaps of selectedcarbenes.
Table 3: Carbene substituent combinations.
Table 4: Availability and pricing of selected polyamines. (Aldrich, 2011)
Table 5: Solubility data of 1,4,7-triphenyl-1,4,7-triazaheptane (3e).
Table 6: Batch yields of 2-(tert-butylamino)-ethyl chloride hydrochloride (12d).
Table 7: Product yields from R-NH2 (5 eq) and Br-CH2CH2-Br (1 eq).
Table 8: Product yields (in %) for primary amines (5 eq) + 1,3-dibromopropane (1 eq).
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Table 9: Crystal data and structure refinement for 25.
Table 10: Atomic coordinates ( x 104) and equivalent isotropic displacementparameters (Å2x 103) for 25. U(eq) is defined as one third of the trace of theorthogonalized Uij tensor.
Table 11: Bond lengths [Å] and angles [°] for 25.
Table 12: Anisotropic displacement parameters (Å2x 103) for 2 5. Theanisotropic displacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2h k a* b* U12 ].
Table 13: Hydrogen coordinates ( x 104) and isotropic displacement parameters(Å2x 103) for 25.
Table 14: Crystal data and structure refinement for 12d.
Table 15: Atomic coordinates ( x 104) and equivalent isotropic displacementparameters (Å2x 103) for 12d. U(eq) is defined as one third of the trace of theorthogonalized Uij tensor.
Table 16: Bond lengths [Å] and angles [°] for 12d.
Table 17: Anisotropic displacement parameters (Å2x 103)for 12d . Theanisotropic displacement factor exponent takes the form: -2π2[ h2a*2U11 + ... + 2 hk a* b* U12 ].
Table 18: Hydrogen coordinates ( x 104) and isotropic displacement parameters(Å2x 103) for 12d.
Table 19: Hydrogen bonds for 12d [Å and °].
Table 20: Crystal data and structure refinement for 13d.
Table 21: Atomic coordinates ( x 104) and equivalent isotropic displacementparameters (Å2x 103) for 13d. U(eq) is defined as one third of the trace of theorthogonalized Uij tensor.
Table 22: Bond lengths [Å] and angles [°] for 13d.
Table 23: Anisotropic displacement parameters (Å2x 103)for 13d . Theanisotropic displacement factor exponent takes the form: -2p2[ h2a*2U11 + ... + 2 hk a* b* U12 ].
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Table 24: Hydrogen coordinates ( x 104) and isotropic displacement parameters(Å2x 103) for 13d.
Table 25: Hydrogen bonds for 13d [Å and °].
Table 26: Crystal data and structure refinement for 1,3-di-tert-butylimidazoliumbromide.
Table 27: Atomic coordinates (x 104) and equivalent isotropic displacementparameters (Å2x 103)for 1,3-di-tert-butylimidazolium bromide. U(eq) is defined asone third of the trace of the orthogonalized Uij tensor.
Table 28: Bond lengths [Å] and angles [°] for 1,3-di-tert-butylimidazoliumbromide.
Table 29: Anisotropic displacement parameters (Å2x 103) for 1,3-di-tert-butylimidazolium bromide. The anisotropic displacement factor exponent takesthe form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12].
Table 30: Hydrogen coordinates (x 104) and isotropic displacement parameters(Å2 x 103) for 1,3-di-tert-butylimidazolium bromide.
Table 31: Solubility of 3-(ethyl)-aza-1,5-dichloropentane hydrochloride (15).
Table 32: Solubility of 3-(tert-butyl)-aza-1,5-dichloropentane hydrochloride (16).
Table 33: 1,3-Di-tert-butylimidazolium chloride solubility organized according tosolubility differences between boiling and room temperature solutions.
List of Figures
Figure 1: Compounds synthesized in this thesis.
Figure 2: Grubbsʼ first and second generation olefin metathesis catalysts.
Figure 3: Mesomeric extremes of a carbene / diradical allene.
Figure 4: Electron configuration order of ground state closed shell singlets.
Figure 5: Frontier orbitals of triplet and singlet carbenes.
Figure 6: Aromatic and non – aromatic carbenes.
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Figure 7: Isodesmic reactions (B3LYP/6-31G(d)//B3LYP/6-31G(d)) of carbenes35 and 36 calculated at 298.15 K.
Figure 8: Tris-carbene complex with M = Ca made from 1-tert-butylimidazol.
Figure 9: Forced dimerization of carbenes by tethering.
Figure 10: Possible modes of interconversion of carbene dimers.
Figure 11: Dimerization of 1,3-bis(iso-propyl)benzimidazol-2-ylidene.
Figure 12: Ethylenediamine dendrimeric polymers for water purification.
Figure 13: Facial and meridial N,N",N""-trimethyl-1,4,7-triazaheptane.
Figure 14: Anti – cancer drug thiotepa.
Figure 15: Nitrogen mustards currently in use as chemotherapy agents.
Figure 16: Isolated polyamine yields from primary amines R-NH2 (R = Me, Et,iPr, tBu, Ph) and 1,2-dibromoethane.
Figure 17: Polyamine yields from R-NH2 and Br-CH2CH2CH2-Br.
Figure 18: N – substituted piperazines and cyclooctanes.
Figure 19: N – substituted aziridines and azetidines.
Figure 20: Purification strategy for [N3P]+Cl- (25).
Figure 21: 13C NMR (C6D6) spectrum of 25.
Figure 22: Bis – carbene ligands in catalytic complexes.
Figure 23: Nitrogen electron withdrawal by tosyl groups.
Figure 24: Silylene precursors.
Figure 25: Phosphorus and silicon multiple bonds.
Figure 26: X-Ray structure of 25.
Figure 27: X-ray structure of 12d.
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Figure 28: X-ray structure of 13d.
Figure 29: X-ray structure of 1,3-Di-tert-butylimidazolium Bromide.
List of Schemes
Scheme 1: Synthetic strategy for stabilizing bonds P$N and Si=O.
Scheme 2: Polymerization of a reactive P$N intermediate.
Scheme 3: Arduengoʼs imidazol-2-ylidene synthesis.
Scheme 4: Synthesis of the first stable open – chain carbene 40.
Scheme 5: Synthesis of 1,3-bis(neopentyl)benzimidazol-2-ylidene 43.
Scheme 6: Synthesis of quinone-based Janus bis-carbenes.
Scheme 7: Benzene-linked Janus bis-carbene synthesis.
Scheme 8: Synthesis of imidazolin-2-ylidenes by reduction of thioureas.
Scheme 9: Imidazolin-2-ylidene synthesis by thermal elimination.
Scheme 10: Nitrogen substitution of CH groups in imidazol-2-ylidenes.
Scheme 11: Synthesis of Wanzlick carbene – metal complexes.
Scheme 12: Deuteration of imidazol-2-ylidenes.
Scheme 13: Products from NH3 and 1,2-dichloroethane.
Scheme 14: CO2 and H2S gas stream purification using amines.
Scheme 15: Synthesis of N,N"-dicyclohexylethylenediamine.
Scheme 16: Synthesis of N,N"-diphenyl-1,3-propanediamine.
Scheme 17: Synthesis of N,N"-diphenyl-1,3-propanediamine using protectinggroups.
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Scheme 18: Urea synthesis from polyamines and phosgene.
Scheme 19: Synthesis of an aza – macrocycle with organosilyl groups.
Scheme 20: Alkylation products from methylation of ethylenediamine.
Scheme 21: Gelbardʼs strategy for alkylating terminal nitrogens of polyamines.
Scheme 22: Singly substituted ethylenediamine by amination of halo – amines.
Scheme 23: Triamine synthesis from ethylene oxide and a primary amine.
Scheme 24: N,N"-diphenyl-1,3-propanediamine from a cyclic carbamate.
Scheme 25: Substituted diamines from bis – azide compounds.
Scheme 26: Polymerization of Cl-CH2CH2-NH3Cl under basic conditions.
Scheme 27: Aziridine synthesis by ring closure of # halo – amines.
Scheme 28: Alkylation of aziridines by active methylene compounds.
Scheme 29: Synthetic methods for preparing N,N"-dialkyl(aryl)piperazines.
Scheme 30: Ring closure of nitrogen mustards to piperidines and piperazines.
Scheme 31: 1-Methyl-4-phenyl-4-cyanopiperdine synthesis.
Scheme 32: 1-Amino-4-methylpiperazine synthesis.
Scheme 33: Gelbardʼs N – terminal substitution of polyamines.
Scheme 34: Reaction of primary amines with 1,2-dibromoethane.
Scheme 35: Possible reaction paths and intermediates leading to N –substituted piperazines and triamines. A: no acid required, B: acid required, C>> D: 13 is more reactive than aziridines under basic conditions, E >> F: ringclosure is favored.
Scheme 36: Diamines and polyamines from primary amines and 1,3-dibromopropane.
Scheme 37: Ring-opening reactions of N-tert-butyl aziridine and N-tert-butylazetidine with aniline.
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Scheme 38: Synthesis of 25 from N,N",N""-tri-tert-butyl-1,4,7-triazaheptane.
Scheme 39: Elimination of iso-butene from 25.
Scheme 40: Diminishing yields in tBu-NH2+Br--CH2CH2-Br (13d) synthesis.
Scheme 41: Substituted piperazines from substituted diamines.
Scheme 42: N – Substituted piperazines from N – substituted nitrogenprecursors.
Scheme 43: Thermolysis of a stable carbene and the protonated carbene.
Scheme 44: Synthesis of N – tethered bis-imidazolium salts.
Scheme 45: Protecting strategies using [R-NH+(CH2CH2-X)2][X-].
Scheme 46: Protecting groups to triamines using [R-NH2+-CH2CH2-X][X-].
Scheme 47: Synthesis of N,N"-disubstituted ethylenediamines.
Scheme 48: Synthesis of N-tButyl azetidine.
Scheme 49: Synthesis of N,N"-disubstituted 1,3-propanediamines.
Scheme 50: Synthesis of 12d.
Scheme 51: Synthesis of 13d.
Scheme 52: Synthesis of 14.
Scheme 53: Synthesis of 15.
Scheme 54: Synthesis of 16.
Scheme 55: Synthesis of 19.
Scheme 56: Synthesis of 20.
Scheme 57: Synthesis of 20.
Scheme 58: Synthesis of 21.
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Scheme 59: Synthesis of 22.
Scheme 60: Synthesis of 23.
Scheme 61: Synthesis of 24.
Scheme 62: Synthesis of 25.
Abbreviations
Compound Name Abbreviation
R
1-Adamantyl Ad
R Benzyl Bn
% Cyclic voltammetry CVR Cyclohexyl Cy
Br
Br 1,2-Dibromoethane DBE
Br
Br 1,3-Dibromopropane DBP
H2NHN NH2
1
Diethylenetriamine DETA
O O CH3H3C1,2-Dimethoxyethane DME
NCH3
HCH3CO N,N-Dimethylformamide DMF
xvi
H3C CH3SO Dimethyl sulfoxide DMSO
% Diffential scanninggravimetry / thermalgravimetry
DSG / TG
(HO2CCH2)2N-CH2CH2-N(CH2CO2H)2
EthylenediaminetetraaceticAcid
EDTA
% Equivalent Eq% Electron spin resonance ESR
H3C CH2R
Ethyl Et
% Gas chromatography –mass spectroscopy
GC-MS
H3C CHCH3
R
iso-Propyl iPr
CH3R
Methyl Me
% Nuclear magneticresonance
NMR
R
Phenyl Ph
CH3
R
para-Tolyl p-Tol
CH3CR
H3C CH3tert-Butyl tBu
3
H2NHN NH2
Tetraethylenepentamine TEPA
xvii
2
H2NHN
NH2
Triethylenetetramine TETA
O Tetrahydrofuran THF
Si(CH3)4 Tetramethylsilane TMS
H3C S RO
O p-Toluenesulfonyl Ts
R
Triptycyl Trp
- 1 -
Chapter 1 – Introduction and Background
- 2 -
1.1. Synthetic Overview
Compounds 1 – 25 (Figure 1) were synthesized to explore their ability of
shielding reactive atoms with steric and electronic stablization.
RNH
NHR
N
N R
R
N R
RNH
NHR
N R
N R
RNH
NHR
N R
RNH
NHR
RN
NR
1 2
3
4
5
NH
NH
R
R
NR
6
7
R
R
N
N
NH
NH
N R
R
R8
9
tBuNH
NH
10
tBuNH
NH
11
tBuNH2Cl
Cl
12d
tBuNH2Br
Br
13d
14
NH+
Cl
Cl
Me
Cl-
15
NH+
Cl
Cl
Et
Cl-
16
NH+
Cl
Cl
tBu
Cl-
17
N
Cl
Cl
Et
- 3 -
18
N
Cl
Cl
tBu
19
tBu
N+
NC H
H
Cl-
20
tBu
N
NC H
21
tBu
MeN
NC+ H
I-
22
tBuNC+ H
tBuNC+ H
N
N
2Br-
23
tBuNC+ H
tBuNC+ H
N
N
2Br-
24
tBuNC+ H
tBuNC+ H
N
N
2Br-
25
+ Cl-
N P:N
N
tBu
tBu
tBu
Figure 1: Compounds synthesized in this thesis.
This thesis describes simple one – pot procedures for the synthesis of
ethylenediamines 1, piperazines 2, and polyamines 3 – 5. For the corresponding
investigation of 1,3-propane diamines, azetidines 6 were isolated for R = tBu.
Propanediamines 7 were isolated for R = Me, Et, iPr, tBu, and Ph. Cyclooctanes 8 were
- 4 -
possible reaction products but were never detected or isolated. Triamines 9 were
isolated for R = Me, Et, iPr, and Ph, but not for R = tBu. Ring opening reactions
provided asymmetric diamines 10 and 11. Polyamine building blocks of type R-NH2X-
CH2CH2-X (12d , 13d) and R-NHX(-CH2CH2-X)2 (1 4 – 16) were synthesized.
Compounds 17 and 18 were considered as polyamine building blocks but not
synthesized for safety reasons. Thermal elimination of iso-butene lead to a synthetic
route to tert-butylimidazole hydrochloride (19), as well as 20 – 24. A novel type of
phosphenium cation (25) (Figure 1) was obtained as the PO2Cl2 salt from triamine
ligand 3d.
- 5 -
1.2. Motivation
A main goal of this thesis was to obtain compounds to synthesize a stable
silicon – oxygen double bond R2Si=O (28) and a stable phosphorus – nitrogen triple
bond R2P!N (30) (Scheme 1).
N SiN
N
tBu
tBu
tBuClCl
N Si:N
N
tBu
tBu
tBu N SiN
N
tBu
tBu
tBu O2 K
- 2 KCl
O=N2
- N2
26 27 28
N PN
N
tBu
tBu
tBu N N+ N- N PN
N
tBu
tBu
tBu NNaN3
- NaCl
!
- N2
+ Cl-
N P:N
N
tBu
tBu
tBu
25 29 30
Scheme 1: Synthetic strategy for stabilizing bonds P!N and Si=O.
To accomplish this, we first needed to develop a reliable synthesis of a ligand
capable of stabilizing these reactive functional groups. We hypothesized that triamine
ligands of the type R1-NH-CH2CH2-N(R2)-CH2CH2-NH-R1 would meet our requirements.
The idea to use triamine ligands for extra stabilization came from previous experiments
in our group (Scheme 2) using tBu-N(-CH2CH2-NH-tBu)2, Ph-N(-CH2CH2-NH-Ph)2, and
Me-N(-CH2CH2-NH-tBu)2. These results indicated that triamine ligands have many
- 6 -
advantages for isolating and controlling reactive functional groups. Our next step will be
exploring silicon and phosphorus multiple bonds with the ligand synthesis established.
NP
N
tBu
tBu
N3N
PN
tBu
tBu
N! 110 °C
+N
PN
N
tBu
tBu
NN
tBu
tBu
NN
tBu
tBuN
P N
P
‡
- N2
31 32 33
94%
34
4%
Scheme 2: Polymerization of a reactive P!N intermediate.
It was found that N,N"-di-tert-butylethylenediamine was not sufficient to stablize
the phosphorus nitrogen triple bond in 32 (Scheme 2).1
1.3. Carbenes
Diamino ligands are important building blocks for imidazol-2-ylidenes
(Arduengo carbenes), imidazolin-2-ylidenes (Wanzlick carbenes), and benzimidazol-2-
ylidenes (Hahn carbenes). Arduengo, Wanzlick, and Hahn carbenes have become
important compounds in olefin metathesis catalysis and led to the Grubbsʼ 2nd
generation industrial catalysts which are the largest diamino carbene application to date
(Figure 2). Robert H. Grubbs and Richard R. Schrock shared the 2005 Nobel Prize for
Chemistry for “Development of the Metathesis Method in Organic Synthesis”.2
- 7 -
C
P(Cy)3
P(Cy)3
CCl
Cl
PhH C
C
P(Cy)3
CCl
Cl
PhH
NN
Ru
1st Generation Grubbs' Catalyst 2nd Generation Grubbs' Catalyst
Ru
Figure 2: Grubbsʼ first and second generation olefin metathesis catalysts.
Following initial synthetic work by Wanzlick in the 1970ʼs, who showed that
imidazolium salts are precursors to imidazolin-2-ylidenes (Wanzlick carbenes),3, 4
Arduengo patented the synthesis of imidazolium salts, the precursors to imidazol-2-
ylidenes (Arduengo carbenes) in 1991.5 Wanzlick prepared imidazolium salts from
thioureas by heating with strong acid,3, 4 but Arduengo described a reliable, high yield
process for their synthesis from paraformaldehyde, aqueous glyoxal, HX, and primary
amines in his 1991 patent.5 Imidazolium salts are the most common precursors to
Arduengo carbenes and numerous patents have appeared after Arduengoʼs work, with
only minor procedural variations.6 The following section outlines the synthesis,
principles of stabilization, and physical properties of diamino carbenes. Imidazolin-2-
ylidenes are prepared from N,N"-dialkyl(aryl)ethylenediamines, as are the corresponding
silylenes and germylenes. These important dicoordinate species are the motivation for
the synthesis of N,N"-dialkylethylenediamines. To better understand why N,N"-dialkyl
amines are unique, a brief discussion of carbenes is required.
- 8 -
1.3.1. Singlet and Triplet Carbenes
Carbenes are neutral compounds featuring a divalent carbon atom with only six
electrons in its valence shell. Closed shell singlet carbenes have a filled and a vacant
orbital, therefore they possess ambiphilic character (Lewis acid and base), while triplet
carbenes have two singly occupied orbitals and are usually considered to be diradicals.7
C:
Carbene Diradical Allene
C
Figure 3: Mesomeric extremes of a carbene / diradical allene.
If a triplet carbene substantially delocalizes unpaired carbene carbon electrons
through its # - system it can be considered a diradical allene.7 This is the case for bis-9-
anthryl carbene (Figure 3) because calculations show the true mesomeric structure is
closer to a diradical allene than a triplet carbene, with approximately 55% of the electron
spin of the carbene carbon delocalized through the # - system.8 An influencing factor is
the formation of four aromatic rings by disruption of the two central rings of the anthryl
groups.8
Carbenes can have four possible arrangements of their valence electrons:
closed shell singlet, triplet, open shell singlet, and the doubly excited state.
- 9 -
CR1
R2
p!
" CR1
R2
p!
" CR1
R2
p!
"
Closed Shell Singlet(E1)
Open Shell Singlet(E3)
Triplet(E2)
CR1
R2
p!
"
Doubly Excited Singlet(E4)
Carbene Energy: E1 < E2 < E3 < E4
Figure 4: Electron configuration order of ground state closed shell singlets.
A pictorial molecular orbital representation is shown in Figure 4 which applies to
Wanzlick, Arduengo and Hahn carbenes as well as acyclic diaminocarbenes.9, 10 The
doubly excited state (E4) is always the highest energy state, but the order of the other 3
states (E1, E2, E3) differs depending on substituents R1 and R2.
Triplet Carbene!Epy - Epx! " 2 eV
Singlet Carbene!Ep# - E$! > 2 eV
p#
R1 CR2
xy
z
90 - %
$
x$
py
R1 C R2
xy
z
px
Figure 5: Frontier orbitals of triplet and singlet carbenes.
Considering a prototype carbene, the bond angle can be either linear or bent,
and both geometries can be described by different sp hybridization (Figure 5).9 The
linear geometry implies an sp – hybridized carbene center with two nonbonding
degenerate orbitals (px and py). Bending the molecule breaks this degeneracy and the
carbene carbon adopts an sp2 hybridization: the py orbital remains nearly unchanged,
- 10 -
while the px orbital is stabilized and has $ - character.6 The carbene ground-state
multiplicity can be related to the relative energy of the p# and $ orbitals.6, 9 In 1968,
Roald Hoffmann noted that 2 eV is the minimum value of the energy gap %Ep# - E$% to
impose a singlet ground state, whereas a value equal to or below 1.5 eV leads to a
triplet ground state (Figure 3).9 When the energy gap is intermediate (2 eV > %Ep# -
E$% > 1.5 eV), the ground state is influenced by other factors such as steric properties
of carbene substituents.9
%Ep# - E$% & 2 eV ' Triplet
%Ep# - E$% > 2 eV ' Singlet
If substituents R1 and R2 make the carbene center part of a 5 – membered ring
(forced bending), and as a carbene changes from linear to bent, the singlet – tripet gap
increases and the energy of the $-orbital drops with respect to the energy of the #-
orbital.6, 9 If substituents R1 and R2 are # donors such as alkyl-substituted amino
groups, the same is true (mesomeric effects). For compounds that have substituents R1
and R2 that do not possess geometrical constrainsts, or any special stabilizing
properties, e.g.- methylene (H-C:-H), the lowest energy state is triplet (E2: Figure 4).
The main properties of substituents R1 and R2 that have influence on the electronic and
geometric structure of carbenes are: electronegativity (inductive effects), # donation
from substituent to carbene #-orbital (mesomeric effects), and geometry (ring
constraints, steric effects).6
- 11 -
As the angle R1-C:-R2 decreases the $-orbital becomes more asymmetric and
reaches farther from the carbon atom (one small lobe, one large lobe), so qualitatively it
is easy to see why placing an electron pair in the $-orbital versus the #-orbital reduces
electron-electron repulsion to the electrons in the bonds, especially when mesomeric
stablization is taking place (Figure 5).6
1.3.2. Stabilization of Carbenes
1.3.2.1. Steric Effects
Steric stabilization of carbenes refers to the shielding of the carbene center by
substituents R1 and R2 (R1-C:-R2). In general, as the substituents become bulkier, the
bond angle (( R1-C:-R2) increases to a maximum of 180°.11 Small substituents allow
the carbene center to come into close proximity of reactants, while large substituents
keep the carbene center isolated12 and stabilize all carbenes kinetically.11 Calculations
show steric effects also influence ground state spin multiplicity in the absense of strong
electronic effects (Table 1).6
For the first five carbenes in Table 1 (methylene,11 bis-methyl carbene,11 bis-
tert-butyl carbene,13 bis-1-adamantyl carbene,14 bis-triptycyl carbene12) the bond angles
generally increase for both the singlet and triplet states with increasing substituent steric
bulk. The same applies to the series of carbenes with aromatic substituents (bis-phenyl
carbene,11 bis-1-naphthyl carbene,11 bis-9-anthryl carbene11) (Table 1).
- 12 -
Table 1: Computational bond angles and singlet / triplet energy gaps (Eg, in kcal•mol-1) of selected
carbenes.
Carbene Angle[deg]
Singlet
Angle[deg]Triplet
Eg Method Basis Set Ref.
H
HC:
101.6 135.4 -11.8 a B3LYP 6-311+G(d,p) 11
CH3
CH3C:
112.6 133.7 0.2 B3LYP 6-311+G(d,p) 11
C:
125.1 141.9 -5.16 B3LYP TZ2P 12, 13
C:
125 149 -9.3 B3LYP 6-31G(d) 12, 14
C:
129.3 153.3 -14 B3LYP 6-31G(d) 12
C:
119.5 142.9 -2.94 B3LYP 6-311+G(d,p) 11
C:
121.62 173.62 -3.74 B3LYP 6-311+G(d,p) 11
C:
147.28 180.00 -15.70 B3LYP 6-311+G(d,p) 11
a) exp: -9.05
- 13 -
Aromatically substituted carbenes Ar-C:-R and Ar-C:-Ar have significantly
shorter carbene – aryl bonds in the triplet state compared to the singlet state because of
radical delocalization through the aryl groups leading to partial double bond character.11
As the size of the aryl groupʼs #-system increases, the delocalization increases (Table
1).11 For optimum delocalization, the plane of aryl rings should be perpendicular to the
carbene # orbital, but sterics often prevent this as is the case for bis-phenyl carbene,
bis-1-naphthyl carbene, and bis-9-anthryl carbene which all have a propeller
geometry.11 As substituent bulk increases, forcing a wider carbene angle, the triplet
state generally becomes the ground state for aryl carbenes because aryl # interaction
with the carbene sp2 orbital decreases, raising the energy of that molecular orbital,
therefore making the singlet state unfavorable.8, 11 Most bis-aryl, aryl-alkyl, and bis-alkyl
carbenes have triplet ground states, while most bis-alkyl carbenes capable of
hyperconjugation have singlet ground states.8, 12 Most triplet carbenes with aryl
substituents partially delocalize the unpaired carbene electrons, however the structures
are generally closer to triplet carbenes than diradical allenes.8
Singlet and triplet carbenes are more stabilized by alkyl groups capable of
hyperconjugation than by hydrogen. This stabilization is usually larger for singlets than
for triplets.12 For carbenes with bulky alkyl substituents, steric repulsion forces the
carbene angle to widen, causing the carbene atom to adopt more # character in its sp2
orbital. This geometric constraint destabilizes the singlet state.12 Substituents
incapable of hyperconjugation do not favor a singlet ground state.7 Stable triplet
carbenes have been more elusive than stable singlet carbenes.8
- 14 -
1.3.2.2. Electronic Effects
There are two distinct mechanisms of electronic stabilization for carbenes:
mesomeric and inductive. Mesomeric stabilization is electron donation from a
substituent into the carbene #-orbital. Inductive stablization is back donation from the
carbene sp2 (sigma) orbital to the substituent through sigma bonds.
NC:
NH
HNC:
NH
H35 36
Figure 6: Aromatic and non – aromatic carbenes.
Mesomeric and inductive stabilization of the carbene center, along with steric
bulk and geometric properties of the substituents, are the variables that combine to
dictate the ground state spin multiplicity of the carbene.6
Calculations of pairwise and isodesmic reactions performed on the unsaturated /
saturated pair 35 and 36 (Figure 6, Figure 7) provide an example for the significance of
aromatic stablization in imidazol-2-ylidenes. Hydrogenation ())G = -14.44 kcal•mol-1),
oxidation with oxygen ())G = -7.30 kcal•mol-1), and oxidation with CO2 ())G = -7.47
kcal•mol-1) is less exothermic for 35 than for 36.15
Imidazol-2-ylidenes, imidazolin-2-ylidenes, benzimidazol-2-ylidenes, and open
chain carbenes (Alder carbenes), and any singlet carbene with substituents more
electronegative than carbon benefit from inductive stabilization.6 Inductive stablization
- 15 -
of the $ lone pair is caused by the polarization of the substituent – carbene bonds (R1)*-
+C*+,(R2)*- by electronegative elements in R1 and R2, leading to a more positive
carbene carbon, lowering the energy of the $ lone pair.16
Mesomeric, inductive, and steric effects are three independent variables whose
effects combine to produce a triplet or singlet carbene (Table 2).6 For the series of
carbenes F-C:-F, F-C:-Cl, F-C:-Br, F-C:-I the bond angles increase for both the singlet
and triplet state as the size of the halogen substituent increases.17
NC:
NH
H
NC:
NH
H
+
+
H2
H2
N
NH
H
N
NH
H
HC
H
HC
H
NC:
NH
H
NC:
NH
H
+
+
N
NH
H
N
NH
H
C
C
O
O
1/2 O2
1/2 O2
NC:
NH
H
NC:
NH
H
+
+
N
NH
H
N
NH
H
C
C
O
O
CO2
CO2
+
+
CO
CO
!G = -11.35 kcal•mol-1
!!G = -7.47 kcal•mol-1
!G = -18.82 kcal•mol-1
!G = -79.1 kcal•mol-1
!!G = -7.3 kcal•mol-1
!G = -86.4 kcal•mol-1
!G = -16.44 kcal•mol-1
!!G = -14.44 kcal•mol-1
!G = -30.88 kcal•mol-1
Figure 7: Isodesmic reactions of carbenes 35 and 36 calculated at the B3LYP/6-31G(d)//B3LYP/6-
31G(d) level.
- 16 -
Table 2: Computational bond angles and singlet / triplet gaps of selected carbenes.
Carbene SingletAngle (°)
TripletAngle (°)
S – T Gap(kcal•mol-1)[singlet positive/ t r i p l e tnegative]
Method Ref
F-C:-F 104.0 118.0 56.43 GVB(1/2) 17F-C:-Cl 105.6 121.7 37.09 GVB(1/2) 17F-C:-Br 106.3 122.8 31.89 GVB(1/2) 17F-C:-I 107.2 124.1 25.46 GVB(1/2) 17Cl-C:-Cl 109.0 126.1 20.04 GVB(1/2) 17Cl-C:-Br 110.2 127.6 16.12 GVB(1/2) 17H-C:-F 102.2 120.6 15.83 GVB(1/2) 17Br-C:-Br 111.5 129.2 12.48 GVB(1/2) 17Cl-C:-I 111.5 129.2 11.10 GVB(1/2) 17Br-C:-I 113.0 131.2 7.80 GVB(1/2) 17H-C:-Cl 101.4 123.7 6.39 GVB(1/2) 17H-C:-Br 101.8 125.4 4.03 GVB(1/2) 17I-C:-I 114.6 133.4 3.78 GVB(1/2) 17H-C:-I 102.6 127.7 0.77 GVB(1/2) 17F-C:-SiH3 105.5 126.0 -1.31 GVB(1/2) 17Cl-C:-SiH3 108.1 130.8 -8.45 GVB(1/2) 17H-C:-H 104.8 130.2 -9.71 GVB(1/2) 17Br-C:-SiH3 110.4 133.8 -10.60 GVB(1/2) 17I-C:-SiH3 113.1 137.3 -12.90 GVB(1/2) 17H-C:-SiH3 110.4 141.0 -19.08 GVB(1/2) 17SiH3-C:-SiH3
180.0 180.0 -19.60 GVB(1/2) 17
Li-C:-Li 180 180 (3-g-),
88.1 (3A2)-21.3 ab init io
GVB,SCF, CI
18
Na-C:-Na na 180 (3-g-),
86 (3A2) [7kcal•mol-1morestable than3-g
-]
na ab init ioGVB,SCF, CI
19
The singlet – triplet gaps decrease along this series because inductive and
mesomeric stablization is lower from the heavier halogens than the more
- 17 -
electronegative lighter halogens that have better #-orbital overlap with the carbene #-
orbital.17 The same trends apply for the stability in the series F2C:, Cl2C:, Br2C:, and
I2C:.17 High substituent steric bulk and low substituent electronegativity generally favor
a triplet carbene ground state, while low substituent steric bulk (or tethered substituents
forcing a low carbene bond angle) and high substituent electronegativity favor a singlet
ground state.6, 20
Li2C: is a highly reactive species that haunts the computational literature but
has yet to be studied experimentally. Low level calculations by Mavridis in 1982
showed a near degeneracy of the lowest singlet and triplet states, but with the
inaccuracies of the calculation methods used, it was impossible at the time to predict
with certainty whether the molecule is a singlet or triplet, though the triplet state was
considered more likely.18 We are currently performing calculations on Li2C:.
Table 3: Carbene substituent combinations.
R2
R1-C:-R2
$-push,#-push
$-push,#-pull
$-pull,#-push
$-pull,#-pull
$-push,#-push
PhosphinosilylcarbenesR2P-C:-SiR3
$-push,#-pull
DiborylcarbenesR2B-C:-BR2
$-pull,#-push
DiaminocarbenesR2N-C:-NR2
R1
$-pull,#-pull
- 18 -
The ideal substituents to stablilize singlet carbenes should preserve the
electroneutrality of the carbene center.6 Experimentally, there are three ways to do this:
1. two #-donor, $-attractor substituents (push, push mesomeric / pull, pull inductive
substitution pattern), such as diaminocarbenes, 2. two #-attractor $-donor substituents
(pull, pull mesomeric / push, push inductive substitution pattern), such as
diborylcarbenes and 3. a #-donor and a #-acceptor substituent (push, pull mesomeric
substitution pattern), such as phosphinosilylcarbenes (Table 3).6
1.3.3. Synthesis of Diaminocarbenes
Diamino carbenes are at present accessible by three different routes:
deprotonation of imidazolium salts,3, 4, 21, 22 reduction of thioureas,23 and thermal
elimination of methanol or HX (X = CCl3, OR).3, 4, 6, 24
1.3.3.1. Deprotonation of Imidazoium Salts
In 1970, Wanzlick and co-workers reported that the deprotonation of
imidazolium salts with potassium tert-butoxide produced Arduengo carbenes.3, 4, 21
Following the same principle, in 1991, Arduengo et al. obtained “A Stable Crystalline
C a r b e n e ”, 3 8 , in near quantitative yield by deprotonation of 1,3-di-(1-
adamantyl)imidazolium chloride 37 with sodium or potassium hydride in the presence of
catalytic amounts of either potassium tert-butoxide or DMSO anion (scheme 5, R = 1-
adamantyl). The colorless, crystalline imidazol-2-ylidene 38 is thermally stable and
melts at 240-241 °C without decomposition (Scheme 3).22
- 19 -
N+C
N
1Ad
1Ad
HN
C:N
1Ad
1Ad
NaH
- NaCl- H2(g)
Cl-
3738
Scheme 3: Arduengoʼs imidazol-2-ylidene synthesis.
Alder et al. synthesized 40 (Scheme 4), the first diaminocarbene without the
constraints of ring geometry to help stabilize it.25
(iPr)2NC O
H POCl3
(iPr)2N+C Cl
HCl-
(iPr)2N-H
iPr NC
NiPr
Cl-
iPr
iPr
+ H
iPr NC:
NiPr
iPr
iPr
LDA
39
40
Scheme 4: Synthesis of the first stable open-chain carbene 40.
In 1999, Hahn isolated 4 3, the first benzene annulated carbene 1,3-
bis(neopentyl)benzimidazol-2-ylidene (Scheme 5).26
- 20 -
NC
NS
NC:
NNa/KTol.
Na/KTHF
NCH2
N
O
NC:
N
O
HHHH
HHH H
H
HH
H
H2 Transfer
NH
NH
Cl2C=S
NH2
NH2XCORLAH
41 42 43
Scheme 5: Synthesis of 1,3-bis(neopentyl)benzimidazol-2-ylidene 43.
In 2006, Bielawski et al. deprotonated bis – imidazolium salts to synthesize
Janus bis – carbenes, a variation of benzimidazol-2-ylidenes with two carbene
functional groups (Scheme 6, Scheme 7).27
O
OBr
BrBr
Br NC:
NN:C
N
Mes
Mes Mes
MesO
ON
NN
N
Mes
Mes Mes
MesO
O
HH
2 Br-
++
HN
N
Mes
Mes
+i ii
i = 4 eq N,N!-dimesitylformamidineii = 2 eq NaN(SiMe3)2
44 45
Scheme 6: Synthesis of quinone-based Janus bis-carbenes.27
- 21 -
NO2
NO2Cl
Cl NO2
NO2HN
HN
R
RNH2
NH2HN
HN
R
R
N
NN
N
R
R H
HH +
X-
N
NN
N
R
R R!
R!
HH
2 X-
++
NC:
NN:C
N
R
R R!
R!
i ii
iii
vi v
4647
iv
iv = Pd / C / HO2CHv = 2 eq R!-Xvi = 2 eq NaN(SiMe3)2
i = R-NH2 / Pd catii = Pd / C / H2(g)iii = HC(OEt)3 / HX
Scheme 7: Benzene-linked Janus bis-carbene synthesis.
N CN R
MBCNNR
H N(SiMe3)2
N CN R
Figure 8: Tris-carbene complex with M = Ca made from 1-tert-butylimidazole.
In 2009, Hitchcock et al. synthesized tris-carbene complexes of calcium,
strontium, and barium [{HB(tBuIm)3}M{N(SiMe3)2}(tBuIm)n] by combining the tris-
imidazole compound [HB(tBuIm)3]2+•2Br- with MI2 (M = Ca, Sr, Ba) and 4 KN(SiMe3)2 in
a one – pot reaction (Figure 8).28
- 22 -
1.3.3.2. Reduction of Thioureas
Preparation of imidazolin-2-ylidenes from carbenium salts requires three
synthetic steps: 1. synthesis of the aminal, 2. conversion to the carbenium salt, and 3.
deprotonation to the imidazolin-2-ylidene. Preparation of imidazolin-2-ylidenes from
thioureas only requires two synthetic steps: 1. synthesis of the thiourea, and 2.
reduction to the imidazolin-2-ylidene.
R1
R2N
NC:
NR1
R2N
C SNR1
R2N
CH2
R1
R2NH
NH
Br
Br
R1
Cl
NH2+Cl-
R1
OH
NH ii
R1
NH2C CH2
iii
iv v vi vii
i
i: SOCl2 / CH2Cl2 / r.t. / 24 hrsii: R2-NH2 / H2O / 180 °C / 48 hrsiii: R2-NH2 / 225 °C / 24 hrsiv: R1-NH2 / H2O / r.t. / 168 hrs
v: CH2O / r.t. / 48 hrsvi: S8 / 160 °C / 12 hrsvii: K / THF / 66 °C / 2 hrs
Scheme 8: Synthesis of imidazolin-2-ylidenes by reduction of thioureas.
In 1993, Kuhn and co-workers prepared alkyl-substituted imidazol-2-ylidenes
through a new and versatile approach: reduction of imidazol-2-thiones with potassium
in boiling THF.23 Denk et al. extended this approach to imidazolin-2-ylidenes (Scheme
8).20, 29-31 The first imidazolin-2-ylidene to be prepared in this way was 1,3-di-tert-butyl-
imidazolin-2-ylidene.20
- 23 -
1.3.3.3. Diaminocarbenes from Thermal Elimination
Wanzlick developed the 1,1 thermal elimination route to imidazolin-2-ylidenes3,
4 affording a third unique synthesis for diaminocarbenes (Scheme 9).
NC
N
HCCl3
NC
N
HO Et
NC:
N150 °C 200 °C- HCCl3 - EtOH
Scheme 9: Imidazolin-2-ylidene synthesis by thermal elimination.
:N
NC
N+
H
[ClO4]-
:N
NC
N OH
MeNaOMeMeOH
80 °C0.1 torr- MeOH
:N
NC:
N
O
NH
H2N CN
H
Cl
N+H
Cl-
O
POCl3
Ac2ONa[ClO4]
+
48
Scheme 10: Nitrogen substitution of CH groups in imidazol-2-ylidenes.
- 24 -
In 1995, Enders et al. reported that using Wanzlickʼs thermal elimination
method (Scheme 9) 1,2,4-triazol-5-ylidene 48 could be obtained from 5-methoxy-1,3,4-
triphenyl-4,5-dihydro-1H-1,2,4-triazole by thermal elimination (80 °C) of methanol in
vacuum (0.1 mbar) (Scheme 10).24
Compound 48 became the first commercially available stable aminocarbene
(Scheme 10).24
1.3.4. Reactivity of Diaminocarbenes
1.3.4.1. Dimerization
Dimerization to olefins is a fundamental reaction pathway of carbenes. The
weakest carbon – carbon double bonds known are in fact dimers of diaminocarbenes.6
Metal complexes with carbene ligands can be made by adding enetetramines to the
metal starting material because the weak carbene – carbene bond allows the
enetetramines to behave as protected carbene ligands (Scheme 11).32, 33
NC
N
N
NC
Cl
Cl
ClPt
PEt3
Et3P
ClPt+
N
NPt PEt3
Cl
Cl
C
Scheme 11: Synthesis of Wanzlick carbene – metal complexes.
- 25 -
Lappert et al. prepared transition metal – carbene complexes with platinum,
ruthenium, osmium, and numerous other metals starting from enetetramines (Scheme
11).32, 33
The extremely weak carbon – carbon double bond of enetetramines (10 – 20
kcal•mol-1) manifests itself with easy dissociation. Enetetramines also have a very high
reduction potential (as high as lithium).
Wanzlick observed that imidazolin-2-ylidenes dimerize3, 4 while Arduengo found
that imidazol-2-ylidenes remain monomeric.22, 34, 35 The variables that influence this
fascinating carbene behavior have been investigated experimentally and
computationally.
H.W. Wanzlick showed that imidazolin-2-ylidenes dimerize (1960).3, 4 In order to
do this he needed to distinguish between carbene monomers and dimers
(enetetramines). At the time, Wanzlick did not have the multitude of analytic equipment
available today. As would be expected, 13C NMR shifts are very different for Wanzlick
carbene monomers and enetetramines, but this at that time (1960 – 1970) was
unavailable to Wanzlick. Chemically, carbenes and enetetramines react similary
towards metals, metal complexes, O2, H2O, S8 and many other substrates. Today it is
also possible to calculate the heats of formation of carbene – metal bonds, and run the
experiment in a calorimeter to differentiate. Again, Wanzlick could not do this because
reliable calculations were not available in 1960. MS electron impact experiments are
not directly applicable to differentiate between monomers and dimers because E.I. can
induce dissociation as can the pressure and temperature of the MS system. However,
- 26 -
chemical ionization experiments work for this class of compounds. Wanzlick was finally
able to show that he had enetetramines through molecular weight determination
(melting point depression / boiling point elevation experiments).
MO arguments suggest that diaminocarbene dimerization follows a non – least
motion pathway of the $ - orbital inserting into the vacant # - orbital.6 Calculations by
Alder et al. estimate diaminocarbene dimerization barriers to be over 25 kcal•mol-1.16
Carbene dimerization is controlled by sterics and electronics. Aromaticity
prevents the dimerization of imidazol-2-ylidenes by adding enough electron density to
the carbene #-orbital, making it unapproachable by the $ - orbital of another carbene
molecule.10, 16 Therefore even imidazol-2-ylidenes with small substituents such as
methyl and ethyl do not dimerize. When a benzene ring is annulated to an imidazol-2-
ylidene, such as in the work of Bielawski or Hahn, the aromaticity of the benzimidazol-2-
ylidene is diluted and the stabilization is reduced. For this reason, the Hahn carbenes
behave like imidazolin-2-ylidenes and do dimerize for small N-substituents (Me, Et, iPr).
Steric effects also play a key role in carbene dimerization. For symmetric
imidazolin-2-ylidenes, Denk et al. have proven the line between dimer and monomer is
iso-propyl / tert-butyl.20 Substituents equal to or smaller than iso-propyl lead to
dimerization, and substituents equal to or larger than tert-butyl remain monomeric.
Denk et al. also demonstrated that for imidazolin-2-ylidenes, just one tert-butyl group
provides enough steric and electronic stabilization to the carbene center to prevent
dimerization.29 tert-Butyl groups create significant steric strain in the dimers, they are
also very good at electronically stabilizing carbenes.29 For the aromatically substituted
- 27 -
imidazolin-2-ylidenes, the borderline between monomer and dimer is a mixture of 1,3-
diphenyl-imidazolin-2-ylidene and 1,3-dimesityl-imidazolin-2-ylidene which contains A=B
dimer. Bulkier substituents lead to monomeric carbenes. This pair of diamino carbenes
has been established as the line between monomer and dimer for diamino carbenes
bearing aromatic substituents.29
N
MeN
N
MeN
C CN
N
N
NC C
49 50
Figure 9: Forced dimerization of carbenes by tethering.
AB B
A
AB B
A
AB B
A A:B B
A:
AB B
A
A:B:
AB B
A
AB B
A
AB B
A: AB B:
A: AB B
A
B:A:Carbene:
Metathesis:
Mixed:
Figure 10: Possible modes of interconversion of carbene dimers.
The benzimidazol-2-ylidenes 49 and 50 exist as enetetramine dimers because
they have been forced into close proximity by tethering (Figure 9). These Hahn
carbenes would be monomeric if they were not tethered.36
- 28 -
Wanzlick and co-workers proposed that imidazolin-2-ylidene dimers interconvert
according to Figure 10.37
Denk proved the Wanzlick equilibrium exists with crossover experiments. In
thermal experiments mixtures of A=A and B=B equilibrate to statistical mixtures: [(1
A=A) : (2 A=B) : (1 B=B)] at temperatures of 100 – 200 °C. Wanzlick carbene
monomers were not observed in the NMR spectra.20, 29, 37, 38
NC:
N
NC
N
N
NC
51 (51)2
Figure 11: Dimerization of 1,3-bis(iso-propyl)benzimidazol-2-ylidene.
One year later Hahn synthesized a benzimidazol-2-ylidene that exists in
equilibrium with its dimer in solution, thus directly proving the existence of the Wanzlick
equilbrium by NMR (Figure 11).39
1.3.4.2. Reactions with Common Molecules
Diamino carbenes imidazol-2-ylidenes and imidazolin-2-ylidenes are both inert
towards CO, O2, and H2 in the absence of a catalyst. Both types of carbenes form
aminals with hydrogen in the presence of a platinum catalyst, are hydrolyzed to amides,
and form ureas when oxidized with NO. Hydrolysis of Wanzlick carbenes (imidazolin-2-
ylidenes) proceeds quickly while hydrolysis of Arduengo carbenes (imidazol-2-ylidenes)
- 29 -
is very slow. Interestingly, the hydrogenation of imidazol-2-ylidenes leads to aminals
rather than saturation of the HC=CH moiety.15 Deuteration of imidazol-2-ylidenes
proceeds according to Scheme 12.40
C:
RN
NR
C:
RN
NR
RN
NR
C+ DH
H
-C
RN
NR
C+ DH
RN
NR
C+ DD
H
+ D+ - H+ + D+ - D+ D
H
H
H
C:
RN
NR
-C
RN
NR
C+ DD
RN
NR
C+ DD
DD
D
- H+
- D+ + D+
Scheme 12: Deuteration of imidazol-2-ylidenes.
In the next section the synthesis and use of 1,2-ethylenediamines, which are
crucial building blocks for the synthesis of imidazolin-2-ylidenes, will be discussed.
1.4. Ethylenediamine
Ethylenediamine is mainly produced by heating ethylene dichloride (Cl-CH2CH2-
Cl) with ammonia at 100 °C in the liquid phase under pressure.41 The product
distribution is controlled by reactant ratio, pH, reactor geometry, temperature, pressure,
and cycling of products back into the reactor.
- 30 -
Cl
Cl+
NH2
NH2
NH
NH2
NH2
NH
NH2
NH
NH2
NH
NH2
NH
NH
NH2
En
DETA
TETA
TEPA
+ + +NH3
Scheme 13: Products from NH3 and 1,2-dichloroethane.
Byproducts are diethylenetriamine (DETA), triethylenetetramine (TETA), and
tetraethylenepentamine (TEPA) (Scheme 13). The amine hydrochlorides formed in the
process are neutralized with lime, caustic soda, or other bases. Products are separated
by fractional distillation.41 This spectrum of highly useful synthetic building blocks
motivated us to investigate the reaction of 1,2-dibromoethane with primary amines.
Handling amines under a dry inert atmosphere of nitrogen or argon proved to be
necessary to prevent reaction with CO2, and H2O.41, 42 The petrochemical industry uses
this property of amines to separate CO2, H2S, and other acidic gases from gas
mixtures.41, 42
2 R1R2NH + CO2 ! R1R2N-CO2- + R1R2NH2
+
2 R1R2R3N + H2S ! 2 R1R2R3NH+ + S2-
Scheme 14: CO2 and H2S gas stream purification using amines.
The most common amines used for CO2 and H2S removal are ethylenediamine,
diethylenetriamine (DETA), triethylenetetramine (TETA), and tetraethylenepentamine
- 31 -
(TEPA). Both are very effective at capturing these gases and are also corrosion
inhibitors (Scheme 14).41, 42
Ethylenediamine is mainly used in detergents, resins and polymers, crop
protection agents, paper chemicals, lubricants, corrosion inhibitors, surfactants, and
pharmaceuticals.41
NH2NH
OOO
On
NH2NH
OOO
On
H2N NH
O OO
On
H2N NH
O OO
On
N N
Figure 12: Ethylenediamine dendrimeric polymers for water purification.
Ethylenediamine finds use in water purification technology (Figure 12).41, 43
Ethylenediamine dendrimeric polymers bearing quartenary ammonium sites have a
broad range antimicrobial activity.41, 43 Quartenary ammonium functional groups can be
introduced to the polymer in Figure 12 after the polymer is made sufficiently large, or
linked to a stationary phase.43 Unlike free salts, supported quartenary ammonium
functional groups do not leach into the environment and this reduces replacement
costs.41, 43 The antimicrobial properties of these ethylenediamine copolymers come
from quartenary ammonium sites permeating cell walls and killing bacteria.41, 43
- 32 -
Wanzlickʼs work in the 1970ʼs on imidazol-2-ylidenes and imidazolin-2-ylidenes
showed that ethylenediamine ligands are versatile tools in carbene chemistry.3, 4 Since
then, many discoveries have been made in the carbene field based on manipulation of
substituted ethylenediamine ligands.2, 6, 29
1.5. Polyamines
1.5.1. Substituted Ethylenediamines and Polyamines
The N,N"-disubstituted ethylenediamines 1 and their homologous
diethylenetriamines and tetramines are versatile building blocks for the synthesis of
organic and inorganic compounds.31, 43-48 They find use for the synthesis of aza-crown
ethers,47, 49-56 functionalized polymers,57-61 and, more recently, for the synthesis of
stable carbenes,15, 20, 30, 37, 38, 40, 62, 63 stable silylenes,64-73 and related species.74, 75 Their
complexes with manganese, copper, and silver76-78 have been studied as homogeneous
catalysts and their Pd(II) and Pt(II) complexes have served as model compounds to
study the interaction of cis-platin and related anticancer drugs with DNA.79-82
Polyamines have been used in the treatment of mitochondrial and degenerative
diseases.83 While polyamines R-NH-(CH2CH2-NR)n-H are valuable building blocks, they
are either expensive or unavailable commercially (Table 4).
- 33 -
Table 4: Availability and pricing of selected polyamines. (Aldrich, 2011)
Aldrich Pricing ($ / Kg ) of Polyamines R-NH-(CH2CH2-NR)n-H
n = 1 n = 2
Me $ 12,000 $ 348,000
Et $ 10,200 naiPr $ 9,520 natBu $ 7,080 na
R G
roup
Ph $ 4,240 na
In 1936, J. Van Alphen reported the reaction of 1,2-dibromoethane with
ammonia. The numerous products isolated include ethylenediamine (En), diethylene
diamine (piperazine), diethylenetriamine (DETA), triethylenetetramine (TETA) and
triethylene diamine (N-(CH2CH2)3-N).84 Van Alphen found that combining
triethylenetetramine (TETA) with benzaldehyde (Ph-CO-H) forms a diheterocyclic
compound with all nitrogen atoms fully substituted. Reaction with sodium metal
followed by treatment with ethanol returns the original polyamine TETA, so the
benzaldehyde reaction introduces a nitrogen protecting group. There are two nitrogen –
protected compounds from TETA and benzaldehyde reported.85 Van Alphen found that
ethylenediamine reacts with 1,3-dibromopropane yielding H2N-CH2CH2-NH-
CH2CH2CH2-NH-CH2CH2-NH2, a compound used to reduce silver salts. This amine
forms colored copper complexes from copper salts, as well as colored nickel complexes
from nickel salts. In the presence of CS2, a bis – thiourea forms from the above
tetramine.86 Longer polyamine chains made from 1,3-dibromopropane and
ethylenediamine form poly – thioureas.87
- 34 -
Since the work of J. Van Alphen not much research went into polyamines until
Gelbard et al. used nitrogen mustards for the synthesis of triamines, as well as imine
reduction to triamines.88, 89
In 2002, Yoshimi et al. converted amino alcohols R-NH-CH2CH2-OH to [R-NH2+-
CH2CH2-Cl][Cl-] with SOCl2 in chloroform. These nitrogen hemi mustards and primary
amines lead to diamines.90 N-Ethyl-Nʼ-propylethylenediamine was synthesized in 35%
yield from [Et-NH2+-CH2CH2-Cl][Cl-] and iPr-NH2. N-Cyclopropyl-N ʼ-
ethylethylenediamine was synthesized from [Et-NH2+-CH2CH2-Cl][Cl-] and cyclopropyl
amine in 43% yield. Numerous asymmetrically substituted diamines were used to make
diazepines to manipulate dopamine and serotonin levels tested in rat studies.90 Current
pricing and availability of polyamines are shown in Table 4.
Alkyl or aryl substituted diamines and polyamines are prepared by reaction of
primary amines with X-(CH2)n-X,31 by alkylation of ethylenediamines or
polyethylenediamines,91 by nitrogen salt reduction (R1R2N+=CR3R4),88 by reaction of
primary amines with nitrogen mustards or hemi – mustards,92 by halogenation of amino
alcohols followed by reaction with primary amines,89 by ring opening reactions of certain
esters,93 and by reductive deazotization of N3-(CH2)n-N3.94
In 2010, N,N"-dicyclohexyl-ethylenediamine was prepared (Scheme 15) by
reaction of 1,2-dibromoethane with cyclohexylamine (50%).31, 95
- 35 -
NH2 Br
Br
NH
NH+5
Scheme 15: Synthesis of N,N"-dicyclohexylethylenediamine.
In 1962, Daniels et al. prepared Ph-NH-(CH2)3-NH-Ph using dropwise addition of
1 mole of Br-(CH2)3-Br to 5 moles of aniline.96 In 1960, Fischer et al. found that Br-
(CH2)3-Br forms N-phenyl-azetidine (78%) and Ph-NH-(CH2)3-NH-Ph (22%) when
reacted with aniline (Scheme 16).97 Both products are isolated by fractional
distillation.97 Ph-NH-(CH2)3-NH-Ph is a stabilizer for polyvinyl acetal resins, an
antioxidant for rubber, and a respiratory and vasomotor stimulant.98
Br
Br
NH
NHN
NH2+ +5
Scheme 16: Synthesis of N,N"-diphenyl-1,3-propanediamine.
- 36 -
NH
NH
N
N
C
C
OCH3
OCH3
NaOHBr
BrN +2COCH3
Na
Scheme 17: Synthesis of N,N"-diphenyl-1,3-propanediamine using protecting groups.
In 1951, Billman et al. prepared Ph-NH-(CH2)3-NH-Ph (20%) from Br-(CH2)3-Br
and Ph-N(Na)-CO-CH3, followed by acetate removal with NaOH (Scheme 17).98 In
1956 (o-CH3-C6H4)-NH-(CH2)3-NH-(C6H4-o-CH3) was prepared from Br-(CH2)3-Br and o-
CH3-C6H4-NH2, preceding work by Daniels et al.99 Diamines have even been produced
from waste glycerol catalyzed by bacteria.100
Cl ClCO
HN N NHR R
R
HN N NHR R
R
CO
N N NHR R
R
HN N NR R
R
+ +
Scheme 18: Urea synthesis from polyamines and phosgene.
In 1947, Boon et al. found that combining phosgene with N,N"-
dialkylethylenediamines or N,N",N""-trialkyl-1,4,7-triazaheptanes led to ureas L-CO-L,
- 37 -
where L is a polyamine ligand (80%) (Scheme 18).101-103 In the case of diamines,
imidazolidones were also obtained.101 These ureas were investigated as respiratory
stimulants after the discovery that O=C(NEt2)2 has such properties.101 The triamine
ligand MeN(-CH2CH2-N(Me)-CH2C6H4CH2-Cl)2 was prepared in 1994 from MeN(-
CH2CH2-NHMe)2 and ClCH2C6H4CO2Me.50
Si
NH N
N HN
Si
N
Si
NN
Si
N
MeMe Me
Me
Et Et
Et Et
ROHMeMeMe
Me
EtEt
Et Et
Li
Li
Scheme 19: Synthesis of an aza – macrocycle with organosilyl groups.
As shown in Scheme 19 dimethyldivinylsilane, Me2Si(-CH=CH2)2, and N,N"-
diethyl-N-lithio-ethylenediamine react to form aza – macrocycles having organosilyl
groups.104
NH2
NH2 Me-X
NH2
NHMe
NH2
NMe
Me
NH
NHMe
MeNH
NMe
Me
MeN
NMe
Me
MeMe
+ + + +
Scheme 20: Alkylation products from methylation of ethylenediamine.
- 38 -
In 1966, Roe et al. obtained mixtures of Me-NH-CH2CH2-NH2, Me-NH-CH2CH2-
NH-Me, Me2N-CH2CH2-NH2, Me2N-CH2CH2-NH-Me, and Me2N-CH2CH2-NMe2 when
alkylating ethylenediamine with methylating agents (Scheme 20).91
NH
NH2
NH2
NH
N
N
C R2R1
CR1 R2
OCR1 R2 NH
NH
NH
R2R1
R1 R2
LiAlH4
ROH+
- H2O
Scheme 21: Gelbardʼs strategy for alkylating terminal nitrogens of polyamines.
In 1969, Gelbard et al. found that alkylation of H2N-(CH2CH2-NH)n-H with ketones
or aldehydes followed by reduction led to terminally substituted diamines, triamines, and
polyamines in yields ranging from 80% - 95% (Scheme 21).88 This method converts
H2N-CH2CH2-NH2 to iPr-NH-CH2CH2-NH-iPr using acetone, but is limited to iminium
salts as it cannot introduce tert-butyl or phenyl groups.88 In 1977, Jutz et al. found that
R1R2N+=CR3R4 groups are reduced by NaBH4 to R1R2N-CHR3R4.105, 106
NH3Cl
Cl
NH2
NHEt
Et-NH2
Scheme 22: Singly substituted ethylenediamine by amination of halo – amines.
In 1988, Goldner et al. prepared Et-NH-CH2CH2-NH2 (70% yield) by reaction of
[Cl-CH2CH2-NH3]+Cl- with excess ethylamine (Scheme 22).92 Their product workup was
- 39 -
similar to the workup used in the synthesis of polyamines from 1,2-dibromoethane and
primary amines.31
In 1966, Gelbard synthesized [iPr-NH(-CH2CH2-Cl)2]+Cl- by reaction of ethylene
oxide with iso-propyl amine, followed by chlorination with SOCl2 (Scheme 23).89
OiPr-NH2
N
OH
OH
iPrSOCl2
NH
Cl
Cl
iPr
+ Cl-
N
NH
NH
iPr
iPr
iPr
iPr-NH2
Scheme 23: Triamine synthesis from ethylene oxide and a primary amine.
Reaction of [iPr-NH(-CH2CH2-Cl)2]+Cl- with two equivalents of iso-propyl amine
yielded 20% iPr-N(-CH2CH2-NH-iPr)2.89 Triamine yields were higher when aromatic
primary amines were used (Scheme 23).89
OCN O
Ph-NH2KOHNH
OC
OH
H2O
O
OHCN O
HN
NH
NH
- CO2
Scheme 24: N,N"-diphenyl-1,3-propanediamine from a cyclic carbamate.
- 40 -
In 1975, Ph-NH-(CH2)3-NH-Ph was prepared by nucleophilic attack on (-N(Ph)-
(CH2)3-O-CO-) at a CH2 site by aniline, evolving CO2 (52%) (Scheme 24).93 Harder
nucleophiles like OH- attacked at the carbonyl site, producing carbamates.93
R1-BCl2R2HCn(H2C) N
N N+N-
N+N-
R2HCn(H2C) N
NR1
R1
B
B
ClCl
ClCl- N2
R2HCn(H2C) NH
NHR1
R1
- HO-BCl2
H2O
Scheme 25: Substituted diamines from bis – azide compounds.
In 1992, N,N"-disubstituted diamines R1-NH-CHR-(CH2)n-NH-R1 have been
prepared from bis – azides N3-CHR-(CH2)n-N3 and R1-BCl2 followed by aqueous workup
(70%) (Scheme 25).94
Mixtures including polyamines have good adhesion properties to different
materials.107-110 Adhesives made with ethylenediamines, diethylenetriamines, and other
polyamines are used to bind layers of explosion – resistant laminated glass.111
Adhesion between glass layers reduces the quantity of glass projectiles in accidents /
explosions.111 Polyamide adhesives for the lamination of polyethylene and mylar films
are prepared from polyamines and polycarboxylated butadiene polymers.112
Polyethylenimine, (-CH2CH2-NH-)n, as copolymer, is used as wood adhesive in
plywood, giving it excellent shear strength and water resistance.113 Polyamine –
crosslinked epoxy resin adhesives are used for securing optical fibers in bundles.114
Linear or branched polyamides, prepared from polyamines, can be mixed with
- 41 -
polyisocyanates or epoxides to make heat curable polymers that seal or join metals.115-
117
Cl
NH3Cl+
CH2 CHCH2
nCH2 CH
CH2n
NH2N
HNN
NHN
HN
x
y
z1
z2
z3
H
H
H
HNaOHHeat
Scheme 26: Polymerization of Cl-CH2CH2-NH3Cl under basic conditions.
In 2001, Kuo et al. combined polyallylamine (-CH2CH[CH2NH2]-)n and [Cl-
CH2CH2-NH3]+Cl- to get “comb – burst” polymers in quantitative yields (Scheme 26),
useful in metal – chelating applications.118 The term “comb – burst” refers to the shape
of the polymer resembling a comb backbone with each comb tooth being a highly
branched polyamine.118 N,N"-Diphenyl-ethylenediamine is used in the manufacture of
metal clad polyimide laminates.119 Polyethylenimine polymers are used to deliver
nucleic acids in gene therapy.120 Diamines R-NH-(CH2)n-NH-R, where R = alkyl, aryl, or
H, and n = 1 – 6, are commonly used as copolymers along with piperazines and other
amines.121 Polyamide polymers are used in desalination applications.61, 122
Diamines and polyamines are excellent ligands for coordination chemistry.51, 53,
80, 81, 123 Polyamine complexes with most metals are known, for example rhodium is
complexed by N,N"-diphenyl-ethylenediamine in Rh[(Ph2P-C6H4CO)2(Ph-N-CH2CH2-N-
Ph)].124-126 N,N",N""-Trimethyl-1,4,7-triazaheptane coordinates to [Re(CO)3(H2O)3]+
facially to form [Re(CO)3L]+ (2007) (Figure 13).127
- 42 -
CN C
NH
CNH
CMe
Me
Me
O
O
O
CN OH2
NH
NH
Me
Me
Me
Re+1 Pt+2
Figure 13: Facial and meridial complexes of N,N",N""-trimethyl-1,4,7-triazaheptane.
Similar complexes Tc(CO)3L made with polyamine ligands L are used as
radiopharmaceuticals.127 The meridial complex [Pt(H2O)L]2+ was synthesized from
N,N",N""-trimethyl-1,4,7-triazaheptane (Figure 13).79 Mondal et al. synthesized nickel
complexes with N,N",N""-trimethyl-1,4,7-triazaheptane.80 Manganese complexes with
Me-NH(-CH2CH2-N(Me))2-H and Me-NH(-CH2CH2-N(Me))3-H are used in catalysis.76
Chiral aza – crown ethers were prepared from chiral 1,2-diphenyl ethylenediamines.47
Aza – crown ethers have also been prepared by the Mannich reaction.49 Aza –
macrocycles are used in ATP binding and coordination to metals,128 and are often
prepared by cyclizing N – substituted polyamines.54, 59 Aza – crown ethers are used in
the treatment of metal – sensitive degenerative diseases such as Parkinson's disease,
Alzheimer's disease, Lou Gehrig's disease, Binswanger's disease, Olivopontine
cerebellar degeneration, Lewy body disease, diabetes, stroke, atherosclerosis,
myocardial ischemia, cardiomyopathy, nephropathy, ischemia, glaucoma, presbycusis,
and cancer because they form stable complexes with most metals including Cu, Co, Fe,
Zn, Cd, Mn, and Cr, all metals of importance in neurological and other diseases.83
Mixed oxygen and nitrogen crown ethers are prepared by cyclizing Cl-CH2CH2-O-
- 43 -
CH2CH2-NH-R.55 Osmium – diamine complexes are used in the dihydroxylation of
alkenes.45 While nucleophilic substitution of R-Br fragments by amines typically takes
place under mild conditions, nucleophilic substitution of Ar-Br fragments normally
requires a metal – amine catalyst such as copper and forcing conditions.129
Diamines are used in the synthesis of cyclic thioureas.62, 102 N,N"-Diphenyl-
ethylenediamine is used as a component in phosphorescent organic electroluminescent
devices.130 Zirconocenes R2Zr(Ph-N-(CH2)3-N-Ph) have been prepared from Zr(Ph-N-
(CH2)3-N-Ph)Cl2(THF)2 and R = Cp type ligands.126, 131, 132 N-Arylhexahydropyrimidines
were synthesized by condensation of N-aryl-N"-alkyl-(aryl)-1,3-propanediamines with
aldehydes.133 N,N"-disubstituted-ethylenediamines are used in the preparation of anti –
allergenic medicines.134 Bis – aminals have been sythesized by the double
condensation of diamines or triamines with glyoxal.44
1.5.2. Aziridines
Aziridines are important building blocks in the synthesis of polyamines and
polymers that are typically prepared by elimination of a leaving group from haloamines
and similar molecules (Scheme 27).7, 135
X
NHR
- HX RN
Scheme 27: Aziridine synthesis by ring closure of . halo – amines.
- 44 -
Aziridines are used in organic synthesis,136, 137 as polymers and copolymers,41,
138, 139 and as anti cancer drugs (Figure 14).140
PN
SN N
Figure 14: Anti – cancer drug thiotepa.
As of 2008, they are one of five classes of alkylating agents used as
chemotherapy agents.140 Tris(1-aziridinyl)phosphine sufide, S=P(-N[-CH2CH2-])3, also
known as thiotepa, is used against breast, ovarian, and bladder cancers (Figure 14).140
N-tert-Butyl aziridine undergoes ring opening reactions when attacked by
nucleophiles.7 In 1968, Stamm found that excess CH2(CO2Et)2 ring opens N-tert-butyl
aziridine in the presence of LiH to tBu-NH-CH2CH2-CH(CO2Et)2 (Scheme 28).136
Et O C CH2C O Et
O O tBuN+ Et O C C O Et
O O
NHtBu
Scheme 28: Alkylation of aziridines by active methylene compounds.
The most important application of N-tert-butyl aziridine is in polymer chemistry.
N-tert-Butyl aziridine is a versatile building block and has been used as a copolymer to
prepare block, graft, comb, and star polymers.138 In 1984, Goethals et al. used N-tert-
- 45 -
butyl aziridine to prepare block copolymers with stryrene, butadiene, N-methyl aziridine,
THF, and ethylene oxide.141 Prior to this in 1981, Munir et al. prepared poly-tert-butyl
aziridine grafted to silica, by reacting silica, N-tert-butyl aziridine and H2N-CH2CH2CH2-
Si(-OEt)3 as a linking agent.139 In 1987, Goethals et al. quarternized poly-N-tert-butyl
aziridine with several alkylating agents resulting in incomplete alkylation. Nitrogen
atoms adjacent to alkylated nitrogen atoms (tBu) were unable to behave as nucleophiles
except toward powerful alkylating agents such as methyl trifluoromethanesulfonate.
Once alkylated, the quarternized poly-N-tert-butyl aziridine gradually decomposed,
releasing iso-butene.142 In 1996, Christova et al. cationically polymerized N-tert-butyl
aziridine using tetracyanoethylene as an electron acceptor.143 Only linear polymers
were detected, without any trace of tetracyanoethylene in the poly-N-tert-butyl aziridine
chains.143 In 1977, Bossaer et al. cationically polymerized N-tert-butyl aziridine with
[Et3O]+[BF4]- and found little cross linking between poly N-tert-butyl aziridine chains.
The steric bulk of the tert-butyl group of an aziridinium cation prevents nucleophilic
attack from the amino functionalities of (-(tBu)N-CH2CH2-)n.144 Goethals et al. found in
1977 that N-tert-butyl aziridine polymerizes more rapidly than N-tert-butyl azetidine
under identical conditions, owing to the differences in steric strain.145
1.5.3. Piperazines
N,N"-Dialkyl(aryl)piperazines are used in organic synthesis,7 pharmaceutical
production,140 petrochemical operations,41 and as components in polymers, plastics,
and adhesives.41, 111
- 46 -
N
NR
R
Cl
N
Cl
R
Br
Br
OH
OH
N
NH
HR-NH2
R-X
R-NH2Cat.
R-NH2Cat. / No Cat.
PO
OO O Cl
Cl
ClR-NH2
Scheme 29: Synthetic methods for preparing N,N"-dialkyl(aryl)piperazines.
N,N"-Dialkyl(aryl)piperazines are synthesized (Scheme 29) by cyclization of
nitrogen mustards with primary amines,146, 147 by the reaction of 1,2-dibromoethane with
primary amines (catalytic and non - catalytic) (2003),31, 148 by the catalyzed reaction of
ethylene glycol with primary amines,149-151 and by alkylation of piperazine by applicable
alkyl substituents R.152
N
X
X
R1
R2NH2
R3 C CH2C R3
O OR2N
NR1
R3 C C C R3O O
NR1
Scheme 30: Ring closure of nitrogen mustards to piperidines and piperazines.
In 1966, Katritzky synthesized 1-alkyl-4-tert-butylpiperazines from primary alkyl
amines and tBu-N(CH2CH2-Cl)2 in excellent yields.147 Besides producing 1-ethyl-4-tert-
- 47 -
butylpiperazine, 1-iso-propyl-4-tert-butylpiperazine, and N,N"-di-tert-butylpiperazine in
excellent yields with this method, Katritzky et al. used tBu-N(CH2CH2-Cl)2 to synthesize
numerous piperidines in good yields (Scheme 30).147 Haloamines such as tBu-
N(CH2CH2-Cl)2 are excellent precursors to piperidines and piperazines.7, 147
In 1977, a similar synthesis was developed by Bissell, who obtained good yields
of N,N"-diphenylpiperazine (and other piperazines) from the reaction of aniline (or other
primary aryl amines) with tris(chloroethyl) phosphate, O=P(-O-CH2CH2-Cl)3.146
In 1986, White et al. patented the synthesis of N,N"-dialkylethylenediamines such
as N,N"-di-tert-butylethylenediamine from primary amines, 1,2-dibromoethane, and a
copper catalyst.148 The major side products were N,N"-dialkylpiperazines, and amine
products had to be freed from the copper catalyst by complexing Cu2+ with EDTA.148
In 1991, Marsella synthesized mixtures of N,N"-dialkylethylenediamines, N,N"-
dialkylpiperazines, and N-alkylethanolamines from primary amines and ethyleneglycol in
the presence of RuCl2(PPh3)3 at low temperatures (120 °C),150 and this work led to a
patent (Scheme 29).151 Increasing the ratio of ethylene glycol to primary amine did not
significantly change the yield of N-alkylethanolamine, but it increased the ratio of N,N"-
dialkylpiperazine to N,N"-dialkylethylenediamine (1991).150 In most cases equimolar
amounts of N,N"-dialkylpiperazine and N,N"-dialkylethylenediamine were formed and
conveniently isolated by fractional distillation, so this synthesis is economical for both
products. For the reaction of ethyleneglycol with tert-butyl amine, increasing the ratio of
ethyleneglycol to tert-butyl amine from 2.9 : 1 to 3.0 : 1 increased the ratio of N,N"-di-
tert-butylpiperazine to N,N"-di-tert-butylethylenediamine from 3 : 84 to 14 : 37.150 In both
- 48 -
cases the dominant product was N,N"-di-tert-butylethylenediamine. The study shows
the f ine balance between N,N"-di-tert-butylpiperazine and N,N"-di-tert-
butylethylenediamine, since a negligible change in reactant ratio leads to a massive
change in the product ratio. Three years prior, in 1988, Su et al. patented a similar
catalytic process for the synthesis of N,N"-di-tert-butylpiperazine from ethylene glycol
and tert-butyl amine.149 Piperazines form from ethylene glycol and primary amines
using Ru2+, Ru3+
, and other metals as catalysts.149-151
In 2005, Ouk et al. synthesized mixtures of N-methylpiperazine and N,N"-
dimethylpiperazine from piperazine and dimethyl carbonate, an environmentally benign
compound, replacing toxic methylating agents like methyl iodide and dimethyl sulfate.152
N,N"-Dimethylpiperazine was the main product, but it was not possible to form only one
product in this system.152 A by – product of this reaction was carbamate formation
caused by carbonylation of piperazine competing with methylation.152
1.5.4. Haloamines
Nitrogen mustards find use as components in polymerization catalysts,153 as
copolymers154 and crosslinking agents,155 in organic synthesis,7 and as chemotherapy
agents.140 They are highly useful precursors to piperadines and piperazines.7
After Ludowieg et al. in 1948, in 1949 Abrams et al. synthesized Me-N(-CH2CH2-
OH)2 from methylamine and ethylene oxide.156, 157 Reaction of Me-N(-CH2CH2-OH)2
with SOCl2 yields [Me-NH(-CH2CH2-Cl)2]+Cl-.157 Numerous others have reported using
a similar method to obtain nitrogen mustards and haloamines from amino alcohols and
- 49 -
SOCl2 in good yields.156, 158-161 In 1981, [H3N+-CH2CH2-Cl]Cl- was prepared by reaction
of H2N-CH2CH2-OH with HCl, with continuous removal of water.162 Similar methods
yield [H3N+-CH2CH2-X]X- from H2N-CH2CH2-OH and HX (X = F, Cl, Br, I).163, 164
In 2003, Zeng polymerized Me-N(-CH2CH2-Cl)2 and obtained a highly branched
polymer with many quarternary amino groups.154 Nitrogen mustards are widely used
cross linking agents in polymer chemistry.41, 155
Nitrogen mustards are one of five main classes of alkylating agents used as
chemotherapy agents and are one of the oldest types of anticancer drugs (Figure 15).140
The first alkylating agent to be used medicinally (1942) was chlormethine, Me-N(-
CH2CH2-Cl)2, which is still used in the treatment of Hodgkinʼs disease, non – Hodgkinʼs
lymphoma, breast cancer, lung cancer, and melanoma.140
N CH3
Cl
Cl
Chlormethine
N
Cl
ClHO2C
Chlorambucil
N
Cl
ClH2N
HOO
Melphalan
N
Cl
Cl
NHPO O
Cyclophosphamide
NPOCl
OHN Cl
Ifosfamide
Figure 15: Nitrogen mustards currently in use as chemotherapy agents.
Nitrogen mustards readily form aziridinium ions that alkylate bases, including
DNA strands. The anticancer activity of nitrogen mustards results from intrastrand and
- 50 -
interstrand cross linking of DNA, preventing transcription and the growth of new cells
(Figure 15).140
Substitution is another common reaction with many nucleophiles,7 e.g.- Me-N(-
CH2CH2-Cl)2 forms Me-N(-CH2CH2-SH)2 and Me-N(-CH2CH2-SeH)2 by nucleophilic
substitution.165 In 1987, Golding et al. synthesized Me-N(-CH2CH2-X)2 (X = -S-SO3-, -
NH2, -S-C+(NH2)2Cl-) from Me-N(-CH2CH2-Cl)2 and S2O32-
, ammonia, and thiourea.166
In 2004, Parisel et al. synthesized the novel PN ligand (4-MeO-C6H4)-N(-CH2CH2-P(4-
MeC6H4)2)2 from (4-MeO-C6H4)-N(-CH2CH2-Cl)2 and (4-MeC6H4)2P(O)H.167
N
Cl
Cl
Me + CCH2
NC
N
NMe
Scheme 31: 1-Methyl-4-phenyl-4-cyanopiperdine synthesis.
1-Methyl-4-phenyl-4-cyanopiperdine was synthesized in 1986, by Mueller et al.
168 and in 1996, by Gnecco et al. 169 from Me-N(-CH2CH2-Cl)2 and Ph-CH2-CN (Scheme
31). Piperidines with a wide variety of substituents have been obtained by condensing
nitrogen mustards with various methylene compounds.170 Asymmetrically substituted
N,N"-dialkyl(aryl)piperazines are synthesized from nitrogen mustards and primary
amines.146, 147, 166 Symmetrically substituted piperazines can be synthesized from
nitrogen mustards,146, 147, 171 but this is not economical since there are one step
procedures for these compounds from inexpensive reagents.31, 149-151
- 51 -
N
Cl
Cl
Me +N
NMe
NH2
H2N NH2
Scheme 32: 1-Amino-4-methylpiperazine synthesis.
In 2004, Kushakova et al. synthesized 1-amino-4-methylpiperazine by
condensing Me-N(-CH2CH2-Cl)2 with hydrazine (Scheme 32).172 In 1973, Hauptmann
showed [H2N+(-CH2CH2-Cl)2]Cl- can be N – acylated by amides, carboxylic acid
anhydrides, and acid chlorides.173 Others have observed similar nucleophilic behavior
of haloamines.174
- 52 -
Chapter 2 – Results and Discussion
- 53 -
2.1. Reaction of 1,2-Dibromoethane with Primary Amine
Despite earlier reports in the literature175-179 about the reaction of 1,2-
dibromoethane with primary amines, the synthetic scope of the reaction has remained
unclear. Denk and Krause31 have previously obtained N,N"-di-tert-butylethylenediamine
and N,N"-di-iso-propyl ethylenediamine from the respective primary amines and 1,2-
dibromoethane in the context of research on stable carbenes,15, 20, 30, 37, 38, 62, 63
silylenes,64-73 and related species.74, 75 It was of interest to see if the developed
methodology can be extended to other primary amines as well.
Despite their structural simplicity, the synthesis of N,N"-disubstituted
ethylenediamines 1 and indeed of substituted ethylenediamines in general is not
straightforward because the reaction of ethylenediamine with alkylating agents like
methyl iodide is known to give mixtures of monoalkylated and polyalkylated compounds.
The introduction of N-protective groups can in principle solve this problem but also adds
protection and deprotection as two additional synthetic steps.88, 101, 175, 176, 180, 181
As already mentioned, the reductive alkylation of ethylenediamines with acetone
was used by Gelbhard et al. for the synthesis of the N-iso-propyl derivatives (Scheme
33).88, 180, 181
N
N
NH2
NH2
NH
NHAcetone LiAlH4R-OH
Scheme 33: Gelbardʼs imine approach to polyamines.
- 54 -
However, this approach only allows the introduction of substituents of the general
type RR"CH- which excludes common substituents R such as tert-butyl or phenyl.
Aldehydes form rather reduction resistant cyclic imidazolidines and are not well suited
for the reductive alkylation of ethylenediamines. Acylation with ketones and subsequent
reduction of the N-acyl amines circumvents the problem of polyalkylation but requires
the use of expensive complex hydrides (LiAlH4) in stoichiometric quantities.
A potentially general route for the synthesis of N,N'-disubstituted
ethylenediamines 1 that does not require multiple steps, special equipment or
expensive reagents is the reaction of primary amines with 1,2-dibromoethane (Scheme
34). Earlier studies in our group showed that 4 equivalents of primary amine and 1
equivalent of 1,2-dibromoethane led to good yields of N,N'-disubstituted
ethylenediamines. The reactions were conducted on a 25 g scale, the polyamine side –
products were identified by GC-MS, but the negligible amount formed initially prevented
isolation. To form a polyamine chain with n amino groups requires a polyamine chain
with n-1 amino groups. For this reason it is expected that longer polyamine chain yields
will be lower than shorter polyamine chain yields. To obtain gram quantities of longer
polyamines, the reaction must be accordingly performed on a bulk scale. To allow the
isolation of previously identified polyamines (GC – MS), and to isolate new polyamines,
the reaction was carried out on a kg scale. Previously, the 4 : 1 ratio led to stirring
problems due to the precipitation of HBr salts. To decrease the amount of undissolved
material, and to facilitate stirring, water was added to the reaction.
- 55 -
Br
BrRNH
NHR
N
N R
R
N R
RNH
NHR
N R
N R
RNH
NHR
N R
RNH
NHR
RN
NR
+ + + +5 eq R-NH2
20 °C / 1 wk
1 2
3
4
5
Scheme 34: Reaction of primary amines with 1,2-dibromoethane.
The reactions of 1,2-dibromoethane with primary amines RNH2 (R = Me, Et, iPr
and tBu) were carried out at room temperature with identical reaction conditions (section
3.1.). Aniline, which was included as a representative of aromatic amines, was found to
be less reactive, and unlike the alkylamines, required heating.
The reaction of primary amines RNH2 (R: Me, Et, iPr, tBu and Ph) with 1,2-
dibromoethane gave N,N"-disubstituted ethylenediamines R-NH-CH2CH2-NH-R (1) i n
yields ranging from 10 % (1a, R = Me) to 70 % (1d, R = tBu; 1e, R = Ph) (Figure 16).
Piperazines and N-substituted polyethyleneimines were identified (1H NMR, 13C NMR
and EI-MS) as side products of the reaction and isolated by fractional distillation.
Piperazines 2 are formed in yields ranging from 3% to 10% and can be separated from
the diamines 1 by distillation, except for R = Me and Ph, which were separated by
aluminum oxide columns. The polyamine homologues RNH-[CH2CH2NR]n-H (3 – 5)
were isolated in yields ranging from 0.1 % (n = 4, R = iPr) to 14 % (n = 2, R = iPr). The
yields of 1 increase with the size of the substituent R. This trend may reflect decreasing
- 56 -
solubility of the amines bearing larger organic groups in water. Isolation of amines from
the bulk mixtures first required neutralization (NaOH) and phase separation. The
organic layer was decanted from the aqueous phase. Finally the organic phase was
dried over NaOH pellets numerous times until they were unattacked indicating the
organic mixture was dry and ready for fractional distillation. For the more hygroscopic
amines (R = Me, Et) the drying procedure was repeated more times than for the less
hygroscopic mixtures. Lower ethylenediamines (R = Me, Et) are also more hygroscopic
than the higher ethylenediamines (R = iPr, tBu, Ph). This makes recovery from the
aqueous phases more difficult.
Figure 16: Isolated polyamine yields from primary amines R-NH2 (R = Me, Et, iPr, tBu, Ph) and 1,2-
dibromoethane.
- 57 -
N
N
Br
NH
Br
Br
NH
NH N
NH
NH
N
NH
N
NH
R
R
R
R
R R
R
R
R
RRN2
13
1 3 4
A
B
C
D
E F
13 13
R
R
Scheme 35: Possible reaction paths and intermediates leading to N – substituted piperazines and
triamines. A: no acid required, B: acid required, C >> D: 13 is more reactive than aziridines under basic
conditions, E >> F: ring closure is favored.
For all R groups, the polyamine yields decrease with increasing chain length.
This result supports the hypothesis that to form a polyamine with n amino groups, a
polyamine with n-1 amino groups must be consumed (Scheme 35). No obvious trend
between substituent groups (R) exists for piperazine and polyamine yields. The
dimerization of aziridines to piperazines occurs in the reaction of N-tert-butyl aziridine
with aniline. Besides forming tBu-NH-CH2CH2-NH-Ph, a significant amount of N,N"-di-
tert-butylpiperazine was obtained that accounts for about 50% of the N-tert-butyl
aziridine in the reaction. Under these reaction conditions N,N"-di-tert-butylpiperazine
could only have come from the dimerization of N-tert-butyl aziridine (Scheme 35).
- 58 -
The best yields of 1 were obtained by reacting 1,2-dibromoethane (1 eq.) with an
excess of the primary amine (5 eq). Attempts to use the addition of auxiliary bases like
NaOH or Na2CO3 to reduce the amount of primary amine to the theoretically required
amount (2 eq) led to lower yields.
The reactions did not require organic solvents but an adequate amount of water
greatly facilitated stirring by dissolving the voluminous amine hydrobromide salts which
form in the course of the reaction. Methylamine and ethylamine were accordingly used
in form of the readily available aqueous solutions. Apart from facilitating stirring, the
presence of water also accelerates the reactions.31 This effect was first noticed for tert-
butyl amine which gave a 75 – 80 % yield of 1d after only 24 hours at r.t. in water as
solvent whereas the reaction in hexanes (no water) required four days of boiling and the
use of an efficient overhead stirrer to give 1d in 50 % yield.72
Unlike tert-butyl amine, the sterically less hindered amines (R = Me, Et, iPr)
reacted in exothermic fashion and required ice cooling and slow mixing of the
components to prevent losses of the volatile amine. Despite their initial exothermic
nature, completion still required ~ 2 weeks at r.t which exceeded the reaction time
required for R = tBu (3d). This discrepancy may result from solubility effects operating
in the generally biphasic reaction mixtures. While the lipophilic 1,2-dibromoethane will
reside predominantly in the organic phase, the amines will reside in the aqueous phase
for R = Me, Et and iPr but in the organic phase for R = tBu.
The use of water or the sequence of the addition of the reagents did not
significantly influence the product distribution.
- 59 -
The less reactive aniline required heating, which (contrast to R = alkyl) was also
required to prevent a solidification of the reaction mixture. The mixture solidified upon
cooling and the workup (addition of NaOH) is best done while the reaction mixture is still
warm. With the exception of aniline, the reactions were conveniently carried out in
ordinary screw cap storage bottles connected to a bubbler and inert gas line.
Fractional distillation through a 20 cm Vigreux column separated the homologous
amines 1, 3, 4, and 5 (GC control) but gave mixtures of the ethylenediamines 1 and
piperazines 2 that required redistillation.31 Distillation failed to separate 1a /2a
(azeotrope) and 1e/2e (small boiling point difference). Pure materials (GC) were
obtained by continuous liquid – liquid counter extraction with hexane – water which
leads to enrichment of the more lipophilic piperazines 2 in the organic phase. Complete
separation was also achieved by column filtration of the piperazine / ethylenediamine
mixtures (ca. 1 g of mixture in 10 mL of hexanes) through a 30 cm column of neutral
Al2O3. The piperazines have significantly lower retention times and are thus readily
separated from the diamines which were obtained as second fractions with the more
polar CH2Cl2 as eluent. The former method is better suited for large quantities while the
column filtration is better suited for small amounts.
The generally very hygroscopic alkyl substituted ethylenediamines required
extensive drying over solid NaOH and subsequent distillation from sodium. Distillation
from NaOH or CaH2 was found to be insufficient. 1,4,7-Triphenyl-1,4,7-triazaheptane
has a high boiling point and is best purified by recrystallization (Table 5), however it can
also be distilled.
- 60 -
Table 5: Solubility data of 1,4,7-triphenyl-1,4,7-triazaheptane (3e).
Solu
tion
Mol
arity
(mol
/ L
Solve
nt)
0.00
0
0.00
2
0.01
5
0.02
3
0.02
7
0.10
0
0.46
9
0.91
6
Solu
tion
Mol
arity
(mol
/ kg
Solve
nt)
0.00
1
0.00
3
0.02
3
0.02
9
0.03
8
0.11
6
0.31
4
0.69
1
Solu
tion
Mol
arity
( mol
/ kg
Solu
tion)
0.00
1
0.00
3
0.02
3
0.02
9
0.03
8
0.11
1
0.28
5
0.56
2
Solu
tion
W/V
%(g
/ L
Solve
nt)
0.2
0.6
5.1
7.6
8.9
33.1
155.
5
303.
6
Solu
tion
W/W
%(g
/ kg
Solve
nt)
0.2
1.0
7.8
9.6
12.7
38.3
104.
2
229.
1
Solu
tion
W/W
%(g
/ kg
Solu
tion)
0.2
1.0
7.7
9.5
12.5
36.9
94.4
186.
4
Solv
ent MeO
H
Pent
ane
Hexa
ne
EtO
H 95
%
Et2O
Tolu
ene
CHCl
3
CH2C
l 2
- 61 -
Purification of 1,4,7-triphenyl-1,4,7-triazaheptane (3e) (m.p. = 118 – 119 °C, b.p.
= 250 – 252 °C / 0.1 torr) required distillation under dynamic vacuum. This involved
occasionally heating the distillation apparatus with a Bunsen burner to prevent
solidification and over – pressure from blockages. While the resulting product was pure,
recrystallization was explored as an alternative purification method. Of the solvents
tested (Table 5), only methylene chloride and chloroform dissolve significant amounts of
1,4,7-triphenyl-1,4,7-triazaheptane. Methanol and 95% ethanol are the best
recrystallization solvents for 1,4,7-triphenyl-1,4,7-triazaheptane because they have the
largest differences of product solubility between room temperature and boiling solvent.
The multiplicities and relative intensities of the 1H NMR and 13C NMR signals and
the comparison of the shifts in 2 - 5 with those of 1 allowed the assignment of most
signals although the assignment becomes more difficult with increasing chain length.
The methylene protons RNHCH2 attached to the outermost nitrogen were observed as
broad singlets, triplets or with higher multiplicities (e.g.- q). H,D-exchange experiments
with D2O reduced the signals to triplets and confirmed that the higher multiplicities were
caused by coupling with the NH protons.
The EI-MS spectra of the ethylenediamines (1, 3 - 5) showed [M+1] peaks which
presumably result from the formation of stable hydrates (and loss of [OH]•) in the
spectrometer. This also explains why the less hygroscopic piperazines show the usual
[M]+• peaks.
- 62 -
2.2. Reaction of 1,3-Dibromopropane with Primary Amines
The high yield synthesis for N,N"-dialkyl(phenyl)ethylenediamines from primary
amines and 1,2-dibromoethane suggested the investigation of the reaction of primary
amines with 1,3-dibromopropane, because N,N"-dialkyl(phenyl)-1,3-propanediamines
are important ligands in organic7 and inorganic synthesis (Scheme 36).6
Br
Br
NH
NH
R
R
R
R
N
N
NH
NH
N R
R
R
5 eq R-NH2
20 °C / 1 wk+ +
NR
+
6
7 8
9
Scheme 36: Diamines and polyamines from primary amines and 1,3-dibromopropane.
Figure 17: Polyamine yields from R-NH2 and Br-CH2CH2CH2-Br.
- 63 -
Identical conditions were used in the reactions of 1,3-dibromopropane with
primary amines and 1,2-dibromoethane with primary amines. The reactions of 1,3-
dibromopropane were scaled down to 50% of the reactions of 1,2-dibromoethane
because of higher reagent cost (Scheme 36).
The reaction of 1,3-dibromopropane with primary amines produces N,N"-
dialkyl(phenyl)-1,3-propanediamines in good yields and N,N",N""-trialkyl(phenyl)-1,5,9-
triazanonanes as valuable side – products that are readily separated by fractional
distillation (Figure 17).
Like the reaction of 1,2-dibromoethane with primary amines, the only obvious
product distribution trend is the higher yield of diamines compared to triamines (Figure
17). There is no obvious trend for the substituents. An apparent anomaly is the
isolation of N-tert-butylazetidine (b.p. = 30 – 32 ºC / 0.1 torr). For R = Me, Et, iPr, and
Ph the reaction mixtures did not contain N-substituted azetidines. One possible
explanation is that N-methyl azetidine, N-ethylazetidine, and N-iso-propylazetidine are
too volatile and boiled off before the crude mixtures were analyzed. However this does
not explain the absence of N-phenylazetidine which would be involatile enough to
remain in its crude reaction mixture. It is possible that Ph-NH-CH2CH2CH2-Br does not
cyclize.
A similarity to the reaction of 1,2-dibromoethane with primary amines is
the generally lower yield observed for N,N"-dialkyl(phenyl)-1,3-propanediamines for
smaller alkyl groups (Me, Et) compared to larger alkyl groups (iPr, tBu, Ph). This may
reflect the more hygroscopic nature of amines with smaller alkyl groups. The crude
- 64 -
mixtures were initially dried by storing over NaOH pellets, which causes phase
separation into an upper organic phase and a lower aqueous phase. The upper organic
phases were decanted and stored over fresh NaOH pellets, and this procedure was
repeated until no water could be drawn from the mixtures by NaOH. Higher
percentages of material were lost to the lower aqueous phase during the drying
procedure for R = Me and R = Et because those amines are more hydrophilic than for
the respective diamines with R = iPr, tBu, and Ph.
R
R
N
N
RN
NR
Figure 18: N – substituted piperazines and cyclooctanes.
The main products of the reactions of 1,2-dibromoethane and 1,3-
dibromopropane with primary amines were the respective diamines R-NH-(CH2)n-NH-R.
A major difference between the two reactions is that large quantities of piperazines were
formed, but no N,N"-dialkyl(aryl)-1,5-diaza-cyclooctanes were observed even in trace
amounts with (GC-MS) (Figure 18). This is readily understood as formation of six –
membered rings are more stable than eight – membered rings.7
A further difference between the reactions 1,2-dibromoethane and 1,3-
dibromopropane with primary amines is the lack of isolation of aziridines vs. the
isolation of azetidines.
- 65 -
tBuN
tBuN
RN
RN
6d6
Figure 19: N – substituted aziridines and azetidines.
The highly exothermic but kinetically slow ring opening reaction of aziridine is
well known and catalyzed by copper and other metals.41 The reaction of 1,2-
dibromoethane with primary amines did not yield aziridines for any R group, however
aziridines could have played a role as intermediates, and HBr catalyzed reactions could
have consumed them. N – substituted aziridines are known to be less stable than N –
substituted azetidines if both have the same R group, since 3 – membered rings are
less stable than 4 – membered rings.7 Once formed, an azetidine is also more likely to
persist than an aziridine (Figure 19).
To explore the possibility of synthesizing diamine ligands with different
substituents R1-NH-(CH2)n-NH-R2, and to quantify stability differences between N-tert-
butylaziridine and N-tert-butylazetidine, ring opening reactions of both compounds with
aniline were examined (Scheme 37).
The reactants N-tert-butylaziridine (b.p. = 99 °C / 760 torr) and N-tert-
butylazetidine (b.p. = 30 °C / 1 torr) are volatile, and high temperatures would be
required, so standard pressure reactions in glassware were ruled out. Stainless steel
Swagelok vessels were used. The Swagelok vessels used consist of a stainless steel
body, with two stainless steel caps, one for each end of the vessel.
- 66 -
24 hrs NH
5 eq C6H5-NH2225 °C
24 hrs NH
5 eq C6H5-NH2350 °C
24 hrs
5 eq C6H5-NH2225 °C
No Reaction
tBuN
tBuN
tBuNH
tBuNH
6d
10
11
Scheme 37: Ring-opening reactions of N-tert-butyl aziridine and N-tert-butyl azetidine with aniline.
N-tert-Butylaziridine was sealed in a Swagelok vessel with five equivalents of
aniline and heated at 225 °C for 24 hours. The major product was 10, N-tert-butyl-N"-
phenylethylenediamine (52%), with N,N"-di-tert-butylpiperazine as the only side –
product (40%). Distillation isolated N-tert-butyl-N"-phenylethylenediamine in 52% yield.
The Swagelok vessel, weighed before and after the experiment, confirmed that no
volatile materials were lost.
The same experiment was performed with N-tert-butylazetidine. Heating at 225
°C for 24 hours had no effect and NMR indicated the presence of only starting
materials. However, at 350 °C, all N-tert-butylazetidine reacted (Scheme 37), but the
yield was low (17%). The Swagelok vessel weighed before and after the experiment
confirmed the loss of volatile materials. To overcome the leakage problem, the
experiment was repeated by flame sealing N-tert-butylazetidine with 5 equivalents of
- 67 -
aniline in heavy wall glass tubing (10 mm outer diameter) so that 25% of the sealed
volume was occupied by liquid. The sealed glass tube was placed inside a Swagelok
vessel (to catch glass fragments if failure occured) along with 25% by volume water to
equalize the pressure on the glass. After heating at 350 °C for 24 hours, N-tert-butyl-N"-
phenyl-1,3-propanediamine was the only crude product and no material was lost.
Identical results from heating in a glass vessel and heating in a Swagelok vessel also
rule out significant effects of metal catalysis on the reaction from the stainless steel
vessel.
These experiments demonstate the higher reactivity of N-tert-butylaziridine and
the higher stability of N-tert-butylazetidine at least regarding the reaction with aniline.
Asymmetric diamines R1-NH-(CH2)n-NH-R2 can be synthesized in good yields from N-
tert-butylaziridine and N-tert-butylazetidine.
2.3. Phosphenium Cation Stabilization with Triamine Ligands
Previous work by Denk et al. on low coordinate phosphorus has shown that
phoshorus can exist in coordination number 2 as a cation when stabilized by electron
rich ethylenediamine ligands.74, 75 To further explore the stablization of dicoordinate
phosphenium cations, intramolecular # – donation was investigated.
- 68 -
25
+ Cl-
NH
N
NH
tBu
tBu
tBu
2.5 eq Et3N 5.5 mL Toluene20 °C / 24 hrs
- 2 eq [Et3NH]+Cl-+ PCl3
1 eq0.506 g
1 eq1.000 g
N P:N
N
tBu
tBu
tBu
Crude Yield = 73%Yellow Solid
3d
Scheme 38: Synthesis of 25 from N,N",N""-tri-tert-butyl-1,4,7-triazaheptane.
N,N",N""-Tri-tert-butyl-1,4,7-triazaheptane was selected as the stabilizing ligand
because tert-butyl groups were successful at stabilizing dicoordinate phosphorus in
previous studies,74, 75 and because radially symmetric tert-butyl groups lead to less
complex product NMR spectra than non – symmetric alkyl groups.
One equivalent of PCl3 was added to a mixture of N,N",N""-tri-tert-butyl-1,4,7-
triazaheptane in toluene with triethylamine as auxiliary base (Scheme 38). The
exothermic reaction immediately precipitated triethylamine hydrochoride and the mixture
changed from clear to cloudy. The result was chlorophosphane 25, a dicoordinate
phosphenium cation stabilized by intramolecular # – donation.
The crude mixture was frit filtered and washed with toluene which dissolves the
phosphenium cation and leaves behind triethylamine hydrochloride (Figure 20). NMR
(1H, 13C, 31P) of the filtrate mixture indicated the presense of side – products. The
filtrate was extracted with hexane, separating the side – products from the target
phosphenium cation. The side – products were insoluble in hexane, soluble in toluene,
- 69 -
had many 13C NMR signals, and were involatile from low temperatures up to 300 °C /
0.1 torr.
Crude Mixture
Filtrate(1.132 g)
Residue 1(1.574 g)[Et3NH]+Cl-
Residue 2(0.166 g)Unknown
Extract(0.909 g)[N3P]+Cl-Yellow Solid
1. Frit Filtration2. Wash 3 ! 5 mL Toluene
Extract 3 ! 5 mL Hexane
ReactionTheoretical Yield [N3P]+Cl-: 1.237 g
Figure 20: Purification strategy for [N3P]+Cl- (25).
- 70 -
Cl-
(D)H2C
N P+
N
H2(C)C
(D)H2CCH2(C)
N
tBu(B)
tBu(B)
tBu(A)
25
tBu(A)
tBu(B)
?
?tBu(A)
tBu(B)
CH2(C)CH2(D)
Figure 21: 13C NMR (C6D6) spectrum of 25.
The presence of 13C – 31P coupling in 13C NMR is a useful identification tool for
phosphenium cation 25, as it allows it to be distinguished from 3d, a compound with the
- 71 -
same number and pattern of peaks (Figure 21). All 13C signals of 25 are doublets, while
all 13C signals of 3d are singlets. The presence of two extra signals in the 13C NMR
spectrum of 25 indicates 25 was still contaminated with 3d.
Cl-
N P:N
N
tBu
tBu
tBu N P:N
N
tBu
tBu
+
25
- H2C=C(CH3)2
- HCl
Scheme 39: Elimination of iso-butene from 25.
X – ray analysis of the 0.909 g sample of 25 shows an unexpected counter – ion,
[PO2Cl2]-, instead of Cl-. NMR analysis (1H, 13C, 31P) of the 0.909 g quantity of 25
indicates there is only one compound present. If the counter – ion was [PO2Cl2]-, the
maximum yield could only be 0.800 g. Therefore, the reaction product could not have
been 25•[PO2Cl2]-. NMR analysis of our sample does show the presence of a minor
- 72 -
impurity. It is possible the X – ray crystallographer analyzed an impurity crystal rather
than a crystal of the major product. We need to examine the 0.909 g sample of 25 by
elemental analysis to confirm our reaction product was 25•Cl-, but regardless of counter
– ion issues, N,N",N""-tri-tert-butyl-1,4,7-triazaheptane has stabilized a dicoordinate
phosphenium cation.
The structure of chlorophosphane 25 (A.2.1.) is similar to boat S4N4. The bond
distance of the central tert-butyl group to the central nitrogen in 25 is 1.567 Å, while in
methylamine the C – N bond distance is 1.47 Å. Steric repulsion contributes to this
lengthened bond, as well as electron depletion of the central nitrogen by the
phosphenium cation. It was suspected that this central C – N bond was weak, and
potentially close to a transition state of a decomposition reaction to eliminate iso-butene
from 25 (Scheme 39). This is not the case considering DFT calculations indicate the C
– N bond of 25 is nearly as strong as the C – N bond in methylamine, and the the X –
ray data indicate no nucleophiles are in close proximity of the central tert-butyl group.
2.4. Synthesis of N,N",N""-tri-tert-butyl-1,4,7-triazaheptane
The ability of N,N",N""-tri-tert-butyl-1,4,7-triazaheptane to stabilize a dicoordinate
phosphenium cation prompted investigation of improved synthetic methods for this
ligand. The reaction of 1,2-dibromoethane with tert-butyl amine produces N,N",N""-tri-
tert-butyl-1,4,7-triazaheptane but only in low yields (2%).31 In the search for an ideal
precursor to N,N",N""-tri-tert-butyl-1,4,7-triazaheptane, the HX salts of tBu-NH-CH2CH2-
Br, and tBu-NH-CH2CH2-Cl, were explored.
- 73 -
Filtrate Precipitate145 g
Precipitate67 g
Precipitate45 g
Precipitate28 g
Precipitate23 g
Precipitate16 g
Filtrate
Filtrate
Filtrate
Filtrate
Filtrate
1. Reflux2. Cool to 20 °C3. Crystallize Product
Reaction: tBu-NH-CH2CH2-OH + 48% aq. HBrTheoretical Yield tBu-NH2
+Br--CH2CH2-Br: 463 g
Total Precipitate (tBu-NH2+Br--CH2CH2-Br)
Yield: 324 g, 70%
1. Reflux2. Cool to 20 °C3. Crystallize Product
1. Reflux2. Cool to 20 °C3. Crystallize Product
1. Reflux2. Cool to 20 °C3. Crystallize Product
1. Reflux2. Cool to 20 °C3. Crystallize Product
1. Reflux2. Cool to 20 °C3. Crystallize Product
Scheme 40: Diminishing yields in tBu-NH2+Br--CH2CH2-Br (13d) synthesis.
The first precursor tested was [tBu-NH2+-CH2CH2-Br][Br-] because it was an
intermediate in the reaction of 1,2-dibromoethane with tert-butyl amine. The goal was to
obtain N,N",N""-tri-tert-butyl-1,4,7-triazaheptane from [tBu-NH2+-CH2CH2-Br][Br-] and tBu-
- 74 -
NH-CH2CH2-NH-tBu in one step. In the synthesis of [tBu-NH2+-CH2CH2-Br][Br-] it
appears that diminishing yields after each reflux / precipitate cycle initially follow a
logarithmic decay (Scheme 40). Once 60% of the theoretical 13d has been collected
the yields diminish linearly. Extrapolating from the data: six precipitate collections is
efficient, and a seventh precipitate would be insignificant.
The salt [tBu-NH2+-CH2CH2-Br][Br-] was obtained from 48% HBr and the amino
alcohol tBu-NH-CH2CH2-OH. The synthesis of [tBu-NH2+-CH2CH2-Br][Br-] proceeds in
equilibrium controlled stages (Scheme 40). After refluxing, the reaction mixture was
allowed to cool to room temperature and precipitation of [tBu-NH2+-CH2CH2-Br][Br-] was
induced by scratching the reaction flask with a glass rod. After removal of the filtrate
from the reaction mixture by frit filtration, further heating formed more product. Without
product removal of the salt, further heating of the reaction mixture did not improve
yields. Heating / filtration cycles were performed until the returns were negligible.
The cascade of isolated yields illustrated in Scheme 40 indicates the synthesis of
[tBu-NH2+-CH2CH2-Br][Br-] is an equilibrium reaction. In contrast, the high yield
synthesis of [tBu-NH2+-CH2CH2-Cl][Cl-] from tBu-NH-CH2CH2-OH and SOCl2 (Table 6) is
not controlled by equilibrium because SO2(g) leaves the reaction vessel allowing the
reaction to proceed to completion.
- 75 -
Table 6: Batch yields of 2-(tert-butylamino)-ethyl chloride hydrochloride (12d).
The synthesis of [tBu-NH2+-CH2CH2-Cl][Cl-] proceeds in one step, and the yields
were substantially higher (Table 6) than for [tBu-NH2+-CH2CH2-Br][Br-]. The first two
batches of crude [tBu-NH2+-CH2CH2-Cl][Cl-] were frit filtered, and were pure by NMR,
but had impurities (increased m.p. after diethyl ether washes). Batches 3 and 4 were
purified by washes of diethyl ether, and after this treatment recrystallization did not raise
the melting point.
Experiments with [tBu-NH2+-CH2CH2-Br][Br-] and [tBu-NH2
+-CH2CH2-Cl][Cl-] did
not provide high yields of N,N",N""-tri-tert-butyl-1,4,7-triazaheptane. Two main
experiments were explored: [tBu-NH2+-CH2CH2-X][X-] plus tert-butyl amine and [tBu-
NH2+-CH2CH2-X][X-] plus tBu-NH-CH2CH2-NH-tBu. In both reactions mole ratio, water
quantity, and addition of NaOH or triethyl amine were varied. The results were either
polymer formation, or the formation of N,N"-di-tert-butylpiperazine, together with traces
(GC-MS) of N,N",N""-tri-tert-butyl-1,4,7-triazaheptane. Some of these experiments had
excellent yields of N,N"-di-tert-butylpiperazine (> 80%). These results are not surprising
since different halo – amines are known to dimerize or polymerize.118
- 76 -
In both experiments, the formation of N,N"-di-tert-butylpiperazine can be
accounted for by the dimerization of two [tBu-NH2+-CH2CH2-X][X-] molecules, after being
fully or partially deprotonated by tert-butyl amine or tBu-NH-CH2CH2-NH-tBu.
tBuNH2Cl
CltBuN!+
H2C!+H
tBuN
‡
tBuN+
tBuN H
tBuN!+CH2!+
tBuN H
‡
tBuN+ H
tBuN
tBu
tBuN
N
tBuNH
NHtBu
2d
1d
12d
Scheme 41: Substituted piperazines from substituted diamines.
Another possible mechanism of N,N"-di-tert-butylpiperazine formation could have
involved dimerization of N-tert-butylaziridine (Scheme 41), which was observed in our
reaction of aniline with N-tert-butylaziridine. Piperazines have a thermodynamic
advantage (6 – membered ring formation) over other compounds and that is why they
were the major products of these reactions, irrespective of concentration, temperature,
mole ratio, and auxiliary bases.
Compounds structurally similar to 3-(tert-butyl)-aza-1,5-dichloropentane
hydrochloride (16) are widely used to add piperazine and piperidine groups into organic
- 77 -
molecules containing amino or nucleophilic CH2 functionalities.7 Despite this, under the
correct conditions, it was hypothesized that [tBu-NH+(-CH2CH2-Cl)2][Cl-] would be an
excellent precursor to N,N",N""-tri-tert-butyl-1,4,7-triazaheptane (3d).
N+
Cl
Cl
tBu
HN+
Cl
tBu
H
tBuNH
N
Cl
tBuNH
tBu
tBu
NH
N+
tBu
tBuN
N
tBuNH
tBuNH
tBuN
tBu-NH2
tBu-NH2Cyclize- HCl
Cyclize- H+
- Cl-
Cyclize- 2 HCl
tBu-NH2
tBu- H+
+ H+
2d
3d
16
Scheme 42: N – Substituted piperazines from N – substituted nitrogen precursors.
Experiments on 3-(tert-butyl)-aza-1,5-dichloropentane hydrochloride plus tert-
butyl amine explored variations of mole ratio, temperature, concentration, and auxiliary
bases. As with the experiments on [tBu-NH2+-CH2CH2-X][X-], the major reaction product
was N,N"-di-tert-butylpiperazine. While not the desired product, Scheme 42 shows a
possible mechanism of piperazine formation for the reaction.
In the reactions of the HX salts of tBu-NH-CH2CH2-Br, and tBu-NH-CH2CH2-Cl,
ring closure to N,N"-di-tert-butylpiperazine dominated, even though numerous other
- 78 -
products could have formed. For these precursors to N,N",N""-tri-tert-butyl-1,4,7-
triazaheptane to be successful, protecting groups on attacking amino groups must be
used to prevent cyclization. This adds protection and deprotection as two additional
synthetic steps, and these steps may have challenges of their own. For this reason the
most convenient synthesis for N,N",N""-tri-tert-butyl-1,4,7-triazaheptane is the reaction of
1,2-dibromoethane with tert-butyl amine.
2.5. Salts as Carbene Precursors
1,3-Di-tert-butylimidazol-2-ylidene hydrochloride is a valuable carbene ligand in
catalyst research. The synthesis of 1,3-di-tert-butylimidazol-2-ylidene hydrochloride
yields brown crude material that is only 95% pure by NMR. It is of interest to purify this
compound because it is the precursor to 1,3-di-tert-butylimidazol-2-ylidene, a valuable
carbene ligand. Crude 1,3-di-tert-butylimidazol-2-ylidene hydrochloride is not well
purified by recrystallization from common solvents because either the compound
solubility is too low to be practical, or the impurities are just as soluble as the
compound. They require multiple recrystallizations typically leading to a low isolated
yield. However, the best recrystallization solvents for this compound are 95% ethanol
and iso-propanol. In an attempt to purify 1,3-di-tert-butylimidazol-2-ylidene
hydrochloride by sublimation, iso-butene was eliminated yielding 1-tert-butylimidazole
hydrochloride (19). Initially it was thought the sublimation worked because yellow
crystals had formed on the condenser, but NMR analysis showed only the presence of
the decomposition product 1-tert-butylimidazole hydrochloride (Scheme 43).
- 79 -
1.5 eq NaOH- H2O- NaClYield = 82%
tBuN
NC H
tBuN
NC:
- CH2=C(CH3)2Yield = 100%
tBuN
N+
H
C H
Cl-
- CH2=C(CH3)2Yield = 75%
tBuN
NC+ H
Cl-
225 °C12 hrs
225 °C12 hrs
CCH3
H3C
CCH3
H3C CH2
CH2 H
H
20
19
Scheme 43: Thermolysis of a stable carbene and the protonated carbene.
The synthesis of imidazolium salts from primary amines, glyoxal, para-
formaldehyde, water, and an acid catalyst was introduced by A. J. Arduengo. The
synthesis of 1-tert-butylimidazole (20) has been reported in the literature.182 The
thermolysis of 1,3-di-tert-butylimidazol-2-ylidene hydrochloride was conducted, and after
recrystallization, 1-tert-butylimidazole hydrochloride (19) was obtained in good yield, so
the method was extended to the free carbene 1,3-di-tert-butylimidazol-2-ylidene. The
result was quantitative conversion of 1,3-di-tert-butylimidazol-2-ylidene to 1-tert-
butylimidazole. No side – products were detected by NMR. The clean elimination of
tert-butyl groups from 1,3-di-tert-butylimidazol-2-ylidene and related compounds may be
a useful protective group strategy in multistep syntheses.
- 80 -
Pd
N C
CN
n(H2C)
N
N
X1
X2
tBu
tBu
PdPd
N C
CN
n(H2C)
N
N
X1
X2
tBu
tBu
Pd
Figure 22: Bis – carbene ligands in catalytic complexes.
For example, the synthesis of tethered N – heterocyclic carbenes for use in
catalysis can be accomplished (Figure 22).123, 183, 184
The reaction of 1-tert-butylimidazole with Br-(CH2)n-Br was investigated as a
synthetic route to tethered imidazolium salts, because they are precursors to tethered N
– heterocyclic carbenes. When four equivalents of Br-(CH2)n-Br (n = 1, 2, 3) were
combined with only one equivalent of 1-tert-butylimidazole, only tethered imidazolium
salts (22, 23 , 24) were obtained, and no [tBuIm+Br-]-(CH2)n-Br (52) was observed
(Scheme 44). Yields were: 22 = 25%, 23 = 87%, and 24 = 90%. [tBuIm+Br-]-(CH2)n-Br
(n = 1, 2, 3) is substantially more reactive toward nucleophiles than Br-(CH2)n-Br (n = 1,
2, 3), because all of it was consumed despite the large excess of Br-(CH2)n-Br.
- 81 -
tBu
N
NC H
tBuN
C+ H
tBuN
C+ HN
n(H2C)N
Br- 2 Br-tBuN
C+ H
Brn(H2C)
N
Br-(CH2)n-Br
20
22 (n = 1)23 (n = 2)24 (n = 3)
20
52
Scheme 44: Synthesis of N – tethered bis-imidazolium salts.
2.6. Outlook and Future Experiments
The formation of N,N",N""-tri-tert-butyl-1,4,7-triazaheptane was hindered by the
competing reactions leading to N,N-di-tert-butylpiperzine. Nitrogen protecting groups
can be used to supress these (Figure 23).
N
Cl
tBu
tBuN S
O
O
Figure 23: Nitrogen electron withdrawal by tosyl groups.
Nitrogen atoms attached to tosyl groups (Figure 23) undergo electronic
deactivation, and become less nucleophilic. The intermediate in Figure 23 is therefore
not likely to ring – close to form a piperazine due to the steric and electronic interference
- 82 -
from the tosyl group. Protecting group strategies for N,N",N""-tri-tert-butyl-1,4,7-
triazaheptane will initially focus on tosyl groups.
N
Cl
CltBuNH
tBuNH
tBuNtBuNH2
SCl
O O
SO O
tBuNH
N
Cl
tBuN
tBu
tBuN
N+S!+
O!-
O!-
N
N
tBuN
tBu
tBu
tBuN
N
tBu
tBu tBu
Ts
Ts
Ts
TsCl
tBu-NH-Ts
i
ii iii iv
v
vi
3d
2d
18
i = ", NEt3ii = ", NEt3iii = tBu-NH-Tsiv = NaOH / H2Ov = "vi = NaOH / H2O
Scheme 45: Protecting strategies using [R-NH+(CH2CH2-X)2][X-].
The advantage of the protecting group strategy shown in Scheme 45 is the
synthesis of tBu-NH-Ts only involves inexpensive reagents tert-butyl amine and tosyl
chloride and mild reaction conditions. By reacting [tBu-NH+(CH2CH2-Cl)2][Cl-] with an
excess of tBu-NH-Ts, the main product should be tBu-N(CH2CH2-N(Ts)-tBu)2, an
intermediate protected at both NH sites. Detosylation of tBu-N(CH2CH2-N(Ts)-tBu)2 will
provide N,N",N""-tri-tert-butyl-1,4,7-triazaheptane.
- 83 -
tBuNH
tBuNH
tBuNSCl
O O
TsCl
i
tBuNH2Cl
Cl
tBuNH
NHtBu
tBuN
Cl
Ts
N
NH
tBuN
tBu
tBu
Ts
ii
iii
N+
N+TstBu
Ts tBu
2 Cl-
iv
12d
3d
1d
i = !, NEt3ii = !iii = !, NEt3iv = NaOH / H2O
Scheme 46: Protecting groups to triamines using [R-NH2+-CH2CH2-X][X-].
An alternative protecting group strategy for N,N",N ""-tri-tert-butyl-1,4,7-
triazaheptane is shown in scheme 46. By reacting N – protected tBu-N(Ts)-CH2CH2-Cl
with tBu-NH-CH2CH2-NH-tBu, there should be no opportunity for piperzine formation.
This proposed synthesis should yield N,N",N""-tri-tert-butyl-1,4,7-triazaheptane without
using the chemotherapy agent [R-NH+(CH2CH2-X)2][X-], or its corresponding and highly
toxic nitrogen mustards.
N SiN
N
tBu
tBu
tBu
53 54
N SiN
N
tBu
tBu
tBuH ClH H
Figure 24: Silylene precursors.
- 84 -
Recently, Jeff Hastie synthesized compounds 53 and 54 (Figure 24), precursors
to silylenes structurally similar to the first stable silylene made by Denk in 1994, a critical
silicon molecule featured in books.123
N SiN
N
tBu
tBu
R N PN
N
tBu
tBu
RO N
55 56
Figure 25: Phosphorus and silicon multiple bonds.
Jeff Hastieʼs work shows the value of R-N(-CH2CH2-NH-tBu)2. The next synthetic
targets will be the first stable silicon-oxygen double bond (55) and the first stable
phosphorus-nitrogen triple bond (56) (Figure 25).
- 85 -
Chapter 3 – Experimental Procedures
- 86 -
Melting points were recorded in sealed capillaries and are uncorrected. GC-MS
spectra were obtained with a Varian CP-3800 GC / Saturn 2000 MS combination at an
ionizing voltage of 70 eV and a 30 m x 0.25 mm Varian CP 5860 low bleed phenyl –
dimethylsiloxane column (5 % phenyl). Temperature program: 4 min at 50 °C; 10 min
constant heating rate of 20 °C / min; 6 min at 250 °C. HR-MS data of the previously
unknown amines (3d, 3e) were obtained with a VG ZAB-R instrument at the McMaster
Regional Centre for Mass Spectrometry (Hamilton, Ontario). NMR-spectra (chemical
shifts in *) were recorded with a Bruker 400 MHz spectrometer at normal spectrometer
temperature. The 1H NMR and 13C NMR spectra are referenced vs. TMS (internal). The
31P NMR are referenced vs. H3PO4 (internal pipette). All NMR spectra were obtained
with flame sealed samples. All starting materials were obtained from Aldrich Inc. and
used as received. The products were handled in an atmosphere of nitrogen or argon
(purity 99.994 or better). Yields refer to isolated products unless noted otherwise.
Previously described compounds in the literature are identified by their CAS numbers.
Hexanes, pentane, benzene, toluene, diethyl ether, and triethyl amine were dried by
distillation over Na / K alloy with Ph2C=O, after pre-drying by storing over NaOH pellets.
CHCl3 and CH2Cl2 were dried by storing over CaH2. Alkylating compounds [R-NH2+-
CH2CH2-X][X-] were handled with extra caution. All glassware was flame dried under
vacuum prior to use for air / moisture sensitive compounds. All distillations were
performed under vacuum or in an argon atmosphere. All compounds were handled
under an inert atmosphere of nitrogen or argon. All solubility data were obtained by
taking aliquots of the respective solutions, saturated at room temperature. After
- 87 -
weighing the saturated solution, the solvent was removed under vacuum and the
amount of dissolved material determined by weighing.
3.1. Reaction of 1,2-Dibromoethane with Primary Amines
Br
BrRNH
NHR
N
N R
R
N R
RNH
NHR
N R
N R
RNH
NHR
N R
RNH
NHR
RN
NR
+ + + +5 eq R-NH2
20 °C / 1 wk
1 2
3
4
5
Scheme 34: Reaction of primary amines with 1,2-dibromoethane.
General procedure for the reaction of primary amines with 1,2-dibromoethane
(Scheme 34): The primary amine (5 eq), and 1,2-dibromoethane (1 eq, 86 mL) were
mixed in a bottle of suitable size and magnetically stirred at room temperature for 2
weeks. For R = iPr, tBu, Ph: 300 mL H2O was added to the mixture to accelerate the
reaction and keep the HBr salts dissolved (Scheme 47). For R = Me, Et the aqueous
solutions (Me: 40% w/w, Et: 70% w/w) were used and no water was added. Initial ice
cooling was required for the sterically lower alkyl amines (R = Me, Et and iPr). For
aniline, the mixture was boiled for 24 h in a round bottom flask equipped with a
magnetic stir bar and reflux condenser. The amine product mixtures are obtained by
- 88 -
adding NaOH pellets in 20 g portions under ice cooling and constant stirring (caution:
gas evolution of methylamine and ethylamine). The crude amine layer (top) was
separated, stirred with 50 g of NaOH pellets for 24 h and decanted. The procedure was
repeated until the NaOH remained undissolved. The amines 1 – 5 were isolated by
fractional distillation of the crude, predried (NaOH) amine mixture over 5 g of sodium
with the help of a 30-cm Vigreux column. For isolated yields, see Table 7. The
incompletely separated fractions containing 1a / 2a and 1e / 2e were dissolved in the
tenfold volume of hexanes and filtered through a 30 cm column of neutral Al2O3 (10 g / 1
g of amine mixture). The filtrates were collected in 5 mL fractions and the pure (by GC)
fractions combined to give, after evaporation of the solvent in vacuo, the pure amines
1a, 2a, 1e, 2e. Recovery > 90 %.
Table 7: Product yields from R-NH2 (5 eq) and Br-CH2CH2-Br (1 eq).
- 89 -
3.1.1. N,N"-Dimethylethylenediamine (1a) CAS [110-70-3]
Colorless oil, b.p. = 121 – 123 °C (azeotrope: 10% 2a, 90% 1a), b.p. = 119
– 120 °C (pure 1a). 1H NMR (C6D6): 1.03 [s, 2H, N-H], 2.33 [s, 6H, N-
CH3], 2.55 [s, 4H, N-CH2]. 13C NMR (C6D6): 36.7 [N-CH3], 52.0 [N-CH2].
GC-MS (tr = 3.3 min): 89(75) [(M+1)+], 75(5) [H3C-NH-CH2CH2-N+(H)3],
58(100) [H3C-(H)N+(-CH2CH2-)], 57(50) [H3C-N•+(-CH2CH2-)], 56(25) [H3C-N+(=CH-CH2-
)].
3.1.2. N,N"-Dimethylpiperazine (2a) CAS [106-58-1]
Colorless oil, b.p. = 127 – 130 °C. 1H NMR (C6D6): 2.13 [s, 6H, N-CH3],
2.33 [s, 8H, N-CH2]. 13C NMR (C6D6): 46.2 [N-CH3], 55.5 [N-CH2]. GC-
MS (tr = 5.0 min): 114(100) [M•+], 85(15) [H3C-N+(-CH2CH2-)(-CH2CH2•)],
71(30) [H3C-N+(=CH2)(-CH2CH2• )], 70(35) [H3C-N+(=CH2)(-CH=CH2)],
58(25) [H3C-(H)N+(-CH2CH2-)], 57(20) [H3C-N•+(-CH2CH2-)], 56(30) [H3C-N+(=CH-CH2-
)].
3.1.3. 1,4,7-Trimethyl-1,4,7-triazaheptane (3a) CAS [105-84-0]
Colorless oil, b.p. = 55 – 56 °C / 0.1 torr. 1H NMR (C6D6): 1.05 [s, 2H,
NH], 2.10 [s, 3H, R2N-CH3], 2.32 [s, 6H, R-NH-CH3], 2.36 [t, 4H, 3J(H,H)
= 6 Hz, R-NH-CH2CH2], 2.53 [t, 4H, 3J(H,H) = 6 Hz, R-NH-CH2CH2]. 13C
NMR (C6D6): 36.8 [R-NH-CH3], 42.4 [R2N-CH3], 50.1 [R-NH-CH2CH2],
MeNH
NHMe
MeN
NMe
MeNH
NHMe
N Me
- 90 -
57.8 [R-NH-CH2CH2]. GC-MS (tr = 8.2 min): 146(20) [(M+1)+], 115(5) [H3C-NH-
CH2CH2-N+(CH3)(-CH2CH2-)], 101(35) [H3C-NH-CH2CH2-N+(H)(-CH2CH2-)], 89(5) [H3C-
NH-CH2CH2-N+(H)2-CH3], 72(15) [H3C-N+(=CH2)(-CH2CH3)], 58(100) [H3C-(H)N+(-
CH2CH2-)].
3.1.4. 1,4,7,10-Tetramethyl-1,4,7,10-tetraazadecane (4a) CAS [105-78-2]
Colorless, viscous oil, b.p. 89 – 90 °C / 0.1 torr. 1H NMR (C6D6): 1.24
[s, 2H, NH], 2.12 [s, 6H, R2N-CH3], 2.13 [s, 6H, R-NH-CH3], 2.39 [s, 4H,
5,6-CH2], 2.40 [t, 4H, 3J(H,H) = 7 Hz, 3,8-CH2], 2.55 [q, 4H, 3J(H,H) = 7
Hz, 2,9-CH2]. 13C NMR (C6D6): 36.8 [R-NH-CH3], 42.8 [R2N-CH3], 50.2
[2,9-CH2], 56.4 [5,6-CH2], 57.8 [3,8-CH2]. EI-MS (direct inlet): 203(100)
[(M+1)+], 129(5) [H3C-NH-CH2CH2-N(CH3)-CH2CH2-N•+], 115(7) [H3C-
NH-CH2CH2-N+(CH3)(-CH2CH2-)], 72(12) [H3C-N+(=CH2)(-CH2CH3)].
3.1.5. N,N"-Diethylethylenediamine (1b) CAS [111-74-0]
Colorless oil, b.p. = 152 – 153 °C. 1H NMR (C6D6): 0.91 [s, 2H, NH], 1.01
[t, 6H, 3J(H,H) = 7 Hz, R-NH-CH2CH3], 2.53 [q, 4H, 3J(H,H) = 7 Hz, R-NH-
CH2CH3], 2.60 [s, 4H, Et-NH-CH2]. 13C NMR (C6D6): 15.8 [R-NH-CH2CH3],
44.5 [R-NH-CH2CH3], 50.0 [Et-NH-CH2]. GC-MS (tr = 6.2 min): 117(20)
[(M+1)+], 72(20) [H3CH2C-N+(H)(-CH2CH2-)], 58(100) [H3CH2C-N+(H)(=CH2)].
MeNH
NHMe
N Me
N Me
EtNH
NHEt
- 91 -
3.1.6. N,N"-Diethylpiperazine (2b) CAS [102459-01-8]
Colorless oil, b.p. = 171 – 172 °C. 1H NMR (C6D6): 0.99 [t, 6H, 3J(H,H) = 7
Hz, R2N-CH2CH3], 2.25 [q, 4H, 3J(H,H) = 7 Hz, R2N-CH2CH3], 2.40 [s, 8H,
Et-N-CH2]. 13C NMR (C6D6): 12.6 [R2N-CH2CH3], 52.6 [R2N-CH2CH3],
53.4 [Et-N-CH2]. GC-MS (tr = 7.5 min): 142(100) [M•+], 127(30) [H3CH2C-
N(-CH2CH2-)2N+(=CH2)], 113(15) [H3CH2C-N(-CH2CH2-)2N+], 99(30) [H-N(-CH2CH2-
)2N+(=CH2)], 84(75) [•N(-CH2CH2-)2N+], 70(75) [(-CH2CH2-)N+(=C(H)-CH3)], 56(80) [(-
CH2CH2-)N+(=CH2)].
3.1.7. 1,4,7-Triethyl-1,4,7-triazaheptane (3b) CAS [105-93-1]
Colorless viscous oil, b.p. = 66 – 67 °C / 0.1 torr. 1H NMR (C6D6): 0.93
[t, 3H, 3J(H,H) = 7 Hz, R2N-CH2CH3], 1.06 [t, 6H, 3J(H,H) = 7 Hz, R-HN-
CH2CH3], 1.20 [s, 2H, NH], 2.40 [q, 2H, 3J(H,H) = 7 Hz, R2N-CH2CH3],
2.57 [q, 4H, 3J(H,H) = 7 Hz, R-NH-CH2CH3], 2.47 [t, 4H, 3J(H,H) = 5 Hz,
R-NH-CH2CH2], 2.60 [t, 4H, 3J(H,H) = 5 Hz, R-HN-CH2CH2]. 13C NMR
(C6D6): 11.0 [R2N-CH2CH3], 15.0 [R-NH-CH2CH3], 43.3 [R-NH-CH2CH2], 46.9 [R-NH-
CH2CH3], 47.2 [R-NH-CH2CH2], 52.9 [R-NH-CH2CH2]. GC-MS (tr = 9.9 min): 188(10)
[(M+1)+], 129(25) [H3CH2C-NH-CH2CH2-N+(CH2CH3)(=CH2)], 86(75) [H-N(-CH2CH2-
)2N•+(H)], 72(100) [H3CH2C-N+(H)(-CH2CH2-)], 58(40) [(-CH2CH2-)N+(H)(CH3)].
EtN
NEt
EtNH
NHEt
N Et
- 92 -
3.1.8. 1,4,7,10-Tetraethyl-1,4,7,10-tetraazadecane (4b) CAS [24426-33-3]
Colorless viscous oil, b.p. = 139 – 140 °C / 0.1 torr. 1H NMR (C6D6):
0.97 [t, 6H, 3J(H,H) = 7 Hz, R2N-CH2CH3], 1.09 [t, 6H, 3J(H,H) = 7 Hz, R-
NH-CH2CH3], 1.35 [s, 2H, NH ], 2.50 [s, 4H, 5,6-NCH2], 2.43 [q, 4H,
3J(H,H) = 7 Hz, R2N-CH2CH3], 2.62 [q, 4H, 3J(H,H) = 7 Hz, R-NH-
CH2CH3], 2.52 [t, 4H, 3J(H,H) = 6 Hz, Et-NH-CH2CH2], 2.63 [t, 4H,
3J(H,H) = 6 Hz, Et-NH-CH2CH2]. 13C NMR (C6D6): 12.6 [R2N-CH2CH3],
15.8 [R-NH-CH2CH3], 44.7 [R-NH-CH2CH3], 48.3 [R-NH-CH2CH2], 48.8 [R2N-CH2CH3],
53.0 [5,6-CH2], 54.5 [R-NH-CH2CH2]. GC-MS (tr = 11.5 min): 259(5) [(M+1)+], 143(30)
[H3CH2C-NH-CH2CH2-N+(-CH2CH2-)(CH2CH3) ] , 129(40) [H3CH2C-NH-CH2CH2-
N+(CH2CH3)(=CH2)], 86(100) [H-N(-CH2CH2-)2N•+(H)], 72(90) [H3CH2C-N+(H)(-CH2CH2-
)], 58(45) [(-CH2CH2-)N+(H)(CH3)].
3.1.9. N,N"-Di-iso-propylethylenediamine (1c) CAS [4013-94-9]
Colorless oil, b.p. = 169 – 170 °C. 1H NMR (C6D6): 0.98 [d, 12H, 3J(H,H) =
6 Hz, R-NH-CH(CH3)2], 0.88 [s, 2H, NH], 2.58 [s, 4H, iPr-NH-CH2], 2.66
[sept, 2H, 3J(H,H) = 6 Hz, R-NH-CH(CH3)2]. 13C NMR (C6D6): 23.4 [R-NH-
CH(CH3)2], 48.0 [iPr-NH-CH2], 50.7 [R-NH-CH(CH3)2]. GC-MS (tr = 7.2
min): 145(75) [(M+1)+], 86(25) [(-CH2CH2-)(H)N+(-CH(CH3)2)], 72(100) [(H3C)2HC-
(H)N+(=CH2)], 58(25) [(H3C)2HC-N+-H].
EtNH
NHEt
N Et
N Et
iPrNH
NHiPr
- 93 -
3.1.10. N,N"-Di-iso-propylpiperazine (2c) [CAS 21943-18-0]
Colorless viscous oil, b.p. = 178 – 180 °C. 1H NMR (C6D6): 0.90 [d, 12H,
3J(H,H) = 6 Hz, R2N-CH(CH3)2], 2.46 [s, 8H, iPr-N-CH2], 2.73 [sept, 2H,
3J(H,H) = 6 Hz, R2N-CH(CH3)2]. 13C NMR (C6D6): 18.7 [R2N-CH(CH3)2],
49.0 [iPr-N-CH2], 54.4 [R2N-CH(CH3)2]. GC-MS (tr = 9.2 min): 170(40)
[M•+], 155(100) [(H3C)2HC-N(-CH2CH2-)2N+(=C(H)-CH3)], 127(15) [(H3C)2HC-N(-
CH2CH2-)2N+], 112(25) [(H3C-(H)C=)N+(-CH2CH2-)2N•], 98(60) [H2C=N+(-CH2CH2-)2N•],
84(75) [•N(-CH2CH2-)2N+], 70(30) [(-CH2CH2-)N+(=C(H)-CH3)], 56(80) [(-CH2CH2-
)N+(=CH2)].
3.1.11. 1,4,7-Tri-iso-propyl-1,4,7-triazaheptane (3c) CAS [10524-50-2]
Colorless viscous oil, b.p. = 79 – 80 °C / 0.1 torr. 1H NMR (C6D6): 0.89
[d, 6H, 3J(H,H) = 7 Hz, R2N-CH(CH3)2], 1.07 [d, 12H, 3J(H,H) = 7 Hz, R-
NH-CH(CH3)2], 1.30 [s, 2H, NH], 2.43 [t, 4H, 3J(H,H) = 6 Hz, 3,5-CH2],
2.57 [t, 4H, 3J(H,H) = 6 Hz, 2,6-CH2], 2.74 [sept, 2H, 3J(H,H) = 7 Hz, R-
NH-CH(CH3)2], 2.80 [sept, 1H, 3J(H,H) = 7 Hz, R2N-CH(CH3)2]. 13C NMR
(C6D6): 18.3 [R2N-CH(CH3)2], 23.7 [R-NH-CH(CH3)2], 46.8 [2,6-CH2], 49.2 [R-NH-
CH(CH3)2], 50.3 [3,5-CH2], 50.5 [R2N-CH(CH3)2]. GC-MS (tr = 10.8 min): 230(80)
[(M+1)+], 157(5) [(H3C)2HC-NH-CH2CH2-N+(-CH(CH3)2)(=CH2)], 100(100) [(H3C)2HC-
NH-CH2CH2-N•+].
iPrN
NiPr
iPrNH
NHiPr
N iPr
- 94 -
3.1.12. 1,4,7,10-Tetra-iso-propyl-1,4,7,10-tetraazadecane (4c)
Colorless viscous oil, b.p. = 160 – 161 °C / 0.1 torr. 1H NMR (C6D6):
0.96 [d, 12H, 3J(H,H) = 7 Hz, R2N-CH(CH3)2], 1.09 [d, 12H, 3J(H,H) = 7
Hz, R-NH-CH(CH3)2], 1.44 [s, 2H, NH], 2.47 [s, 4H, 5,6-CH2], 2.52 [t, 4H,
3J(H,H) = 7 Hz, 3,8-CH2], 2.62 [s, 4H, 2,9-CH2], 2.76 [sept, 2H, 3J(H,H) =
7 Hz, R2N-CH(CH3)2], 2.85 [sept, 2H, 3J(H,H) = 7 Hz, R-NH-CH(CH3)2].
13C NMR (C6D6): 18.4 [R2N-CH(CH3)2], 23.6 [R-NH-CH(CH3)2], 46.8 [2,9-
CH2], 49.3 [R-NH-CH(CH3)2], 51.1 [5,6-CH2], 51.2 [R2N-CH(CH3)2], 51.5 [3,8-CH2]. GC-
MS (tr = 13.1 min): 315(75) [(M+1)+], 169(25) [(H3C)2HC-N(-CH2CH2-)2N+=C(CH3)2],
100(100) [(H3C)2HC-NH-CH2CH2-N•+]. EI HRMS m/z calculated for 4 c [M+H]+:
315.3488. Found: 315.3479.
3.1.13. 1,4,7,10,13-Penta-iso-propyl-1,4,7,10,13-pentaazatridecane (5c)
Colorless viscous oil, b.p. = 184 – 185 °C / 0.1 torr. 1H NMR (C6D6):
0.96 [d, 12H, 3J(H,H) = 7 Hz, 4,10-R2N-CH(CH3)2], 0.99 [d, 6H, 3J(H,H) =
7 Hz, 7-R2N-CH(CH3)2], 1.09 [d, 12H, 3J(H,H) = 7 Hz, R-NH-CH(CH3)2],
1.48 [s, 2H, NH], 2.53 [s, 12H, 3,5,6,8,9,11-CH2], 2.63 [m, 4H, 2,12-CH2],
2.78 [sept, 2H, 3J(H,H) = 7 Hz, R-NH-CH(CH3)2], 2.87 [sept, 3H, 3J(H,H)
= 7 Hz, 4,7,10-R2N-CH(CH3)2]. 13C NMR (C6D6): 18.3 [4,10-R2N-
CH(CH3)2], 18.5 [7-R2N-CH(CH3)2], 23.4 [R-NH-CH(CH3)2], 46.8 / 49.2 /
iPrNH
NHiPr
N iPr
N iPr
iPrNH
NHiPr
N
N iPr
iPr
N iPr
- 95 -
51.1 / 51.2 / 51.5 / 52.0 / 52.2 [N-CH2 & N-CH(CH3)2]. GC-MS (tr = 15.3 min): 400(10)
[M•+], 169(100) [(H3C)2HC-N(-CH2CH2-)2N+=C(CH3)2], 100(55) [(H3C)2HC-NH-CH2CH2-
N•+]. EI HRMS m/z calculated for 5c [M+H]+: 400.4379. Found: 400.4379.
3.1.14. N,N"-Di-tert-butylethylenediamine (1d) CAS [4062-60-6]
Colorless oil, b.p. = 196 – 198 °C. 1H NMR (C6D6): 0.75 [s, 2H, NH], 1.04
[s, 18H, R-NH-C(CH3)3], 2.57 [s, 4H, tBu-NH-CH2]. 13C NMR (C6D6): 29.4
[R-NH-C(CH3)3], 43.6 [tBu-NH-CH2], 49.8 [R-NH-C(CH3)3]. GC-MS (tr = 8.2
min): 173(100) [(M+1)+], 157(10) [(H3C)3C-NH-CH2CH2-N+(H)=C(CH3)2],
100(10) [(-CH2CH2-)(H)N+-C(CH3)3].
3.1.15. N,N"-Di-tert-butylpiperazine (2d) CAS [10125-77-6]
Colorless solid, m.p. = 83.5 – 84.5 °C, b.p. 205 – 206 °C. 1H NMR (C6D6):
1.02 [s, 18H, R2N-C(CH3)3], 2.53 [s, 8H, tBu-N-CH2]. 13C NMR (C6D6):
26.1 [R2N-C(CH3)3], 46.8 [tBu-N-CH2], 53.1 [R2N-C(CH3)3]. GC-MS (tr =
10.0 min): 198(15) [M•+], 183(100) [(H3C)3C-N(-CH2CH2-)2N+=C(CH3)2],
157(5) [(H3C)3C-N+(H)(-CH2CH2-)2N-CH3], 141(5) [(H3C)3C-N(-CH2CH2-)2N+], 127(55)
[(H3C)3C-N+(-CH2CH2-)(-CH2CH2•)], 98(10) [(H3C)3C-N+(=CH-CH2-)], 85(20) [(H3C)3C-
N•+=CH2], 70(15) [(H3C)2C=N+=CH2], 57(20) [(H3C)3C+].
tBuNH
NHtBu
tBuN
NtBu
- 96 -
3.1.16. 1,4,7-Tri-tert-butyl-1,4,7-triazaheptane (3d) CAS [24426-18-4]
Colorless viscous oil, b.p. = 94 – 95 °C / 0.1 torr. 1H NMR (C6D6): 0.75
[s, 2H, NH], 1.03 [s, 9H, R2N-C(CH3)3], 1.11 [s, 18H, R-NH-C(CH3)3],
2.55 – 2.65 [m, 8H, N-CH2]. 13C NMR (C6D6): 27.4 [R2N-C(CH3)3], 29.5
[R-NH-C(CH3)3], 44.1 [tBu-NH-CH2], 49.8 [tBu-NH-CH2CH2], 52.8 [R-NH-
C(CH3)3], 54.6 [R2N-C(CH3)3]. GC-MS (tr = 11.5 min): 272(50) [(M+1)+],
256(5) [(H3C)3C-NH-CH2CH2-N(C(CH3)3)-CH2CH2-N+(H)=C(CH3)2], 185(60) [(H3C)3C-
NH-CH2CH2-N+(C(CH3)3)=CH2] , 173(10) [ (H3C)3C-NH-CH2CH2-N+(H)2-C(CH3)3],
157(10) [(H3C)3C-NH-CH2CH2-N+(H)=C(CH3)2], 129(75) [(H3C)3C-NH-CH2CH2-
N+(H)=CH2], 113(10) [(H3C)3C-N+(=CH2)-CH2CH2• ], 100(100) [(-CH2CH2-)(H)N+-
C(CH3)3], 73(80) [(H3C)3C-N•+ (H)2], 57(20) [(H3C)3C+].
3.1.17. N,N"-Diphenylethylenediamine (1e) CAS [150-61-8]
Colorless solid, m.p. = 68.5 – 69.0 °C, b.p. = 160 – 162 °C / 0.1 torr. 1H
NMR (C6D6): 2.79 [s, 4H, CH2], 3.19 [s, 2H, NH], 6.40 [d, 4H, 3J(H,H) = 7
Hz, ortho-C6H5], 6.76 [t, 2H, 3J(H,H) = 7 Hz, para-C6H5], 7.15 [t, 4H,
3J(H,H) = 7 Hz, meta-C6H5]. 13C NMR (C6D6): 43.0 [CH2], 113.2 [ortho-
C6H5], 117.8 [para-C6H5], 129.5 [meta-C6H5], 148.5 [ipso-C6H5]. GC-MS (tr
= 15.6 min): 212(25) [M•+], 106(100) [C6H5-N+(H)=CH2], 77(35) [(C6H5)+].
tBuNH
NHtBu
N tBu
NH
NH
- 97 -
3.1.18. N,N"-Diphenylpiperazine (2e) CAS [613-39-8]
Colorless solid, m.p. = 164 – 165 °C. 1H NMR (C6D6): 2.94 [s, 8H, CH2],
6.40 [d, 4H, 3J(H,H) = 7 Hz, ortho-C6H5], 6.85 [t, 2H, 3J(H,H) = 7 Hz, para-
C6H5], 7.22 [t, 4H, 3J(H,H) = 7 Hz, meta-C6H5]. 13C NMR (C6D6): 49.3
[CH2], 116.7 [ortho-C6H5], 120.1 [para-C6H5], 129.3 [meta-C6H5], 151.8
[ipso-C6H5]. GC-MS (tr = 15.6 min): 238(100) [M•+], 225(20) [C6H5-NH-
CH2CH2-N+(C6H5)=CH2], 132(55) [C6H5-N+(=CH2)-CH=CH2], 106(60)
[C6H5-N+(H)=CH2], 104(74) [C6H5-N+!CH], 77(50) [(C6H5)+].
3.1.19. 1,4,7-Triphenyl-1,4,7-triazaheptane (3e) CAS [68360-81-6]
Colorless solid, m.p. = 118 – 119 °C, b.p. = 250 – 252 °C / 0.1 torr.
1H NMR (C6D6): 2.90 [q, 4H, 3J(H,H) = 7 Hz, C6H5-NH-CH2], 3.05 [t,
4H, 3J(H,H) = 7 Hz, C6H5-NH-CH2CH2], 3.17 [s, 2H, NH], 6.36 [d,
4H, 3J(H,H) = 7 Hz, ortho-C6H5-NH-R], 6.61 [d, 2H, 3J(H,H) = 7 Hz,
ortho-C6H5-NR2], 6.74 [t, 2H, 3J(H,H) = 7 Hz, para-C6H5-NH-R],
6.80 [t, 1H, 3J(H,H) = 7 Hz, para-C6H5-NR2], 7.14 [t, 4H, 3J(H,H) = 7
Hz, meta-C6H5-NH-R], 7.22 [t, 2H, 3J(H,H) = 7 Hz, meta-C6H5-NR2].
13C NMR (C6D6): 41.3 [C6H5-NH-CH2], 50.9 [C6H5-NH-CH2CH2], 113.1 [ortho-C6H5-NH-
R], 113.3 [ortho-C6H5-NR2], 117.5 [para-C6H5-NH-R], 117.8 [para-C6H5-NR2], 129.7
[meta-C6H5-NH-R], 129.9 [meta-C6H5-NR2], 148.3 [ipso-C6H5-NH-R], 148.4 [ipso-C6H5-
NR2]. EI -MS (direct inlet): 332(74) [(M+1)+], 225(45) [C6H5-NH-CH2CH2-
N+(C6H5)=CH2], 212(50) [C6H5-NH-CH2CH2-N•+(H)-C6H5], 132(28) [C6H5-N+(=CH2)-
N
N
NH
NH
N
- 98 -
CH=CH2], 120(100) [C6H5-N+(H)(-CH2CH2-)], 106(46) [C6H5-N+(H)=CH2], 91(26) [C6H5-
N•+], 77(48) [(C6H5)+].
3.2. Reaction of 1,3-Dibromopropane with Primary Amines
Br
Br
NH
NH
R
R
R
R
N
N
NH
NH
N R
R
R
5 eq R-NH2
20 °C / 1 wk+ +
NR
+
6
7 8
9
Scheme 36: Diamines and polyamines from primary amines and 1,3-dibromopropane.
General procedure for the reaction of primary amines with 1,3-dibromopropane
(Scheme 36): The primary amine (5 eq), water (20 mL if primary amine is anhydrous)
and 1,3-dibromopropane (1 eq, 50 mL) were combined. With the exception of scale and
water ratio, the procedure is identical to the procedure for primary amines and 1,2-
dibromoethane (section 3.1.). For R = iPr, tBu, Ph: 20 mL H2O was added to the
mixture to accelerate the reaction and improve solubility of HBr salts. See Table 8 for
isolated yields.
Table 8: Product yields (in %) for primary amines (5 eq) + 1,3-dibromopropane (1 eq).
- 99 -
3.2.1. N,N"-Dimethyl-1,3-propanediamine (7a) CAS [111-33-1]
Colorless liquid, b.p. = 144 – 145 °C. 1H NMR (C6D6): 0.72 [s, 2H, NH],
1.52 [p, 2H, 3J(H,H) = 7 Hz, CH2CH2CH2], 2.26 [s, 6H, CH3], 2.49 [t, 4H,
3J(H,H) = 7 Hz, CH2CH2CH2]. 13C NMR (C6D6): 30.7 [CH2CH2CH2], 36.8
[CH3], 51.2 [CH2CH2CH2]. 13C NMR (CDCl3): 29.2 [CH2CH2CH2], 35.5
[CH3], 49.9 [CH2CH2CH2]. GC-MS (tr = 5.6 min): 103(100) [H3C-NH-CH2CH2CH2-
N+(H)2-CH3], 72(35) [H3C-(H)N+(-CH2CH2CH2-)], 58(20) [H3C-(H)N+(-CH2CH2-)].
3.2.2. 1,5,9-Trimethyl-1,5,9-triazanonane (9a) CAS [123-70-6]
Colorless liquid, b.p. = 55 – 56 °C / 0.1 torr. 1H NMR (C6D6): 0.78 [s,
2H, NH], 1.56 [p, 4H, 3J(H,H) = 7 Hz, CH2CH2CH2], 2.10 [s, 3H, R2N-
CH3], 2.29 [s, 6H, R-NH-CH 3], 2.30 [t, 4H, 3J (H,H) = 7 Hz,
CH2CH2CH2], 2.51 [t, 4H, 3J(H,H) = 7 Hz, CH2CH2CH2]. 13C NMR
(C6D6): 28.2 [CH2CH2CH2], 36.9 [R2N-CH3], 42.3 [R-NH-CH3], 51.0
[CH2CH2CH2], 56.6 [CH2CH2CH2]. GC-MS (tr = 10.1 min): 174(25) [(M+1)+], 158(5)
[H3C-NH-CH2CH2CH2-N(CH3)-CH2CH2CH2-N+-H] , 143(7) [H3C-NH-CH2CH2CH2-
N+(CH3)(-CH2CH2CH2-)], 129(3) [H3C-NH-CH2CH2CH2-N+(CH3)(-CH2CH2-)], 115(50)
[H3C-NH-CH2CH2CH2-N+(CH3)(=CH2)], 103(30) [H3C-NH-CH2CH2CH2-N+(H)2-CH3],
85(25) [(-CH2CH2-)N+(CH3)(-CH2CH2•)], 72(50) [H3C-(H)N+(-CH2CH2CH2-)], 58(100)
[H3C-(H)N+(-CH2CH2-)].
NH
NH
Me
Me
NH
NH
N Me
Me
Me
- 100 -
3.2.3. N,N"-Diethyl-1,3-propanediamine (7b) CAS [10061-68-4]
Colorless liquid, b.p. = 160 – 161 °C. 1H NMR (CDCl3): 1.11 [t, 6H,
3J(H,H) = 7 Hz, N-CH2CH3], 1.25 [s, 2H, NH], 1.70 [p, 2H, 3J(H,H) = 7 Hz,
CH2CH2CH2], 2.67 [m, 8H, CH2CH2CH2 & N-CH2CH3]. 13C NMR (CDCl3):
15.2 [N-CH2CH3], 30.2 [CH2CH2CH2], 44.2 [CH2], 48.4 [CH2]. GC-MS (tr
= 7.5 min): 131(5) [(M+1)+], 115(5) [H3CH2C-NH-CH2CH2CH2-N+(H)(=CH2)], 85(50)
[H3CH2C-N•+(-CH2CH2CH2-)], 71(100) [H3CH2C-N•+(-CH2CH2-)], 58(70) [H3CH2C-
N+(H)(=CH2)].
3.2.4. 1,5,9-Triethyl-1,5,9-triazanonane (9b)
Colorless liquid, b.p. = 50 – 51 °C / 0.1 torr. 1H NMR (CDCl3): 1.10 [m,
9H], 1.65 [m, 4H], 2.50 [m, 6H], 2.85 [m, 8H]. 13C NMR (CDCl3): 10.3,
13.9, 26.2, 42.8, 45.9, 47.2, 50.5. GC-MS (tr = 11.5 min): 216(5)
[(M+1)+], 200(3) [H3CH2C-NH-CH2CH2CH2-(H3CH2C)N-CH2CH2CH2-
N+(H)(=CH2) ] , 1 7 1 ( 6 ) [ H3CH2C-NH-CH2CH2CH2-(H3CH2C)N+(-
CH2CH2CH2-)], 143(95) [H3CH2C-NH-CH2CH2CH2-N+(CH2CH3)(=CH2)], 72(100)
[H3CH2C-(H)N+(-CH2CH2-)].
NH
NH
Et
Et
NH
NH
N Et
Et
Et
- 101 -
3.2.5. N,N"-Di-iso-propyl-1,3-propanediamine (7c) CAS [63737-71-3]
Colorless liquid, b.p. = 60 – 62 °C / 0.1 torr. GC-MS (tr = 6.4 min):
159(30) [(M+1)+], 99(10) [(H3C)2HC-N•+(-CH2CH2CH2-)], 85(100)
[(H3C)2HC-N•+(-CH2CH2-)], 72(50) [(H3C)2HC-N+(H)(=CH2)], 58(45)
[(H3C)2HC-N+-H].
3.2.6. 1,5,9-Tri-iso-propyl-1,5,9-triazanonane (9c)
Colorless liquid, b.p. = 135 – 136 °C / 0.1 torr. 1H NMR (CDCl3): 0.95
[d, 6H, 3J(H,H) = 6 Hz, R2N-CH(CH3)2], 1.05 [d, 12H, 3J(H,H) = 6 Hz, R-
NH-CH(CH3)2], 1.20 [s, 2H, NH ], 1.60 [p, 4H, 3J (H,H) = 7 Hz,
CH2CH2CH2], 2.41 [t, 4H, 3J(H,H) = 7 Hz, N-CH2], 2.61 [t, 4H, 3J(H,H) =
7 Hz, N-CH2], 2.76 [sept, 2H, 3J(H,H) = 6 Hz, R-NH-CH(CH3)2], 2.95
[sept, 1H, 3J(H,H) = 6 Hz, R2N-CH(CH3)2]. 13C NMR (CDCl3): 17.7 [R2N-CH(CH3)2],
23.0 [R-NH-CH(CH3)2], 29.1, 46.6, 48.2, 48.9, 49.3. GC-MS (tr = 10.2 min): 258(60)
[(M+1)+], 214(3) [((H3C)2HC-NH-CH2CH2CH2-)2N+], 199(20) [(H3C)2HC-NH-CH2CH2CH2-
((H3C)2HC)N+(-CH2CH2CH2-)] , 185(5) [(H3C)2HC-NH-CH2CH2CH2-((H3C)2HC)N+(-
CH2CH2-)], 171(20) [(H3C)2HC-NH-CH2CH2CH2-((H3C)2HC)N+(=CH2)], 159(20)
[(H3C)2HC-NH-CH2CH2CH2-N+(H)2-CH(CH3)2], 143(8) [(H3C)2HC-NH-CH2CH2CH2-
(H)N+(=CHCH3)], 127(12) [(H3C)2HC-N+(-CH2CH2-)(-CH2CH2CH2•)], 114(20) [(H3C)2HC-
NH-CH2CH2CH2-N•+], 100(100) [(H3C)2HC-(H)N+(-CH2CH2CH2-)], 86(70) [(H3C)2HC-
(H)N+(-CH2CH2-)], 72(35) [(H3C)2HC-N+(H)(=CH2)], 58(20) [(H3C)2HC-N+-H].
NH
NH
iPr
iPr
NH
NH
N iPr
iPr
iPr
- 102 -
3.2.7. N,N"-Di-tert-butyl-1,3-propanediamine (7d)
Colorless solid, m.p. = 60 – 62 ºC. 1H NMR (C6D6): 1.04 [s, 18H,
C(CH3)3], 1.53 [p, 2H, 3J(H,H) = 7 Hz, CH2CH2CH2], 2.59 [t, 4H, 3J(H,H) =
7 Hz, CH2CH2CH2]. 13C NMR (C6D6): 29.3 [C(CH3)3], 33.0 [CH2CH2CH2],
41.4 [CH2CH2CH2], 50.0 [C (CH3)3]. GC-MS (tr = 9.1 min): 188(15)
[(M+2)•+], 187(100) [(M+1)+], 171(5) [(H3C)3C-NH-CH2CH2CH2-N+(H)(=C(CH3)2)],
129(20) [(H3C)3C-NH-CH2CH2CH2-N+-H], 113(15) [(H3C)3C-N•+(-CH2CH2CH2-)],
100(25) [(H3C)3C-(H)N+(-CH2CH2-)], 98(45) [(H3C)3C-(H)N+(-CH2=CH2-)], 86(22)
[(H3C)3C-(H)N+(=CH2)], 74(20) [(H3C)3C-N+(H)3], 73(15) [(H3C)3C-N•+(H)2], 72(20)
[(H3C)3C-N+(H)], 58(10) [(H3C)3C+(•H)], 57(20) [(H3C)3C+], 56(20) [(H3C)2C+(-CH2•)].
3.2.8. N,N"-Diphenyl-1,3-propanediamine (7e)
Clear yellow viscous oil, m.p. = -16 – -17 °C, b.p. = 180 – 181 °C / 0.1
torr. 1H NMR (C6D6): 1.30 [p, 2H, 3J(H,H) = 7 Hz, CH2CH2CH2], 2.73 [q,
4H, 3J(H,H) = 7 Hz, CH2CH2CH2], 3.02 [s, 2H, NH], 6.45 [d, 4H, 3J(H,H)
= 7 Hz, ortho-C6H5], 6.77 [t, 2H, 3J(H,H) = 7 Hz, para-C6H5], 7.19 [t, 4H,
3J(H,H) = 7 Hz, meta-C6H5]. 13C NMR (C6D6): 29.1 [CH2CH2CH2], 41.7
[CH2CH2CH2], 113.2 [ortho-C6H5], 117.7 [para-C6H5], 129.5 [meta-C6H5],
148.7 [ipso-C6H5]. GC-MS (tr = 15.2 min): 226(100) [M•+], 132(50) [C6H5-N+(=CH-CH2-
CH2-)], 106(40) [C6H5-N+(H)(=CH2)], 77(15) [(C6H5+)]. FT-IR [CsI, /(cm-1)]: 3407 m,
3050 m, 3019 m, 2934 m, 2863 m, 1575 l, 1505 l, 1474 s, 1430 s, 1317 m, 1259 m,
1179 m, 1131 s, 1028 s, 991 s, 869 s, 749 l, 693 l, 509 m.
NH
NH
tBu
tBu
NH
NH
- 103 -
3.2.9. 1,5,9-Triphenyl-1,5,9-triazanonane (9e)
Clear orange viscous oil, m.p. = 9 – 10 °C, b.p. = 300 – 301 °C /
0.1 torr. 1H NMR (C6D6): 1.44 [p, 4H, 3J (H,H) = 7 Hz,
CH2CH2CH2], 2.72 [q, 4H, 3J(H,H) = 7 Hz, N-CH2CH2CH2-NH-Ph],
3.00 [t, 4H, 3J(H,H) = 7 Hz, N-CH2CH2CH2-NH-Ph], 3.00 [s, 2H,
NH], 6.46 [d, 4H, 3J(H,H) = 7 Hz, ortho-C6H5-NH-R], 6.64 [d, 2H,
3J(H,H) = 7 Hz, ortho-C6H5-NR2], 6.77 [t, 2H, 3J(H,H) = 7 Hz, para-
C6H5-NH-R], 6.79 [t, 1H, 3J(H,H) = 7 Hz, para-C6H5-NR2], 7.20 [t,
4H, 3J(H,H) = 7 Hz, meta-C6H5-NH-R], 7.24 [t, 2H, 3J(H,H) = 7 Hz, meta-C6H5-NR2]. 13C
NMR (C6D6): 27.2 [CH2CH2CH2], 41.6 [N-CH2CH2CH2-NH-Ph], 49.0 [N-CH2CH2CH2-
NH-Ph], 113.1 [ortho-C6H5-NH-R], 113.3 [ortho-C6H5-NR2], 117.3 [para-C6H5-NH-R],
117.7 [para-C6H5-NR2], 129.5 [meta-C6H5-NH-R], 129.6 [meta-C6H5-NR2], 148.4 [ipso-
C6H5-NH-R], 148.7 [ipso-C6H5-NR2]. FT-IR [CsI, /(cm-1)]: 3404 m, 3050 m, 3021 m,
2947 m, 2868 m, 1575 l, 1505 l, 1476 s, 1320 m, 1260 m, 1178 m, 1072 s, 1036 s, 991
s, 868 s, 747 l, 693 l, 509 m.
NH
NH
N
- 104 -
3.3. Asymmetric Diamines: Ring Opening Reactions of Arizidines and Azetidines
3.3.1. N,N"-Disubstituted Ethylenediamines with Different Substituents (10)
tBuN
tBuNH
NH225 °C / 24 hrs
Ph-NH2
10
Scheme 47: Synthesis of N,N"-disubstituted ethylenediamines.
Aniline (23.5 g, 23.0 mL, 0.250 mol, 5 eq) and N-tert-butyl aziridine (5.00 g, 0.050
mol, 1 eq) were combined in a 50 mL stainless steel vessel (Swagelok) and heated at
225 °C for 24 hrs (Scheme 47). NMR of the crude reaction mixture indicates a 2 : 1
mole ratio of tBu-NH-CH2CH2-NH-Ph (10) : tBu-N(-CH2CH2-)2N-tBu (2d). Vaccuum
distillation through a Vigreux column gave spectroscopically pure 10 as a yellow oil
(5.07 g, 0.026 mol, b.p. = 150 – 152 oC / 0.1 torr, in 52% yield). tBu-N(-CH2CH2-)2N-tBu
(2d) was isolated as the first fraction (30%) of the crude mixture.
1H NMR (C6D6): 0.92 [s, 9H, C(CH3)3], 2.45 [t, 2H, 3J(H,H) = 5.6 Hz, tBu-NH-CH2], 2.85
[q, 2H, 3J(H,H) = 5.6 Hz, CH2-NH-Ph], 4.05 [s, 1H, tBu-NH-CH2], 6.55 [d, 2H, 3J(H,H) =
7.60 Hz, ortho-C6H5], 6.76 [t, 1H, 3J(H,H) = 7.2 Hz, para-C6H5], 7.18 [t, 2H, 3J(H,H) = 8
Hz, meta-C6H5]. 13C NMR (C6D6): 29.2 [C(CH3)3], 41.5 [tBu-NH-CH2], 44.7 [CH2-NH-
Ph], 49.9 [C(CH3)3], 113.3 [ortho-C6H5], 117.5 [para-C6H5], 129.5 [t, meta-C6H5], 149.3
[ipso-C6H5]. 1H NMR (CDCl3): 1.10 [s, 9H, C(CH3)3], 2.81 [t, 2H, 3J(H,H) = 5.6 Hz, tBu-
- 105 -
NH-CH2], 3.17 [q, 2H, 3J(H,H) = 5.6 Hz, CH2-NH-Ph], 4.10 [s, 1H, tBu-NH-CH2], 6.63 [d,
2H, 3J(H,H) = 7.6 Hz, ortho-C6H5], 6.69 [t, 1H, 3J(H,H) = 7.2 Hz, para-C6H5], 7.16 [t, 2H,
3J(H,H) = 8 Hz, meta-C6H5]. 13C NMR (CDCl3): 29.2 [C(CH3)3], 41.6 [tBu-NH-CH2], 44.8
[CH2-NH-Ph], 50.2 [C(CH3)3], 113.0 [ortho-C6H5], 117.3 [para-C6H5], 129.2 [t, meta-
C6H5], 148.6 [ipso-C6H5]. GC-MS (tr = 11.6 min): 194(15) [(M + 2)+], 193(100) [(M + 1)+],
192(12) [M+], 177(3) [Ph-NH-CH2CH2-N+(H)=C(CH3)2], 159(2) [Ph-NH-CH=CH-N+!C-
CH3], 137(2) [Ph-NH-CH2CH2-N+(H)3], 120(5) [Ph-N+(H)(-CH2CH2-)], 108(3) [Ph-N+(H)2-
CH3], 107(45) [Ph-N•+(H)-CH3], 106(35) [Ph-N+(H)=CH2], 86(8) [H2C=N+(H)-tBu], 77(10)
[(C6H5)+], 57(8) [C+(CH3)3].
3.3.2. N-tert-Butyl-Azetidine (6d)
tBuN
Br
Br
tBu-NH2
20 °C / 16 hrs
6d
Scheme 48: Synthesis of N-tButyl azetidine.
tert-Butyl amine (180 g, 259 mL, 2.46 mol, 5 eq), 1,3-dibromopropane (99 g, 50
mL, 0.49 mol, 1 eq), and 20 mL water were combined and stirred for 16 hours at
ambient temperature (Scheme 48). An exothermic reaction lasting approximately 15
minutes occurred shortly after combining the starting materials. A large amount of
insoluble white precipitate became visible by the 12th hour. Once the reaction was
complete excess NaOH was added to neutralize the HBr salts, then the NaOH drying
procedure was applied. NMR of the crude reaction mixture indicates the formation of N-
- 106 -
tert-butyl-azetidine (6d ) and N,N"-di-tert-butyl-1,3-propanediamine (7d). Fractional
distillation through a 30 cm Vigreux column conveniently separates 6d from 7d: 6d (44
g, 52 mL, 0.389 mol, clear liquid: b.p. = 30 – 32 ºC / 0.1 torr, isolated yield = 78%) and
7d (14 g, 0.075 mol, colorless solid: m.p. = 60 – 62 ºC, isolated yield = 15%).
1H NMR (C6D6): 0.95 [s, 9H, C(CH3)3], 1.97 [p, 2H, 3J(H,H) = 8 Hz, CH2CH2CH2], 3.19 [t,
4H, 3J(H,H) = 8 Hz, CH2CH2CH2]. 13C NMR (C6D6): 15.6 [CH2CH2CH2], 23.9 [C(CH3)3],
46.6 [CH2CH2CH2], 51.7 [C(CH3)3]. G C - M S (tr = 4.4 min): 113(30) [tBu-N•+(-
CH2CH2CH2-)], 98(100) [(H3C)2C=N+(-CH2CH2CH2-)], 70(23) [(H3C)2C=N+=CH2].
3.3.3. N-tert-Butyl-N"-phenyl-1,3-propanediamine (11)
tBuN
tBuNH
NH375 °C / 20 hrs
Ph-NH2
11
6d
Scheme 49: Synthesis of N,N"-disubstituted 1,3-propanediamines.
Aniline (1.70 g, 1.70 mL, 19 mmol, 5 eq) and N-tert-butyl azetidine (6d) (0.423 g,
0.5 mL, 4 mmol, 1 eq) were combined in a 50 mL stainless steel vessel (Swagelok) and
heated (Scheme 49). After 90 ºC for 50 hours, NMR shows no reaction. The
temperature was increased to 200 ºC for 48 hours, with no effect. Heating for 20 hours
at 375 ºC cleanly converts starting materials to tBu-NH-CH2CH2CH2-NH-Ph (11).
Sublimation yields 11 as clear, colorless crystals: (0.13 g, 1 mmol, b.p. = 65 – 67 ºC /
- 107 -
0.1 torr, isolated yield = 17%). There was no other material in the Swagelok vessel so it
is likely the missing material was boiled out through leaks in the thread / teflon tape
seal.
1H NMR (C6D6): 0.92 [s, 9H, C(CH3)3], 1.40 [p, 2H, 3J(H,H) = 6 Hz, CH2CH2CH2], 2.37
[t, 2H, 3J(H,H) = 6 Hz, tBu-NH-CH2], 3.00 [q, 2H, 3J(H,H) = 6 Hz, CH2-NH-Ph], 4.55 [s,
1H, tBu-NH-CH2], 6.58 [d, 2H, 3J(H,H) = 7 Hz, ortho-C6H5], 6.77 [t, 1H, 3J(H,H) = 7 Hz,
para-C6H5], 7.22 [t, 2H, 3J(H,H) = 7 Hz, meta-C6H5]. 13C NMR (C6D6): 29.1 [C(CH3)3],
30.3 [CH2CH2CH2], 41.4 [tBu-NH-CH2], 43.7 [CH2-NH-Ph], 50.0 [C(CH3)3], 112.9 [ortho-
C6H5], 117.1 [para-C6H5], 128.2 [meta-C6H5], 149.5 [ipso-C6H5]. GC-MS (tr = 12.6 min):
208(10) [Ph-N•(H)2-CH2CH2CH2-N+(H)2-tBu], 207(75) [Ph-NH-CH2CH2CH2-N+(H)2-tBu],
206(70) [Ph-NH-CH2CH2CH2-N•+(H)-tBu], 191(15) [Ph-NH-CH2CH2CH2-(H)N+=C(CH3)2],
149(5) [Ph-NH-CH2CH2CH2-N+-H], 134(20) [Ph-(H)N+(-CH2CH2CH2-)], 132(35) [(H)3N•-
CH2CH2CH2-N+(H)2-tBu], 120(30) [Ph-(H)N+(-CH2CH2-)], 114(20) [tBu-(H)N+(-
CH2CH2CH2-)], 106(100) [Ph-(H)N+=CH2], 98(30) [(H3C)2C=N+(-CH2CH2CH2-)], 77(26)
[(C6H5)+], 72(38) [tBu-N+-H], 57(15) [C+(CH3)3].
- 108 -
3.4. Triamine Ligand Building Blocks: R-NH2X-CH2CH2-X
3.4.1. 2-(tert-Butylamino)ethylchloride hydrochloride (12d)
tBuNH
OH
tBuNH2Cl
Cl
1.2 SOCl2 / CH2Cl2Reflux 48 hrs
12d
Scheme 50: Synthesis of 12d.
In a 2L flask fitted with a dropping funnel above a 30 cm condenser, connected to
an oil bubbler and maintained under an argon atmosphere, thionyl chloride (214.1 g,
131.3 mL, 1.8 mol, 1.5 eq) was added dropwise to a mixture of tBu-NH-CH2CH2-OH
(140.6 g, 1.2 mol, 1 eq) and methylene chloride (750 mL) over an hour (Scheme 50).
The strongly exothermic reaction is controlled well by the condenser and a large gas
evolution (SO2) takes place. The mixture is refluxed for 48 hours or until gas evolution
stops, with aluminum block temperature 65 °C. A large white precipitate (12d) forms
and is isolated by frit filtration as a colorless solid with melting point 203 – 205 °C. Yield
= 198.2 g, 96%.
1H NMR (CDCl3): 1.50 [s, 9H, C(CH3)3], 3.23 [p, 2H, 3J(H,H) = 8 Hz, tBu-NH2+-CH2],
4.08 [t, 2H, 3J(H,H) = 8 Hz, CH2-Cl], 9.61 [s, 2H, NH2]. 13C NMR (CDCl3): 25.9
[C(CH3)3], 37.8 [tBu-NH2+-CH2], 43.0 [CH2-Cl], 57.9 [C(CH3)3].
- 109 -
Scale up requiring three more batches leads to higher purity at a lower yield.
Batch 1 was purified by frit filtration of the crude product followed by dynamic vacuum
treatment for 48 hours to remove traces of solvent and thionyl chloride. The vacuum
pump was protected from thionyl chloride with two liquid nitrogen traps in series. Batch
2 was purified in the same way as batch 1 plus it received 2 0 100 mL methylene
chloride washes. Batches 3 & 4 were washed with 1 0 100 mL methylene chloride
wash and 2 0 75 mL diethyl ether washes followed by the same vacuum treatment of
the earlier batches. The diethyl ether washes led to a pure white free flowing product
with higher purity than the first two batches. Samples of 12d with melting point 207 –
209 °C were washed with acetone or recrystallized from 95% ethanol, which did not
raise the melting point.
3.4.2. 2-(tert-Butylamino)ethylbromide hydrobromide (13d)
tBuNH
OH
tBuNH2Br
Br
48% w/w aq. HBr
Reflux 24 hrsCollect ppt 13d
Scheme 51: Synthesis of 13d.
In a 2 L flask equipped with a condenser tBu-NH-CH2CH2-OH (207.8 g, 1.773
mol, 1 eq) and 48% w/w aqueous HBr (717.5 gHBr, 1494.7 gSolution, 1003.1 mLSolution,
8.867 mol, 5 eq) were boiled for 24 hours (Scheme 51). The reaction mixture was
cooled to ambient temperature and precipitation of tBu-NH2+Br--CH2CH2-Br (13d) was
- 110 -
induced by gentle scratching of the inside of the flask with a broken glass pipette. The
precipitated 13d was collected by frit filtration and washed with 1 0 50 mL acetone
wash. The filtrate was refluxed for another 24 hours and more 13d was formed, and
was isolated as above. The procedure was repeated until the additional yields were
insignificant. Product (13d): colorless solid, m.p. = 237 – 240 °C (sublimed m.p. = 244
– 245 °C), yield = 324 g, 70%.
1H NMR (D2O, TMS ref): 0.69 [s, 9H, C(CH3)3], 2.85 [t, 2H, 3J(H,H) = 5 Hz, tBu-NH2+-
CH2], 3.00 [t, 2H, 3J(H,H) = 5 Hz, Br-CH2]. 13C NMR (D2O, TMS ref): 24.8 [C(CH3)3],
26.5 [tBu-NH2+-CH2], 43.1 [Br-CH2], 58.0 [C(CH3)3].
3.4.3. 3-(Methyl)aza-1,5-dichloropentane hydrochloride (14) CAS [1000029-85-5]
14
N
OH
OH
Me NH+
Cl
Cl
2.2 SOCl2 / CH2Cl225 °C / 48 hrs
Me
Cl-
Scheme 52: Synthesis of 14.
Thionyl chloride (109.8 g, 67.3 mL, 0.924 mol, 2.2 eq) was added dropwise to
CH3-N(-CH2CH2-OH)2 (50.0 g, 0.420 mol, 1 eq) in 300 mL CH2Cl2 over a period of one
hour (Scheme 52). During the exothermic reaction gas – evolving (SO2, HCl) reaction a
white precipitate initially forms but later dissolves. The resulting clear mixture is allowed
to stir for an additional 48 hours at 20 °C to ensure completion. The solvent and
- 111 -
volatiles are removed by vacuum and the product (14) is isolated by frit filtration. 14 is a
colorless solid with m.p. = 99 – 100 °C. Yield is quantitative (80.8 g), and
recrystallization from acetone does not raise the melting point.
1H NMR (CDCl3): 3.01 [3H, s, CH3], 3.56 [4H, t, 3J(H,H) = 8 Hz, N-CH2], 4.07 [4H, s, Cl-
CH2], 13.50 [1H, s, N,H-Cl]. 13C NMR (CDCl3): 36.5 [N-CH2], 41.1 [CH3], 57.3 [Cl-
CH2]. 1H NMR (D2O / TMS ref): 3.03 [3H, s, CH3], 3.70 [4H, s, N-CH2], 4.00 [4H, s, Cl-
CH2]. 13C NMR (D2O / TMS ref): 37.3 [N-CH2], 40.7 [CH3], 56.9 [Cl-CH2].
3.4.4. 3-(Ethyl)aza-1,5-dichloropentane hydrochloride (15) CAS [3590-07-6]
15
N
OH
OH
Et2.1 SOCl2 / CHCl3Reflux / 2 hrs
NH+
Cl
Cl
Et
Cl-
Scheme 53: Synthesis of 15.
Thionyl chloride (16.2 g, 9.9 mL, 0.136 mol, 2.1 eq) was added to a solution of
Et-N(-CH2CH2-OH)2 (8.7 g, 8.5 mL, 0.065 mol, 1 eq) and chloroform (10 mL) (Scheme
53). The mixture was refluxed for 2 hours. The product isolation was done by frit
filtration with Et2O washes (2 0 50 mL) yielding 15 as a colorless solid (11.0 g, 0.053
mol, m.p. = 125 – 130 °C, isolated yield = 82%).
- 112 -
1H NMR (D2O / TMS ref): 1.28 [t, 3H, 3J(H,H) = 7.5 Hz, CH3CH2-N], 3.36 [q, 2H, 3J(H,H)
= 7 Hz, CH3CH2-N], 3.62 [t, 4H, 3J(H,H) = 6 Hz, N-CH2], 3.91 [t, 4H, 3J(H,H) = 6 Hz, Cl-
CH2].185 13C NMR (D2O / TMS ref): 7.6 [CH3CH2-N], 37.2 [N-CH2], 48.9 [CH3CH2-N],
53.6 [Cl-CH2].185
3.4.5. 3-(tert-Butyl)aza-1,5-dichloropentane hydrochloride (16) CAS [64037-57-6]
16
NH+
Cl
Cl
tBu
Cl-
N
OH
OH
tBu2.1 SOCl2 / CH2Cl2Reflux / 12 hrs
Scheme 54: Synthesis of 16.
Thionyl chloride (SOCl2) (3.49 g, 2.14 mL, 29 mmol, 2.1 eq) was added to a
solution of tBu-N(-CH2CH2-OH)2 (2.25 g, 14 mmol, 1 eq) in methylene chloride (20 mL)
(Scheme 54). The mixture was refluxed for 12 hrs causing gas evolution. The solvent
and all volatiles present were removed by cryogenic distillation, leaving the crude salt.
Crude yield 16 = 92%. Recrystallization from 95% ethanol gave 16 as a colorless solid
(2.79 g, 12 mmol, isolated yield = 70%, m.p. = 166 – 167 °C).185
1H NMR (CDCl3): 1.58 [s, 9H, C(CH3)3], 3.27 [s, 2H, N-CHB-HA], 3.67 [s, 2H, N-CHA-
HB], 4.14 [s, 2H, Cl-CHD-HC], 4.15 [s, 2H, Cl-CHC-HD]. 13C NMR (CDCl3): 24.7
[C(CH3)3], 38.0 [N-CH2], 52.1 [Cl-CH2], 66.4 [C(CH3)3]. 1H NMR (D2O / TMS ref): 1.41
[s, 9H, C(CH3)3], 2.73 [t, 4H, 3J(H,H) = 8 Hz, N-CH2], 3.39 [t, 4H, 3J(H,H) = 8 Hz, Cl-
- 113 -
CH2].185 13C NMR (D2O / TMS ref): 23.9 [C(CH3)3], 38.7 [N-CH2], 52.9 [Cl-CH2], 67.9
[C(CH3)3].185
3.5. Dicarbene Precursors from 1-tert-Butylimidazole
3.5.1. tert-Butylimidazol hydrochloride (19)
19
225 °C2 hrs
tBu
tBuN
NC+ H
Cl-
- H2C=C(CH3)2
tBu
N+
NC H
H
Cl-
Scheme 55: Synthesis of 19.
Di-tert-butylimidazolium chloride (9.28 g, 43.0 mmol) was heated in a sublimation
apparatus for 2 hours at 225 °C under dynamic vacuum (Scheme 55). This results in
iso-butene elimination yielding tert-butyl imidazol hydrochloride (19), as yellow
sublimate (5.156 g, 32 mmol, 75%). 1 9 is readily purified from acetone: 3
recrystallizations led to colorless crystals with constant melting point 191 – 194 °C
(2.257 g, 14 mmol, 32% isolated yield). Sublimation of the crude product does not
improve the melting point or the appearance. The black sublimation residue was
insoluble in all solvents and has an insignificant mass.
1H NMR (CDCl3): 1.75 [9H, s, C(CH3)3], 7.44 [1H, s, CH=CH or CH=CH], 7.51 [1H, s,
CH=CH or CH=CH], 9.50 [1H, s, N2CH]. 13C NMR (CDCl3): 30.2 [3C, C(CH3)3], 59.6
- 114 -
[1C, C(CH3)3], 119.0 [1C, CH=CH or CH=CH], 120.0 [1C, CH=CH or CH=CH], 133.1
[1C, N2CH].
3.5.2. tert-Butylimidazol (20) (source: tert-Butylimidazol hydrochloride)
20
20% w/w aq. NaOH
- H2O- NaCl
tBu
N+
NC H
H
Cl-tBu
N
NC H
19
Scheme 56: Synthesis of 20.
tert-Butylimidazol hydrochloride (19) (1.000 g, 6 mmol, 1 eq) was deprotonated by
20% w/w aqueous NaOH (0.373 gNaOH, 1.865 gsoln, 9 mmol, 1.5 eq) in 5 mL diethyl ether
(Scheme 56). On this scale the reaction was not noticeably exothermic. After one hour
of stirring the mixture at ambient termperature, the aqueous layer was removed with a
separatory funnel and extracted with 2 0 5 mL Et2O. Evaporation of the combined ether
fractions yields tert-butylimidazol (20) as a slightly yellow oil (0.63 g, 82%). NMR data
shown below. The imidazolium salt 19 is not deprotonated by CaH2 at 20 °C in CH2Cl2.
However, when CaH2 (0.262 g, 6 mmol) and 19 (1.000 g, 6 mmol) are heated neat to
150 °C under dynamic vacuum, 20 forms and is collected by distillation (0.432 g, 54 %
isolated yield). Reaction of 19 and NaH under identical conditions yields only 30%
(isolated yield) 20 and significant decomposition of the starting material.
- 115 -
3.5.3. tert-Butylimidazol (20) (source: 1,3-di-tert-Butylimidazol-2-ylidene)
tBu
tBuN
NC:
tBu
N
NC H
225 °C20 hrs
- H2C=C(CH3)220
Scheme 57: Synthesis of 20.
50 mg of 1,3-di-tert-butylimidazol-2-ylidene was heated to 225 °C for 12 hours in
a sealed glass tube (Scheme 57). The clear solid crystals of 1,3-di-tert-butylimidazol-2-
ylidene slowly transformed into a light yellow liquid. Quantitative conversion to tert-
butylimidazol (20) is observed. There was significant gas overpressure when the glass
tube was cut open to retrieve the product, most likely iso-butene. The experiment was
repeated but heating was maintained for 20 hours to test product stability, with the same
result: complete conversion to 20.
1,3-Di-tert-butylimidazol-2-ylidene:
1H NMR (C6D6): 1.51 [18H, s, C(CH3)3], 6.80 [2H, s, CH=CH]. 13C NMR (C6D6): 30.5
[6C, C(CH3)3], 56.0 [2C, C(CH3)3], 114.3 [2C, CH=CH], 212.0 [1C, C:].
tert-Butylimidazole (20):
1H NMR (CDCl3): 1.57 [9H, s, C(CH3)3], 7.11 [2H, s, CH=CH], 7.75 [1H, s, N2CH]. 13C
NMR (CDCl3): 30.1 [3C, C(CH3)3], 53.9 [1C, C(CH3)3], 118.0 [1C, CH=CH or CH=CH],
129.5 [1C, CH=CH or CH=CH], 133.5 [1C, N2CH]. 1H NMR (C6D6): 1.05 [9H, s,
C(CH3)3], 6.74 [1H, s, CH=CH or CH=CH], 7.22 [1H, s, CH=CH or CH=CH], 7.53 [1H, s,
- 116 -
N2CH]. 13C NMR (C6D6): 30.0 [3C, C(CH3)3], 54.5 [1C, C(CH3)3], 117.0 [1C, CH=CH or
CH=CH], 130.0 [1C, CH=CH or CH=CH], 134.0 [1C, N2CH].
3.5.4. 1-tert-Butyl-3-methylimidazol-2-ylidene hydroiodide (21)
21
tBu
N
NC H
tBu
MeN
NC+ H
I-
H3C-I
20
Scheme 58: Synthesis of 21.
Methyl iodide (0.291 g, 2 mmol, 1 eq) was added to dry tert-butylimidazol (20)
(0.204 g, 2 mmol, 1 eq) (scheme 58). A colorless solid (21) immediately forms in a
highly exothermic reaction (0.408 g, 82 %), m.p. = 160 – 161 °C. Purification by
recrystallization from acetone.
1H NMR (CDCl3): 1.75 [9H, s, C(CH3)3], 4.20 [3H, s, CH3], 7.53 [1H, s, CH=CH or
CH=CH], 7.60 [1H, s, CH=CH or CH=CH], 10.13 [1H, s, N2CH]. 13C NMR (CDCl3):
30.3 [3C, C(CH3)3], 37.2 [1C, CH3], 60.7 [1C, C(CH3)3], 119.8 [1C, CH=CH or CH=CH],
124.3 [1C, CH=CH or CH=CH], 135.5 [1C, N2CH].
- 117 -
3.5.5. Bis-(1-tert-butylimidazol-2-ylidene)-1,1-methylene dihydrobromide (22)
22
tBu
N
NC H
tBuN
C+ H
tBuN
C+ HN
N
1 CH2Br2Acetone
75 °C / 48 hrs
2Br-
20
2
Scheme 59: Synthesis of 22.
tert-Butylimidazol (20) (0.500 g, 4 mmol, 1 eq) and dibromomethane (0.600 g, 4
mmol, 1 eq) showed no reaction when stirred in 15 mL acetone at ambient temperature
(Scheme 59). Heating the mixture to 75 °C for 2 days yields 22 as a colorless solid
from the clear solution (yield = 25%). M.p. = 230 °C (dec.).
1H NMR (D2O / TMS capillary ref): 1.66 [18H, s, C(CH3)3], 2.23 [2H, s, N2CH2], 6.64
[2H, s, CH=CH or CH=CH], 7.79 [2H, s, CH=CH or CH=CH], 7.84 [2H, s, N2CH]. 13C
NMR (D2O / TMS ref): 28.7 [6C, C(CH3)3], 30.3 [1C, N2CH2], 59.0 [2C, C(CH3)3], 120.0
[2C, CH=CH or CH=CH], 121.6 [2C, CH=CH or CH=CH], 122.2 [2C, N2CH].
- 118 -
3.5.6. Bis-(1-tert-butylimidazol-2-ylidene)-1,2-ethane dihydrobromide (23)
2
23
tBuN
C+ H
tBuN
C+ HN
N
2Br-tBu
N
NC H
1Br-CH2CH2-BrHexane
150 °C / 5 min20
Scheme 60: Synthesis of 23.
A solution of tert-butylimidazol (20 ) (0.500 g, 5 mmol, 1 eq) and 1,2-
dibromoethane (1.515 g, 10 mmol, 2 eq) in 5 mL hexane was heated to 150 °C for 5
minutes, which lead to the precipitation of a colorless solid (Scheme 60). Heating was
continued for another 12 hours at 100 °C to ensure completion, but no more product
formed. The product of the reaction is 23: crude yield = 87%. M.p. = 280 – 281 °C
after 2 acetone recrystallizations.
1H NMR (D2O / TMS capillary ref): 1.58 [18H, s, C(CH3)3], 4.71 [4H, s, CH2], 7.39 [2H,
s, CH=CH or CH=CH], 7.72 [2H, s, CH=CH or CH=CH], 8.95 [2H, s, N2CH]. 13C NMR
(D2O / TMS capillary ref): 29.9 [6C, C(CH3)3], 49.7 [2C, C(CH3)3], 61.0 [2C, CH2], 121.5
[2C, CH=CH or CH=CH], 122.5 [2C, CH=CH or CH=CH], 135.0 [2C, N2CH].
- 119 -
3.5.7. Bis-(1-tert-butylimidazol-2-ylidene)-1,3-propane dihydrobromide (24)
2
24
tBuN
C+ H
tBuN
C+ H
N
N
2Br-
tBu
N
NC H
20 °C / 72 hrs
1 Br-(CH2)3-BrAcetone
20
Scheme 61: Synthesis of 24.
A solution of tert-butylimidazol (20 ) (0.500 g, 5 mmol, 1 eq) and 1,3-
dibromopropane (1.515 g, 10 mmol, 2 eq) in 15 mL acetone were stirred at ambient
temperature for 3 days precipitating bis-(1-tert-butylimidazol-2-ylidene)-1,3-propane
dihydrobromide (24) as a colorless solid (m.p. = 205 – 206 °C, 90% yield) (Scheme 61).
The reaction is not noticeably exothermic.
1H NMR (D2O / TMS ref): 1.65 [18H, s, C(CH3)3], 2.56 [2H, q, 3J(H,H) = 7 Hz,
CH2CH2CH2], 4.35 [4H, t, 3J(H,H) = 7 Hz, CH 2CH2CH2], 4.80 [2H, s, CH=CH or
CH=CH], 7.54 [2H, s, CH=CH or CH=CH], 7.71 [2H, s, N2CH]. 13C NMR (D2O / TMS
ref): 28.9 [6C, C(CH3)3], 29.6 [1C, CH2CH2CH2], 30.4 [2C, C (CH3)3], 46.8 [2C,
CH2CH2CH2], 120.0 [2C, CH=CH or CH=CH], 123.0 [2C, CH=CH or CH=CH], 126.0
[2C, N2CH]. 1H NMR (CDCl3): 1.72 [18H, s, C(CH3)3], 3.02 [2H, q, 3J(H,H) = 7 Hz,
CH2CH2CH2], 4.76 [4H, t, 3J(H,H) = 7 Hz, CH 2CH2CH2], 7.32 [2H, s, CH=CH or
- 120 -
CH=CH], 8.21 [2H, s, CH=CH or CH=CH], 10.30 [2H, s, N2CH]. 13C NMR (CDCl3):
30.1 [6C, C(CH3)3], 31.2 [1C, CH2CH2CH2], 47.0 [2C, C(CH3)3], 60.5 [2C, CH2CH2CH2],
119.0 [2C, CH=CH or CH=CH], 124.0 [2C, CH=CH or CH=CH], 135.0 [2C, N2CH].
3.6. Stabilization of Reactive Centers Using Intramolecular Dative Bonds
3.6.1. [N3P]+Cl- (25)
25
+ Cl-
NH
N
NH
tBu
tBu
tBu
2.5 eq Et3N 5.5 mL Toluene20 °C / 24 hrs
- 2 eq [Et3NH]+Cl-+ PCl3
1 eq0.506 g
1 eq1.000 g
N P:N
N
tBu
tBu
tBu
Crude Yield = 73%Yellow Solid
3d
Scheme 62: Synthesis of 25.
Phosphorus trichloride (0.51 g, 0.32 mL, 4 mmol, 1 eq) was added to a mixture of
triethylamine (0.93 g, 1.28 mL, 10 mmol, 2.5 eq) and 1,4,7-tri-tert-butyl-1,4,7-
triazaheptane (3d) (1.00 g, 4 mmol, 1 eq) in toluene (4.79 g, 5.54 mL) (Scheme 62).
The mixture was stirred at room temperature for 24 hrs leading to the precipitation of
triethylamine hydrochloride. Purification according to figure 19 affords 25 (yellow solid)
in 73% yield.
1H NMR (C6D6): 1.02 [s, 9H, P++N-C(CH3)3], 1.18 [s, 18H, P+-N-C(CH3)3], 3.01 [m, 8H,
CH2]. 13C NMR (C6D6): 28.8 [d, 3J(C,P) = 11 Hz, P++N-C(CH3)3], 30.1 [d, 3J(C,P) = 17
- 121 -
Hz, P+-N-C(CH3)3], 45.0 [d, 3J(C,P) = 12 Hz, CH2 or C(CH3)3], 49.3 [d, 3J(C,P) = 16 Hz,
CH2 or C(CH3)3], 50.8 [d, 3J(C,P) = 9 Hz, CH2 or C(CH3)3], 53.4 [d, 3J(C,P) = 11 Hz, CH2
or C(CH3)3]. 31P NMR (C6D6, H3PO4 ref): 160.9 [P+], 176.8 [H3PO4].
- 122 -
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- 123 -
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Appendix
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A.1. NMR Data of Commercially Available Starting Materials
A.1.1. 1,2-Dibromoethane CAS [106-93-4]
1H NMR (CDCl3): 3.66 [4H, s, Br-CH2CH2-Br]. 13C NMR (CDCl3): 29.6 [Br-CH2CH2-Br].
1H NMR (C6D6): 2.94 [4H, s, Br-CH2CH2-Br]. 13C NMR (C6D6): 29.6 [Br-CH2CH2-Br].
A.1.2. Methyliodide CAS [74-88-4]
1H NMR (CDCl3): 2.17 [3H, s, I-CH3]. 13C NMR (CDCl3): -23.5 [I-CH3]. 1H NMR
(C6D6): 1.46 [3H, s, I-CH3]. 13C NMR (C6D6): -24.0 [I-CH3].
A.1.3. [(CH3CH2-)3NH]+Cl- CAS [554-68-7]
1H NMR (CDCl3): 1.43 [t, 9H, 3J(H,H) = 8 Hz, CH3], 3.19 [p, 6H, 3J(H,H) = 8 Hz, CH2].
13C NMR (CDCl3): 8.8 [CH3], 46.1 [CH2].
A.1.4. tBu-N(-CH2CH2-)2O CAS [33719-90-3]
In a 50 mL stainless steel (swagelok) vessel tBu-NH-CH2CH2-OH (15.6 g, 0.133
mol, 2.5 eq) and Br-CH2CH2-Br (10.0 g, 4.6 mL, 0.053 mol, 1 eq) were heated at 200 °C
for 24 hrs. The standard base workup outlined in section 3.1. followed by sublimation
isolates tBu-N(-CH2CH2-)2O as colorless crystals (4.2 g, 55%).
1H NMR (CDCl3): 1.12 [s, 9H, R2N-C(CH3)3], 2.68 [t, 4H, 3J(H,H) = 5 Hz, tBu-N-CH2],
3.66 [t, 4H, 3J(H,H) = 5 Hz, O-CH2]. 13C NMR (CDCl3): 28.8 [R2N-C(CH3)3], 44.2 [tBu-
N-CH2], 50.2 [O-CH2], 60.9 [R2N-C(CH3)3].
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A.1.5. N,N"-Di-para-tolylethylenediamine (1f)
Colorless solid, b.p. = 220 – 221 °C / 0.1 torr. 1H NMR (C6D6): 2.23 [s, 6H, CH3], 3.34
[s, 4H, CH2], 3.70 [s, 2H, NH], 6.58 [d, 4H, 3J(H,H) = 18 Hz, ortho-C6H4],
7.00 [d, 4H, 3J(H,H) = 18 Hz, meta-C6H4]. 13C NMR (C6D6): 20.6 [CH3],
43.6 [CH2], 113.4 [ortho-C6H4-CH3], 126.6 [para-C6H4-CH3], 130.0 [meta-
C6H4-CH3], 146.4 [ipso-C6H4-CH3]. GC-MS (tr = 19.2 min): 242(5)
[(M+2)•+], 241(20) [(M+1)+], 240(45) [M•+], 133(5) [H3C-C6H4-N•+(-
CH2CH2-)], 132(5) [H3C-C6H4-N+(=CH-CH2-)], 122(45) [H3C-C6H4-N+(H)2-
CH3], 121(75) [H3C-C6H4-N•+(H)-CH3], 119(52) [H3C-C6H4-N•+=CH2],
118(20) [H3C-C6H4-N+!CH], 105(12) [H3C-C6H4-N•+], 93(10) [C6H5-N•+(H)2], 92(15)
[H3C-(C6H4•+)-H], 91(100) [H3C-C6H4
+], 77(42) [C6H5+].
NH
NH
- 133 -
A.2. X-Ray Data
A.2.1. Phosphenium Cation (25)
Figure 26: X-Ray structure of 25.
Table 9: Crystal data and structure refinement for 25. Identification code 25Empirical formula C16 H35 Cl2 N3 O2 P2Formula weight 434.31Temperature 150(1) KWavelength 0.71073 ÅCrystal system OrthorhombicSpace group P2(1)2(1)2(1)Unit cell dimensions a = 10.5940(3) Å 1 = 90
b = 12.4220(3) Å . = 90c = 16.8510(5) Å 2 = 90
Volume 2217.57(11) Å3
Z 4Density (calculated) 1.301 Mg/m3
Absorption coefficient 0.452 mm-1F(000) 928Crystal size 0.40 x 0.40 x 0.36 mm3
Theta range for data collection 2.80 to 27.50°.Index ranges -13<=h<=13, -15<=k<=16, -21<=l<=21Reflections collected 12332Independent reflections 5001 [R(int) = 0.0363]Completeness to theta = 27.50° 99.3 %Absorption correction Semi-empirical from equivalentsMax. and min. transmission 0.912 and 0.783Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 5001 / 0 / 227Goodness-of-fit on F2 1.053Final R indices [I>2sigma(I)] R1 = 0.0336, wR2 = 0.0762R indices (all data) R1 = 0.0437, wR2 = 0.0817Absolute structure parameter 0.02(6)Extinction coefficient 0.0103(17)Largest diff. peak and hole 0.193 and -0.289 e.Å-3
- 134 -
Table 10: Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for25. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
x y z U(eq)
P(1) 2633(1) 4038(1) 4134(1) 26(1)N(1) 1337(2) 4763(2) 3932(1) 32(1)N(2) 3930(2) 4810(2) 4163(1) 31(1)N(3) 2864(1) 3826(1) 3016(1) 24(1)C(1) 4388(2) 5195(2) 3394(1) 31(1)C(2) 4172(2) 4265(2) 2839(1) 30(1)C(3) 1881(2) 4512(2) 2594(1) 31(1)C(4) 1370(2) 5336(2) 3176(1) 35(1)C(5) 520(2) 5199(2) 4578(1) 36(1)C(6) 461(4) 4403(2) 5259(2) 70(1)C(7) 1072(3) 6251(2) 4883(2) 54(1)C(8) -797(3) 5382(4) 4260(2) 99(2)C(9) 4824(2) 4844(2) 4853(1) 32(1)C(10) 4172(3) 4442(3) 5601(1) 49(1)C(11) 5967(2) 4130(2) 4694(2) 48(1)C(12) 5218(3) 6010(2) 4977(2) 57(1)C(13) 2739(2) 2605(2) 2796(1) 28(1)C(14) 3741(2) 1957(2) 3232(2) 40(1)C(15) 1432(2) 2195(2) 3044(1) 35(1)C(16) 2911(2) 2480(2) 1902(1) 38(1)Cl(1) 6693(1) 3198(1) 1400(1) 44(1)Cl(2) 7552(1) 2498(1) 3106(1) 46(1)P(2) 7814(1) 3741(1) 2316(1) 32(1)O(1) 9112(2) 3710(2) 2040(1) 61(1)O(2) 7182(2) 4682(1) 2655(1) 47(1)
Table 11: Bond lengths [Å] and angles [°] for 25.
P(1)-N(1) 1.6765(18)P(1)-N(2) 1.6768(18)P(1)-N(3) 1.9166(16)N(1)-C(4) 1.460(3)N(1)-C(5) 1.492(3)N(2)-C(1) 1.464(3)N(2)-C(9) 1.501(3)N(3)-C(2) 1.520(3)N(3)-C(3) 1.522(2)N(3)-C(13) 1.567(2)C(1)-C(2) 1.504(3)C(3)-C(4) 1.517(3)C(5)-C(8) 1.512(4)C(5)-C(6) 1.517(4)C(5)-C(7) 1.522(3)C(9)-C(10) 1.521(3)C(9)-C(12) 1.522(3)
- 135 -
C(9)-C(11) 1.524(3)C(13)-C(14) 1.522(3)C(13)-C(16) 1.525(3)C(13)-C(15) 1.533(3)Cl(1)-P(2) 2.0606(8)Cl(2)-P(2) 2.0581(8)P(2)-O(1) 1.4516(17)P(2)-O(2) 1.4634(17)
N(1)-P(1)-N(2) 111.75(9)N(1)-P(1)-N(3) 88.81(8)N(2)-P(1)-N(3) 90.20(8)C(4)-N(1)-C(5) 118.28(17)C(4)-N(1)-P(1) 114.76(14)C(5)-N(1)-P(1) 121.45(15)C(1)-N(2)-C(9) 117.91(17)C(1)-N(2)-P(1) 115.58(14)C(9)-N(2)-P(1) 123.81(14)C(2)-N(3)-C(3) 109.27(15)C(2)-N(3)-C(13) 112.18(15)C(3)-N(3)-C(13) 111.95(15)C(2)-N(3)-P(1) 105.11(11)C(3)-N(3)-P(1) 107.14(12)C(13)-N(3)-P(1) 110.85(11)N(2)-C(1)-C(2) 104.46(17)C(1)-C(2)-N(3) 106.98(16)C(4)-C(3)-N(3) 108.65(17)N(1)-C(4)-C(3) 104.12(16)N(1)-C(5)-C(8) 109.4(2)N(1)-C(5)-C(6) 109.9(2)C(8)-C(5)-C(6) 109.2(3)N(1)-C(5)-C(7) 109.63(19)C(8)-C(5)-C(7) 110.2(3)C(6)-C(5)-C(7) 108.6(2)N(2)-C(9)-C(10) 110.26(18)N(2)-C(9)-C(12) 107.77(18)C(10)-C(9)-C(12) 108.8(2)N(2)-C(9)-C(11) 110.40(18)C(10)-C(9)-C(11) 108.5(2)C(12)-C(9)-C(11) 111.1(2)C(14)-C(13)-C(16) 109.91(18)C(14)-C(13)-C(15) 108.78(18)C(16)-C(13)-C(15) 110.09(18)C(14)-C(13)-N(3) 109.79(16)C(16)-C(13)-N(3) 108.84(16)C(15)-C(13)-N(3) 109.42(15)O(1)-P(2)-O(2) 125.44(13)O(1)-P(2)-Cl(2) 108.32(9)O(2)-P(2)-Cl(2) 106.57(7)O(1)-P(2)-Cl(1) 107.33(9)O(2)-P(2)-Cl(1) 106.87(8)Cl(2)-P(2)-Cl(1) 99.25(3)
- 136 -
Table 12: Anisotropic displacement parameters (Å2x 103) for 25. The anisotropicdisplacement factor exponent takes the form: -2π2[ h2 a*2U11 + ... + 2 h k a* b* U12 ].
U11 U22 U33 U23 U13 U12
P(1) 31(1) 23(1) 23(1) 1(1) 3(1) -2(1)N(1) 32(1) 33(1) 30(1) -1(1) 7(1) 2(1)N(2) 35(1) 36(1) 22(1) 2(1) 0(1) -5(1)N(3) 25(1) 25(1) 23(1) 0(1) 1(1) -1(1)C(1) 36(1) 32(1) 27(1) 1(1) 1(1) -8(1)C(2) 31(1) 32(1) 27(1) -2(1) 5(1) -7(1)C(3) 34(1) 31(1) 29(1) 2(1) -4(1) 5(1)C(4) 39(1) 30(1) 34(1) 3(1) 2(1) 8(1)C(5) 32(1) 42(1) 34(1) -8(1) 8(1) 3(1)C(6) 94(2) 51(2) 64(2) 6(2) 52(2) 4(2)C(7) 67(2) 41(1) 56(2) -17(1) 22(1) -3(1)C(8) 30(2) 204(5) 63(2) -46(3) 2(1) 23(2)C(9) 33(1) 39(1) 25(1) -2(1) -4(1) -1(1)C(10) 43(1) 78(2) 25(1) 6(1) -2(1) 6(1)C(11) 39(1) 63(2) 42(1) 7(1) -1(1) 9(1)C(12) 80(2) 45(2) 45(1) -8(1) -26(1) -10(1)C(13) 30(1) 25(1) 29(1) -4(1) -2(1) 0(1)C(14) 42(1) 29(1) 48(1) -5(1) -9(1) 6(1)C(15) 34(1) 29(1) 43(1) -3(1) 0(1) -7(1)C(16) 42(1) 38(1) 34(1) -11(1) 1(1) -3(1)Cl(1) 42(1) 52(1) 38(1) -1(1) -10(1) 0(1)Cl(2) 71(1) 34(1) 35(1) 7(1) 3(1) 11(1)P(2) 29(1) 35(1) 31(1) 4(1) -1(1) -1(1)O(1) 27(1) 110(2) 46(1) 10(1) 0(1) -3(1)O(2) 68(1) 27(1) 48(1) 0(1) 2(1) 6(1)
- 137 -
Table 13: Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103) for 25.
x y z U(eq)
H(1A) 5296 5381 3422 38H(1B) 3909 5837 3220 38H(2A) 4818 3701 2924 36H(2B) 4223 4510 2280 36H(3A) 2270 4882 2134 38H(3B) 1186 4052 2397 38H(4A) 1932 5971 3207 41H(4B) 515 5576 3019 41H(6A) 1313 4284 5469 105H(6B) 113 3719 5070 105H(6C) -80 4692 5680 105H(7A) 1917 6120 5099 82H(7B) 526 6542 5301 82H(7C) 1127 6770 4447 82H(8A) -1149 4698 4075 149H(8B) -764 5894 3818 149H(8C) -1333 5675 4683 149H(10A) 3439 4898 5715 73H(10B) 4763 4473 6048 73H(10C) 3894 3698 5522 73H(11A) 6398 4379 4213 72H(11B) 5689 3385 4620 72H(11C) 6547 4169 5146 72H(12A) 5645 6275 4499 85H(12B) 5794 6056 5431 85H(12C) 4468 6450 5080 85H(14A) 3656 1194 3095 59H(14B) 3631 2048 3806 59H(14C) 4581 2213 3078 59H(15A) 1353 1432 2905 53H(15B) 779 2609 2767 53H(15C) 1330 2282 3618 53H(16A) 2828 1720 1757 57H(16B) 3751 2739 1750 57H(16C) 2265 2902 1625 57
- 138 -
A.2.2. 2-(tert-Butylamino)ethylchloride hydrochloride (12d)
Figure 27: X-ray structure of 12d.
Table 14: Crystal data and structure refinement for 12d.
Identification code 12dEmpirical formula C6 H15 Cl2 NFormula weight 172.09Temperature 100(2) KWavelength 0.71073 ÅCrystal system MonoclinicSpace group P2(1)/cUnit cell dimensions a = 7.574(4) Å 1 = 90
b = 9.990(5) Å . = 92.769c = 11.916(6) Å 2 = 90
Volume 900.5(8) Å3
Z 4Density (calculated) 1.269 Mg/m3
Absorption coefficient 0.646 mm-1
F(000) 368Crystal size 0.45 x 0.40 x 0.35 mm3
Crystal color/habit colorless/blockTheta range for data collection 2.66 to 28.04°.Index ranges -9<=h<=9, -12<=k<=13, -15<=l<=12Reflections collected 7497Independent reflections 2075 [R(int) = 0.0412]Completeness to theta = 25.00° 99.7 %Absorption correction multi-scan/sadabsMax. and min. transmission 0.8055 and 0.7598Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 2075 / 0 / 94Goodness-of-fit on F2 1.076Final R indices [I>2sigma(I)] R1 = 0.0258, wR2 = 0.0694R indices (all data) R1 = 0.0269, wR2 = 0.0703Extinction coefficient 0.033(3)Largest diff. peak and hole 0.360 and -0.214 e.Å-3
- 139 -
Table 15: Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for12d. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
x y z U(eq)
Cl(1) 3555(1) 3651(1) 4291(1) 22(1)Cl(2) 6457(1) 4549(1) 8098(1) 17(1)N(1) 6461(1) 1831(1) 6769(1) 13(1)C(1) 4064(2) 2777(1) 5577(1) 20(1)C(2) 6010(1) 2434(1) 5642(1) 16(1)C(3) 8305(1) 1227(1) 6939(1) 15(1)C(4) 8369(2) -82(1) 6276(1) 20(1)C(5) 9670(2) 2227(1) 6555(1) 21(1)C(6) 8560(2) 983(1) 8201(1) 20(1)
Table 16: Bond lengths [Å] and angles [°] for 12d.
Cl(1)-C(1) 1.7895(13)N(1)-C(2) 1.4962(14)N(1)-C(3) 1.5255(14)N(1)-H(1C) 0.878(15)N(1)-H(1D) 0.862(16)C(1)-C(2) 1.5109(16)C(1)-H(1B) 0.9900C(1)-H(1A) 0.9900C(2)-H(2A) 0.9900C(2)-H(2B) 0.9900C(3)-C(5) 1.5236(16)C(3)-C(6) 1.5263(17)C(3)-C(4) 1.5298(16)C(4)-H(4A) 0.9800C(4)-H(4B) 0.9800C(4)-H(4C) 0.9800C(5)-H(5A) 0.9800C(5)-H(5B) 0.9800C(5)-H(5C) 0.9800C(6)-H(6A) 0.9800C(6)-H(6B) 0.9800C(6)-H(6C) 0.9800
C(2)-N(1)-C(3) 116.51(8)C(2)-N(1)-H(1C) 108.1(10)C(3)-N(1)-H(1C) 107.4(9)C(2)-N(1)-H(1D) 107.6(10)C(3)-N(1)-H(1D) 107.7(10)H(1C)-N(1)-H(1D) 109.3(14)C(2)-C(1)-Cl(1) 108.90(8)C(2)-C(1)-H(1B) 109.9Cl(1)-C(1)-H(1B) 109.9C(2)-C(1)-H(1A) 109.9
- 140 -
Cl(1)-C(1)-H(1A) 109.9H(1B)-C(1)-H(1A) 108.3N(1)-C(2)-C(1) 108.52(8)N(1)-C(2)-H(2A) 110.0C(1)-C(2)-H(2A) 110.0N(1)-C(2)-H(2B) 110.0C(1)-C(2)-H(2B) 110.0H(2A)-C(2)-H(2B) 108.4C(5)-C(3)-N(1) 109.33(9)C(5)-C(3)-C(6) 110.15(9)N(1)-C(3)-C(6) 105.40(8)C(5)-C(3)-C(4) 111.49(10)N(1)-C(3)-C(4) 108.75(9)C(6)-C(3)-C(4) 111.51(9)C(3)-C(4)-H(4A) 109.5C(3)-C(4)-H(4B) 109.5H(4A)-C(4)-H(4B) 109.5C(3)-C(4)-H(4C) 109.5H(4A)-C(4)-H(4C) 109.5H(4B)-C(4)-H(4C) 109.5C(3)-C(5)-H(5A) 109.5C(3)-C(5)-H(5B) 109.5H(5A)-C(5)-H(5B) 109.5C(3)-C(5)-H(5C) 109.5H(5A)-C(5)-H(5C) 109.5H(5B)-C(5)-H(5C) 109.5C(3)-C(6)-H(6A) 109.5C(3)-C(6)-H(6B) 109.5H(6A)-C(6)-H(6B) 109.5C(3)-C(6)-H(6C) 109.5H(6A)-C(6)-H(6C) 109.5H(6B)-C(6)-H(6C) 109.5
Table 17: Anisotropic displacement parameters (Å2x 103)for 12d. The anisotropicdisplacement factor exponent takes the form: -2π2[ h2a*2U11 + ... + 2 h k a* b* U12 ].
U11 U22 U33 U23 U13 U12
Cl(1) 24(1) 20(1) 22(1) 4(1) -6(1) 3(1)Cl(2) 19(1) 14(1) 17(1) -1(1) 0(1) 2(1)N(1) 14(1) 13(1) 14(1) -1(1) 1(1) 0(1)C(1) 18(1) 21(1) 19(1) 4(1) -1(1) 3(1)C(2) 17(1) 17(1) 13(1) 2(1) 1(1) 2(1)C(3) 13(1) 15(1) 18(1) -1(1) 0(1) 2(1)C(4) 21(1) 17(1) 22(1) -4(1) -1(1) 5(1)C(5) 15(1) 23(1) 27(1) 2(1) 2(1) -2(1)C(6) 22(1) 20(1) 18(1) 1(1) -3(1) 2(1)
- 141 -
Table 18: Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103) for 12d.
x y z U(eq)
H(1C) 5695(19) 1192(15) 6886(12) 21(4)H(1D) 6359(19) 2450(17) 7266(12) 23(4)H(1B) 3776 3344 6224 23H(1A) 3352 1947 5603 23H(2A) 6276 1791 5041 19H(2B) 6721 3253 5540 19H(4A) 9555 -471 6368 30H(4B) 8093 98 5478 30H(4C) 7502 -711 6557 30H(5A) 10857 1918 6793 32H(5B) 9452 3103 6891 32H(5C) 9577 2303 5734 32H(6A) 9700 542 8362 30H(6B) 7606 410 8452 30H(6C) 8540 1841 8599 30
Table 19: Hydrogen bonds for 12d [Å and °].
D-H...A d(D-H) d(H...A) d(D...A) <(DHA)
N(1)-H(1C)...Cl(2)#1 0.878(15) 2.314(15) 3.1839(14) 171.1(13) N(1)-H(1D)...Cl(2) 0.862(16) 2.319(17) 3.1439(15) 160.1(13)
- 142 -
A.2.3. 2-(tert-Butylamino)ethylbromide hydrobromide (13d)
Figure 28: X-ray structure of 13d.
Table 20: Crystal data and structure refinement for 13d.
Identification code 13dEmpirical formula C6 H15 Br2 NFormula weight 261.01Temperature 100(2) KWavelength 0.71073 ÅCrystal system MonoclinicSpace group P2(1)/cUnit cell dimensions a = 7.7204(17) Å 1 = 90
b = 10.375(2) Å . = 92.051c = 12.243(3) Å 2 = 90
Volume 980.1(4) Å3
Z 4Density (calculated) 1.769 Mg/m3
Absorption coefficient 8.202 mm-1
F(000) 512Crystal size 0.22 x 0.20 x 0.10 mm3
Crystal color/habit colorless/blockTheta range for data collection 2.57 to 28.16°.Index ranges -8<=h<=10, -13<=k<=11, -14<=l<=15Reflections collected 7736Independent reflections 2281 [R(int) = 0.0395]Completeness to theta = 25.00° 99.8 %Absorption correction multi-scan/sadabsMax. and min. transmission 0.4399and 0.2365Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 2281 / 0 / 94Goodness-of-fit on F2 1.041Final R indices [I>2sigma(I)] R1 = 0.0275, wR2 = 0.0691R indices (all data) R1 = 0.0336, wR2 = 0.0717Extinction coefficient 0.0025(6)Largest diff. peak and hole 0.894 and -0.552 e.Å-3
- 143 -
Table 21: Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for13d. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.
x y z U(eq)
Br(1) 3562(1) 1342(1) 4276(1) 22(1)Br(2) 6568(1) 461(1) 8093(1) 17(1)N(1) 6493(3) 3201(2) 6753(2) 14(1)C(1) 4132(3) 2246(3) 5640(2) 20(1)C(2) 6030(3) 2598(3) 5671(2) 17(1)C(3) 8297(3) 3809(2) 6898(2) 17(1)C(4) 8547(4) 4082(3) 8115(2) 23(1)C(5) 8332(4) 5051(3) 6235(2) 21(1)C(6) 9655(3) 2835(3) 6530(3) 24(1)
Table 22: Bond lengths [Å] and angles [°] for 13d.
Br(1)-C(1) 1.952(3)N(1)-C(2) 1.497(3)N(1)-C(3) 1.534(3)N(1)-H(1C) 0.89(3)N(1)-H(1D) 0.87(3)C(1)-C(2) 1.510(4)C(1)-H(1B) 0.9900C(1)-H(1A) 0.9900C(2)-H(2A) 0.9900C(2)-H(2B) 0.9900C(3)-C(5) 1.524(4)
C(3)-C(4) 1.522(4)C(3)-C(6) 1.535(4)C(4)-H(4A) 0.9800C(4)-H(4B) 0.9800C(4)-H(4C) 0.9800C(5)-H(5A) 0.9800C(5)-H(5B) 0.9800C(5)-H(5C) 0.9800C(6)-H(6A) 0.9800C(6)-H(6B) 0.9800C(6)-H(6C) 0.9800
C(2)-N(1)-C(3) 117.5(2)C(2)-N(1)-H(1C) 111(2)C(3)-N(1)-H(1C) 107.0(19)C(2)-N(1)-H(1D) 109(2)C(3)-N(1)-H(1D) 105.5(19)H(1C)-N(1)-H(1D) 105(3)C(2)-C(1)-Br(1) 109.04(17)C(2)-C(1)-H(1B) 109.9Br(1)-C(1)-H(1B) 109.9C(2)-C(1)-H(1A) 109.9Br(1)-C(1)-H(1A) 109.9H(1B)-C(1)-H(1A) 108.3N(1)-C(2)-C(1) 108.9(2)N(1)-C(2)-H(2A) 109.9C(1)-C(2)-H(2A) 109.9N(1)-C(2)-H(2B) 109.9C(1)-C(2)-H(2B) 109.9H(2A)-C(2)-H(2B) 108.3C(5)-C(3)-C(4) 111.1(2)C(5)-C(3)-N(1) 108.6(2)C(4)-C(3)-N(1) 105.8(2)
C(5)-C(3)-C(6) 112.0(2)C(4)-C(3)-C(6) 110.3(2)N(1)-C(3)-C(6) 108.8(2)C(3)-C(4)-H(4A) 109.5C(3)-C(4)-H(4B) 109.5H(4A)-C(4)-H(4B) 109.5C(3)-C(4)-H(4C) 109.5H(4A)-C(4)-H(4C) 109.5H(4B)-C(4)-H(4C) 109.5C(3)-C(5)-H(5A) 109.5C(3)-C(5)-H(5B) 109.5H(5A)-C(5)-H(5B) 109.5C(3)-C(5)-H(5C) 109.5H(5A)-C(5)-H(5C) 109.5H(5B)-C(5)-H(5C) 109.5C(3)-C(6)-H(6A) 109.5C(3)-C(6)-H(6B) 109.5H(6A)-C(6)-H(6B) 109.5C(3)-C(6)-H(6C) 109.5H(6A)-C(6)-H(6C) 109.5H(6B)-C(6)-H(6C) 109.5
- 144 -
Table 23: Anisotropic displacement parameters (Å2x 103)for 13d. The anisotropicdisplacement factor exponent takes the form: -2p2[ h2a*2U11 + ... + 2 h k a* b* U12 ].
U11 U22 U33 U23 U13 U12
Br(1) 23(1) 21(1) 21(1) -3(1) -6(1) -3(1)Br(2) 17(1) 16(1) 17(1) 1(1) -1(1) -2(1)N(1) 14(1) 15(1) 14(1) 1(1) -1(1) 0(1)C(1) 18(1) 26(1) 17(1) -4(1) -2(1) -4(1)C(2) 17(1) 20(1) 14(1) -2(1) -1(1) -3(1)C(3) 13(1) 18(1) 20(1) 1(1) -1(1) -2(1)C(4) 22(2) 25(1) 22(2) -1(1) -3(1) -2(1)C(5) 18(1) 21(1) 25(1) 4(1) -3(1) -5(1)C(6) 16(1) 24(2) 31(2) -4(1) 1(1) 0(1)
Table 24: Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103) for 13d.
x y z U(eq)H(1C) 5730(40) 3800(30) 6930(20) 17(8)H(1D) 6440(40) 2620(30) 7270(30) 19(8)H(1B) 3419 3036 5688 24H(1A) 3880 1686 6270 24H(2A) 6741 1815 5567 21H(2B) 6266 3210 5074 21H(4A) 7591 4620 8358 35H(4B) 9647 4535 8250 35H(4C) 8562 3267 8520 35H(5A) 7450 5645 6495 32H(5B) 8092 4856 5462 32H(5C) 9479 5452 6323 32H(6A) 10815 3135 6759 35H(6B) 9581 2753 5732 35H(6C) 9435 1994 6863 35
Table 25: Hydrogen bonds for 13d [Å and °].
D-H...A d(D-H) d(H...A) d(D...A) <(DHA)
N(1)-H(1C)...Br(2)#1 0.89(3) 2.47(3) 3.339(2) 165(3) N(1)-H(1D)...Br(2) 0.87(3) 2.46(3) 3.282(2) 158(3)
- 145 -
A.2.4. 1,3-Di-tert-butylimidazolium bromide
Figure 29: X-ray structure of 1,3-di-tert-butylimidazolium bromide.
Table 26: Crystal data and structure refinement for 1,3-di-tert-butylimidazolium bromide.
Identification code 1,3-di-tert-butylimidazolium bromideEmpirical formula C11 H21 Br N2Formula weight 261.21Temperature 123(2) KWavelength 0.71073 ÅCrystal system MonoclinicSpace group P2(1)/nUnit cell dimensions a = 9.0827(11) Å, 1 = 90
b = 12.4052(15) Å, . = 94.47c = 11.3434(14) Å, 2 = 90
Volume 1274.2(3) Å3
Z 4Density (calculated) 1.362 g/cm3
Absorption coefficient 3.195 mm-1
F(000) 544Crystal size 24.00 x 0.34 x 0.30 mm3
Theta range for data collection 2.44 to 25.45°Index ranges -10<=h<=10, -14<=k<=14, -11<=l<=13Reflections collected 9526Independent reflections 2342 [R(int) = 0.0337]Completeness to theta = 25.00° 99.6 %Absorption correction Multi-scanMax. and min. transmission 0.4474 and 0.0092Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 2342 / 0 / 133Goodness-of-fit on F2 1.018Final R indices [I>2sigma(I)] R1 = 0.0236, wR2 = 0.0537R indices (all data) R1 = 0.0313, wR2 = 0.0573Largest diff. peak and hole 0.458 and -0.289 e Å-3
- 146 -
Table 27: Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for 1,3-di-tert-butylimidazolium bromide. U(eq) is defined as one third of the trace of the orthogonalized Uijtensor.
x y z U(eq)
Br(1) 5636(1) 2662(1) 5766(1) 22(1)N(1) 5951(2) 193(1) 8154(1) 16(1)N(2) 3976(2) -161(1) 7013(1) 15(1)C(1) 7391(2) 236(2) 10073(2) 21(1)C(2) 6623(2) 1953(2) 9060(2) 23(1)C(3) 8521(2) 787(2) 8205(2) 22(1)C(4) 7134(2) 805(2) 8885(2) 17(1)C(5) 5980(2) -890(2) 7894(2) 18(1)C(6) 4751(2) -1111(2) 7182(2) 18(1)C(7) 4738(2) 615(2) 7600(2) 16(1)C(8) 2551(2) 2(2) 6259(2) 17(1)C(9) 2942(2) 163(2) 4982(2) 20(1)C(10) 1795(2) 1003(2) 6708(2) 22(1)C(11) 1598(2) -997(2) 6370(2) 26(1)
Table 28: Bond lengths [Å] and angles [°] for 1,3-di-tert-butylimidazolium bromide.
N(1)-C(7) 1.331(2)N(1)-C(5) 1.376(3)N(1)-C(4) 1.510(2)N(2)-C(7) 1.333(3)N(2)-C(6) 1.379(3)N(2)-C(8) 1.508(2)C(1)-C(4) 1.523(3)C(2)-C(4) 1.516(3)C(3)-C(4) 1.527(3)C(5)-C(6) 1.354(3)C(8)-C(11) 1.522(3)C(8)-C(10) 1.526(3)C(8)-C(9) 1.531(3)
C(7)-N(1)-C(5) 108.16(16)C(7)-N(1)-C(4) 126.11(18)C(5)-N(1)-C(4) 125.66(16)C(7)-N(2)-C(6) 107.89(16)C(7)-N(2)-C(8) 125.21(17)C(6)-N(2)-C(8) 126.85(16)N(1)-C(4)-C(2) 109.36(15)N(1)-C(4)-C(1) 107.85(16)C(2)-C(4)-C(1) 110.28(17)N(1)-C(4)-C(3) 107.19(15)C(2)-C(4)-C(3) 110.68(18)
- 147 -
C(1)-C(4)-C(3) 111.38(17)C(6)-C(5)-N(1) 107.26(18)C(5)-C(6)-N(2) 107.35(18)N(1)-C(7)-N(2) 109.33(18)N(2)-C(8)-C(11) 108.21(16)N(2)-C(8)-C(10) 107.95(16)C(11)-C(8)-C(10) 111.20(17)N(2)-C(8)-C(9) 107.55(15)C(11)-C(8)-C(9) 111.13(17)C(10)-C(8)-C(9) 110.65(17)
Table 29: Anisotropic displacement parameters (Å2x 103) for 1,3-di-tert-butylimidazolium bromide. Theanisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12].
U11 U22 U33 U23 U13 U12
Br(1) 23(1) 19(1) 22(1) 2(1) -6(1) -2(1)N(1) 14(1) 19(1) 13(1) 0(1) 0(1) -1(1)N(2) 13(1) 20(1) 13(1) 2(1) 1(1) -1(1)C(1) 22(1) 28(1) 13(1) 0(1) -3(1) 0(1)C(2) 24(1) 21(1) 22(1) -5(1) -5(1) -2(1)C(3) 18(1) 30(1) 17(1) -3(1) 2(1) -5(1)C(4) 15(1) 21(1) 14(1) -2(1) -2(1) -2(1)C(5) 18(1) 21(1) 17(1) 1(1) 1(1) 3(1)C(6) 19(1) 16(1) 19(1) 0(1) 1(1) 0(1)C(7) 15(1) 17(1) 16(1) 1(1) 2(1) 0(1)C(8) 14(1) 24(1) 14(1) 2(1) -3(1) -2(1)C(9) 19(1) 26(1) 16(1) 0(1) -3(1) 2(1)C(10) 17(1) 33(1) 18(1) 0(1) 0(1) 4(1)C(11) 18(1) 33(1) 25(1) 4(1) -5(1) -6(1)
- 148 -
Table 30: Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2 x 10 3) for 1,3-di-tert-butylimidazolium bromide.
x y z U(eq)
H(1A) 6481 255 10484 32H(1B) 8183 602 10554 32H(1C) 7673 -515 9945 32H(2A) 5714 1947 9471 34H(2B) 6434 2303 8288 34H(2C) 7391 2352 9533 34H(3A) 8311 1133 7434 33H(3B) 8825 38 8090 33H(3C) 9317 1177 8656 33H(5A) 6725 -1389 8164 22H(6A) 4474 -1795 6859 22H(7A) 4461 1352 7620 19H(9A) 3429 -486 4710 30H(9B) 3609 781 4944 30H(9C) 2038 298 4474 30H(10A) 1673 924 7554 34H(10B) 824 1089 6277 34H(10C) 2402 1639 6580 34H(11A) 1433 -1116 7204 38H(11B) 2101 -1625 6064 38H(11C) 647 -894 5915 38
- 149 -
A.3. Solubility Data
A.3.1. 3-(Ethyl)aza-1,5-dichloropentane hydrochloride (15)
Table 31: Solubility of 3-(ethyl)aza-1,5-dichloropentane hydrochloride (15).
Solu
tion
Mol
arity
(mol
/ L
Solve
nt)
0.00
0
0.00
0
0.00
1
0.06
6
0.09
4
0.29
3
0.79
6
0.57
6
0.90
5
1.40
4
3.37
5
23.1
71
Solu
tion
Mol
arity
( mol
/ kg
Solve
nt)
0.00
0
0.00
0
0.00
2
0.07
6
0.11
9
0.19
6
0.60
1
0.72
8
1.03
5
1.78
9
4.26
7
23.1
71
Solu
tion
Mol
arity
( mol
/ kg
Solu
tion)
0.00
0
0.00
0
0.00
2
0.07
5
0.11
6
0.18
9
0.53
4
0.63
3
0.85
3
1.30
6
2.26
8
4.00
5
Solu
tion
W/V
%(g
/ L
Solve
nt)
0.0
0.0
0.2
13.6
19.4
60.5
164.
4
118.
9
186.
9
290.
1
697.
1
4785
.7
Solu
tion
W/W
%(g
/ kg
Solve
nt)
0.0
0.0
0.3
15.8
24.5
40.5
124.
1
150.
3
213.
9
369.
5
881.
3
4785
.7
Solu
tion
W/W
%(g
/ kg
Solu
tion)
0.0
0.0
0.3
15.5
24.0
39.0
110.
4
130.
7
176.
2
269.
8
468.
4
827.
2
Solv
ent
Hexa
ne
Pent
ane
Et2O
Tolu
ene
Acet
one
CHCl
3
CH2C
l 2
EtO
H 95
%
Benz
ene
i PrO
H
MeO
H
H 2O
- 150 -
A.3.2. 3-(tert-Butyl)aza-1,5-dichloropentane hydrochloride (16)
Table 32: Solubility of 3-(tert-butyl)aza-1,5-dichloropentane hydrochloride (16).So
lutio
nM
olar
ity( m
ol /
LSo
lvent)
0.00
5
0.00
9
0.00
7
0.03
6
0.08
9
0.14
7
0.48
5
0.84
5
1.18
8
3.41
1
11.9
65
9.62
3
Solu
tion
Mol
arity
(mol
/ kg
Solve
nt)
0.00
7
0.01
0
0.01
2
0.05
1
0.10
2
0.18
6
0.36
6
1.07
7
1.50
2
2.28
6
11.9
65
12.1
65
Solu
tion
Mol
arity
(mol
/ kg
Solu
tion)
0.00
7
0.01
0
0.01
2
0.05
0
0.10
0
0.17
8
0.33
7
0.86
0
1.11
0
1.48
8
3.14
3
3.15
7
Solu
tion
W/V
%( g
/ L
Solve
nt)
1.1
2.1
1.7
8.4
20.9
34.4
113.
8
198.
3
278.
6
800.
2
2807
.0
2257
.5
Solu
tion
W/W
%(g
/ kg
Solve
nt)
1.6
2.5
2.8
11.9
24.0
43.5
85.9
252.
6
352.
3
536.
3
2807
.0
2853
.9
Solu
tion
W/W
%(g
/ kg
Solu
tion)
1.6
2.4
2.8
11.8
23.4
41.7
79.1
201.
7
260.
5
349.
1
737.
3
740.
5
Solv
ent
Hexa
ne
Tolu
ene
Pent
ane
Et2O
Benz
ene
Acet
one
CH2C
l 2
i PrO
H
EtO
H 95
%
CHCl
3
H 2O
MeO
H
- 151 -
A.3.3. 1,3-Di-tert-butylimidazolium chloride
Table 33: 1,3-Di-tert-butylimidazolium chloride solubility organized according to solubility differencesbetween boiling and room temperature solutions.
Solvent Temperature(°C)
SolutionW/W%(g / kgsolution)
SolutionW/W%(g / kgsolvent)
SolutionW/V%(g / Lsolvent)
SolutionMolarity(mol / kg
solution)
SolutionMolarity(mol / kg
solvent)
SolutionMolarity(mol / L
solvent)
Diethyl Ether 34.6 0.0 0.0 0.0 0.000 0.000 0.000
Diethyl Ether 25 0.0 0.0 0.0 0.000 0.000 0.000
Benzene 80 9.8 9.9 8.7 0.045 0.046 0.040
Benzene 25 9.0 9.1 8.0 0.042 0.042 0.037
1,4-Dioxane 101 3.4 3.4 3.6 0.016 0.016 0.016
1,4-Dioxane 25 1.2 1.2 1.2 0.006 0.006 0.006
Hexane 69 2.5 2.6 1.7 0.012 0.012 0.008
Hexane 25 0.0 0.0 0.0 0.000 0.000 0.000
Acetone 56 122.7 139.9 110.7 0.566 0.645 0.511
Acetone 25 119.9 136.2 107.7 0.553 0.628 0.497
Triethyl Amine 89 7.4 7.4 5.4 0.034 0.034 0.025
Triethyl Amine 25 0.0 0.0 0.0 0.000 0.000 0.000
Acetone / EthylAcetate 1:1
3 65.4 70.0 3 0.302 0.323 3
Acetone / EthylAcetate 1:1
25 46.4 48.7 3 0.214 0.225 3
Acetone / Hexane1:1
3 44.6 46.7 3 0.206 0.215 3
Acetone / Hexane1:1
25 5.0 5.0 3 0.023 0.023 3
Ethyl Acetate 77 51.4 54.2 48.9 0.237 0.250 0.226
Ethyl Acetate 25 0.0 0.0 0.0 0.000 0.000 0.000
Cyclohexanone 155 327.1 486.1 460.4 1.509 2.243 2.124
Cyclohexanone 25 258.0 347.8 329.3 1.190 1.604 1.519
1,2-Dichloroethane 83 267.4 365.0 458.4 1.234 1.684 2.115
1,2-Dichloroethane 25 150.5 177.2 222.5 0.694 0.817 1.027
- 152 -
Methyl EthylKetone
80 179.9 219.4 176.6 0.830 1.012 0.815
Methyl EthylKetone
25 37.2 38.7 31.1 0.172 0.178 0.144
Methylene Chloride 40 493.9 975.9 1293.1 2.279 4.502 5.966
Methylene Chloride 25 277.9 384.9 510.0 1.282 1.776 2.353
Chloroform 61 436.3 774.1 1155.0 2.013 3.572 5.329
Chloroform 25 169.2 203.7 303.9 0.781 0.940 1.402
n-Propanol 97 541.2 1179.4 948.2 2.497 5.441 4.375
n-Propanol 25 243.9 322.5 259.3 1.125 1.488 1.196
Ethanol 100% 78 576.0 1358.4 1071.8 2.657 6.267 4.945
Ethanol 100% 25 271.8 373.3 294.5 1.254 1.722 1.359
iso-Propanol 82 547.4 1209.7 949.6 2.526 5.581 4.381
iso-Propanol 25 114.3 129.1 101.4 0.528 0.596 0.468