effect of solvation on the conformational behavior of...

85

Effect of solvation on the conformational behavior ofstereoelectronic organic compounds and pi-facial selectivity

of sterically unbiased organic systems

Solvation of Stereoelectronic organic compounds Chapter 3.1

86

3.1. Effect of solvation on the conformational behavior of stereoelectronic organiccompounds like cyclic di-aza and aza-oxa systems3.1.1. IntroductionConformational analysis has always been an important topic of research in physical organic

chemistry1 as most of the properties like reactivity2, spectroscopic behaviors etc. depends on

the conformation. This ongoing interest in the conformational behaviour of different organic

systems1 have come into light, since Sachse recognized the existence of two kinds of C-H

bonds for cyclohexane.3 However, it is still a matter of controversy, that, what mostly controls

the properties or stabilities for even the simple systems and hence studies on conformational

analysis is still actively pursued.

The stereoelectronic behavior of X-C-Y containing systems known as the anomeric effect and

that of X-C-C-Y known as gauche effect, where X and Y are any electronegative atoms

containing lone pairs have been studied widely 4-20. The anomeric effect can be defined as the

preference for synclinal over antiperiplanar conformations in a molecular segment, R-X-A-Y with

A having an intermediate electronegativity (like C); Y is more electronegative than A (like N or

O); X is an element with lone pair and R is C or H. The electrostatic model of dipole-dipole

interaction suggests that the anomeric effect arises from the repulsion between the dipole of the

X lone pairs and the A-Y dipole, which destabilizes the ap conformation21 and the A-Y dipole,

which destabilizes the ap conformation.21 The other clarification is based on the charge

delocalization model. This states that the anomeric effect in an R-X-A-Y system is due to Xnp-

σ*A-Y a two electron–two orbital interaction. This confirms that the hyperconjugation takes place

in such systems.

The gauche effect was originally defined as the tendency for a molecule to adopt that structure

which has the maximum number of synclinal (sc, gauche, 60°) interactions between adjacent

electron pairs and/or polar bonds in a molecular fragment X-C-C-Y, where X and Y are two

electronegative substituents.19 Both gauche and anomeric effects are absent when X and Y do

not contain any interacting lone pair. In recent studies, interpretations of gauche effect are

based on hyperconjugation effect.16,18,22-24 The hyperconjugation approach states a two

electron/two orbital interaction which depends on the donor-acceptor ability of the orbitals, on

the energy difference between them and on overlap symmetry.25

Ethylenediamine (EDA) is one of the most studied structures for the conformational analysis for

its vast number of structures available. Schafer et al.26 and Radom et al.27 reported that EDA

consists of 10 minimum energy structures. Electron diffraction experiments in the gas phase

have shown that nonprotonated EDA is predominantly (95%) in a gauche conformation. DFT


87

calculations performed by D. D. Corte et al.28 also showed that gauche conformers are the most

stable conformers in both gas and aqueous phase. The structural stabilities of such types of

molecules depend upon stereoelectronic effect, steric effect and hydrogen bonding. Politzer et

al. calculated computationally the energies of different aza cyclic, acyclic systems and observed

that σ-delocalization of nitrogen pair or anomeric effects are responsible for their extra stability

than the simple cyclic or acyclic systems.29

Conformational analysis of heterocyclic molecules containing the N-C-N; O-C-O and N-C-O

moiety have also been explored experimentally and theoretically.21a,30 However, the influence of

solvent molecules on the conformational behavior of these cyclic systems loaded with

steroelectronic effect is poorly understood. Recent efforts on the conformational stability of 1,3-

diazacyclohexane conformers with different solvents30,31 prompted us to examine the

conformational preference of symmetrical 1,4-diazacyclohexane and –oxa-3-azacyclohexane.

A. Conformational Analysis of 1,4-diazacyclohexane1,4-diazacyclohexane, (Scheme 1) also known as piperazine and is used in preparing

anticancer drugs like Pibobroman.32 It is also used in the production of pharmaceuticals and for

human and veterinary medicinal drugs. Further, it is used as catalyst in urethane production and

also as raw material for preparing antibiotics. Aqueous solution of piperazine also helps to

remove the corrosive gases like CO2, H2S etc.33

Scheme 1In this section, we have reported density functional (DFT) study of 1,4-diazacyclohexane

conformers (Scheme 1) in the gas and aqueous phase. The solvent study has been performed

both with implicit solvent continuum model and explicit solvent molecules. We have examined

the stability of conformers of 1,4-diazacyclohexane with two and four water molecules. Natural

bond orbital analysis (NBO) was performed to obtain the hyperconjugative and steric

contributions towards the stability of 1,4-diazacyclohexane in the gas and solvent phase. We

have also performed molecular dynamics study using Atom-Centered Density Matrix

Propagation (ADMP) for 1,4-diazacyclohexane conformers interacting with four water

molecules.


88

A.3.1.1. Computational DetailsThe structures were fully optimized at Becke’s three parameter exchange functional with the

correlation functional36 of Lee, Yang and Parr (B3LYP)37 with 6-31+G* basis set. Positive

harmonic vibrational frequencies confirmed that the optimized structures were minimal. Single

point calculations were carried out with B3LYP/6-311+G** level of theory.30,38-40 The relative

energies were calculated using the electronic energies obtained with B3LYP/6-311+G** level of

theory. NBO calculations were carried out at B3LYP/6-311+G** level of theory using B3LYP/6-

31+G* optimized geometries.41-43 According to the NBO method, the total SCF energy (Etot) can

be decomposed in two terms. The Lewis energy (ELew) is associated with the localized Hartree

Fock (HF) wave function (corresponding essentially to a Lewis structure, although its

interpretation is not direct), and is obtained by zeroing all the orbital interactions, that is deleting

the off-diagonal elements of the Fock matrix. The delocalization energy (Edel) corresponding to

all the possible interactions between orbitals, is calculated as:-

Edel = Etot - Elew

The B3LYP/6-31+G* optimized geometries were used to calculate the solvation effect at

B3LYP/6-311+G** level employing the Polarizable Continuum (PCM) solvent model.44 The

solvent dielectric constant was set to be the experimental value (ε =78.4 for aqueous solution).

For explicit interactions between the solute and solvent, water has been considered as solvent

molecules. The energies reported for the interaction of water molecules with 1,4-

diazacyclohexane were corrected with basis set superposition error (BSSE) employing the

counterpoise method.45 All calculations were carried out with the Gaussian 03 suite of

programs.46 To examine the relative orientations of explicit water molecules with 1,4-

diazacyclohexane conformers, the Atom-Centered Density Matrix Propagation (ADMP)

method47 was carried out at the B3LYP/6-31G(d) level of theory using the Gaussian 03 suite of

programs. To compromise with the computational cost, these calculations were carried out with

6-31G* basis set instead of 6-31+G* basis set. The default time step of 0.1 fs was used for the

trajectories. The default fictitious electron mass of 0.1 amu was used throughout. ADMP

simulations were carried out for 100 fs with each conformer in presence of water molecules.

Selected snapshots were registered with larger changes in the trajectories in each case.

A.3.1.2. Results and DiscussionA.3.1.2.1. Conformational Analysis in gas and implicit solvent model1,4-diazacyclohexane (1) was optimized in three conformations which differ by the orientation of

N-H bonds: equatorial/equatorial (ee), axial/axial (aa) and equatorial/axial (ea) (Figure 1).

Conformations were fully optimized without any symmetry constraints. Relative energies and


89

NBO results for 1 are summarized in Table 1. The relative energies of 1,4-diaxzacyclohexane in

implicit solvent phase (water with dielectric constant = 78.4) using the gas phase computed

geometries with B3LYP/6-311+G** level are given in Table 1. The 1aa and 1ea conformers are

higher in energy than that of 1ee form. The stability order of these conformers was further

calculated with MP2/6-311+G**48 and B3LYP/6-31G* levels to examine the influence of basis

sets and the methods. The calculated relative energies were found to be similar to that of

B3LYP/6-311+G** level of theory (Table 2). Further Free energy calculations were computed

for these conformers and similar preference was observed (Table 2). According to valence-shell

electron pair repulsion theory (VSEPR), 1ee with axial lone pairs should be expected to be

highest in energy, since lone pairs require more space than bond pairs. However, this situation

has not been borne out in the calculated results (Table 1).

Figure 1. B3LYP/6-31+G* optimized structures for 1ee, 1aa and 1ea conformers of 1,4-

diazacyclohexane [nitrogen: blue; carbon: grey; hydrogen : white].

Table 1: B3LYP/6-311+G**//B3LYP/6-31+G* relative energies (ERel) for the conformers of 1,4-

diazacyclohexane in gas and aqueous phase. Relative energies after removal of

hyperconjugative interaction (ELew), contributions from hyperconjugation (Edel) to the total energy

differences and dipole moment for 1ee, 1aa and 1ea conformers of 1,4-diazacyclohexane in the

gas phase are given. Energies are in kcal/mol.

1ee 1aa 1ea

ERel(gas) 0.0 1.5 3.0

ERel(water) 0.0 0.8 2.6

Elew 0.0 7.0 5.8

Edel 0.0 -5.5 -2.8

Dipole moment (gas) 0.002 0.004 1.60

Table 2. Relative energies of 1ee, 1aa and 1ea conformers of 1,4-diazacyclohexane at MP2/6-

311+G** and B3LYP/6-31G* level of theory. Free energy corrected relative energies for the

parent 1ee, 1aa and 1ea conformers of 1,4-diazacyclohexane at B3LYP /6-31+G* level of

theory are also given Energies are in kcal/mol.


90

1ee 1aa 1ea

MP2/6-311+G** 0.0 1.9 3.0

B3LYP/6-31G* 0.0 0.7 2.8

ERel. Free Energy corr.

(B3LYP/6-31+G*)

0.0 1.3 3.0

The NBO energy decomposition suggests that the ELew energy contributes predominantly

towards the stability of 1,4-diazacyclohexane 1 (Table 1). The hyperconjugative type

interactions in 1aa is stronger compared to 1ee, however, the overall stabilization in the later

case is due to the lower ELew energy (Table 1). The higher ELew term for 1aa shows that the

dipole repulsion between bond pairs is larger than that of the repulsion between the lone pair

and bond pair in 1ee. The conformer 1ea is a result of compromise between avoiding repulsions

and the hyperconjugative stabilization. The highest energy for 1ea is due to attenuated

hyperconjugative effects. The importance of steric effect and dipolar repulsions towards the

stereoelectronic effect in the conformational analysis of 2-methoxy-1,3-

dimethylhexahydropyrimidine was also observed.49 Polarizable continuum model (PCM)

calculations show that the relative stability of 1,4-diazacyclohexane 1 conformers in aqueous

phase is similar to the gas phase results. The relative energy differences are smaller in the

solvent medium than that of the gas phase calculated results. These calculated results suggest

that the conformer with larger hyperconjugative interactions is stabilized more by the solvent.

Numerous cases have been reported on attenuation of the stereoelectronic effect to the

presence of a polar solvent;50 however, this feature is not clearly appreciable for the conformer

of 1,4-diazacyclohexane. Recently, some studies have shown that the stereoelectronic effects

are not attenuated in the presence of a polar solvent.21a,51 Furthermore, the influence of the

polar solvent to stabilize the conformers with larger dipole moments is not significant. The

conformer 1ea with larger dipole moment is less stabilized than that of 1aa with smaller dipole

moment (Table 1).

The selection of geometrical parameters listed in Table 3 permits us to deduce that 1ee, 1aaand 1ea show the tendencies associated with gauche effect and were discussed in many

studies. Briefly, the bonds are elongated when they are in a position anti to the lone pair of

nitrogen, and the angles are widened (Scheme 1 and Table 3). For example, due to the

delocalization of lone pairs, the N-C-C bond angles are larger in 1aa than in 1ee and 1ea. The

C-H bonds antiperiplanar to the lone pairs are relatively longer than the bonds that are not

satisfying such arrangements.

A.3.1.2.2. Conformational analysis of 1,4-diazacyclohexane [1] with two water molecules


91

The influence of hydrogen bonding of polar solvent molecules with the substrates is absent in

the continuum model calculations. Therefore, it is important to examine the effect of hydrogen

bonding of solvent molecules on the stability of 1,4-diazacyclohexane conformers. Interestingly,

the hydrogen bonding of solvent molecules with nitrogen lone pairs can affect the gauche

stabilizations in these cases, and hence the stability of the conformer can be different from the

gas phase and continuum model results. The interaction of water molecules with each

conformer of 1,4-diazacyclohexane has been considered. The DFT B3LYP/6-

311+G**//B3LYP/6-31+G* level relative energies for two explicit water molecules with 1ee, 1aaand 1ea are given in Table 4. Figure 2 shows the interaction of two water molecules with the

nitrogen lone pairs of 1,4- diazacyclohexane conformers. The calculated results suggest that the

1ee conformer is more stable than the 1aa and 1ea conformers (Table 4). The water molecules

form strong hydrogen bonds with the nitrogen atoms of 1,4-diazacyclohexane. The

conformational stability order changed for 1aa and 1ea conformers with explicit water molecules

compared to the gas phase and continuum model results. 1aa conformer was found to be least

stable, while interacting with two water molecules. Comparing the NBO calculated ELewis and Edel

energies for 1ee, 1aa and 1ea show that the Lewis energy is even more detrimental for 1aa with

water molecules, which contributes to make it unstable than 1ee and 1ea conformers (Table 1

and Table 4). Hence, earlier reports have demonstrated that the -NH2 is a good proton acceptor

but a less effective proton donor,52 and that is evident in this study. The interaction of water

molecules with -NH as a proton donor was found to be less stable compared to the case where

-NH is a proton acceptor for 1,4-diazacyclohexane conformers (Figure 3). In the case of 1aa,

water molecules moved away from –N-H donor side to -N-H acceptor side.

Table 3: Geometrical parameters for 1ee, 1aa and 1ea conformers of 1,4-diazacyclohexane in

the gas phase. All distances are in angstroms; angles and dihedrals are in degrees.

Parameters 1ee 1aa 1ea

C6-C9 1.530 1.540 1.530

C2-C3 1.530 1.540 1.530

C6-H7 1.096 1.097 1.096

C6-H8 1.106 1.101 1.106

C3-H5 1.106 1.101 1.106

C3-H13 1.096 1.098 1.096

C9-H15 1.105 1.101 1.105

C9-H16 1.096 1.098 1.096


92

C2-H1 1.096 1.098 1.096

C2-H12 1.105 1.101 1.106

N4-C9-H15 112.50 107.38 111.39

N4-C2-H12 113.54 107.34 111.43

N4-C9-C6 108.90 113.33 109.30

N4-C2-C3 108.95 113.35 109.23

N10-C6-H8 112.51 107.43 107.80

N10-C3-H5 112.49 107.38 107.77

N10-C6-C9 108.94 113.32 112.69

N10-C3-C2 108.93 113.31 112.75

Table 4: B3LYP/6-311+G**//B3LYP/6-31+G* relative energies (ERel) for 1ee, 1aa, 1eaconformers of 1,4-diazacyclohexane with two water molecules. Relative energies after removal

of hyperconjugative interaction (ELew), contributions from hyperconjugation (Edel) to the total

energy differences for 1ee, 1aa and 1ea conformers of 1,4-diazacyclohexane with two water

molecules are given in kcal/mol. BSSE corrected relative energies are given in parenthesis.

Figure 2. B3LYP/6-31+G* optimized structures of the 1ee, 1aa and 1ea conformers of 1,4-

diazacyclohexane with explicit two water molecules are given [nitrogen: blue; carbon: grey;

oxygen : red; hydrogen: white] Hydrogen bond-distances are given in angstroms.

1ee 1aa 1ea

ERel 0.0 (0.0) 3.8 (3.7) 1.1 (1.0)

Elew 0.0 9.4 3.9

Edel 0.0 -5.6 -2.8


93

1ee 1aa 1eaERel. 1.1 0.0 6.8

(kcal/mol)


diazacyclohexane with explicit two water molecules started with N-H proton as donor are given

[nitrogen: blue; carbon: grey; oxygen : red; hydrogen: white] Hydrogen bond-distances are given

in angstroms.

A.3.1.2.3. Conformational analysis of 1,4-diazacyclohexane [1] with four water moleculesExtending the study with explicit solvent molecules, the conformational stabilities of 1,4-

diazacyclohexane conformers was examined with four water molecules. The relative energies

calculated with DFT B3LYP/6-311+G**//B3LYP/6-31+G* level for four water molecules with 1ee,

1aa and 1ea are given in Table 5. The water molecules can either interact with the nitrogen’s of

1,4-diazacyclohexane in a cluster form or can interact in a chain form with the advantage of

more number of hydrogen bonding (Figure 4). We have examined both situations for each

conformer of 1,4-diazacyclohexane. The calculated relative energies for the interaction of four

water molecules in a cluster form with the nitrogen atoms of 1,4-dizazcyclohexane show that

the 1ee and 1ea are energetically similar, whereas, the 1aa conformer is slightly higher in

energy by 0.7 kcal/mol (Table 5). The water molecules form strong hydrogen bonds with the

nitrogen atoms of 1,4-diazacyclohexane and also with each other. The NBO calculations

indicate

Table 5: B3LYP/6-311+G**//B3LYP/6-31+G* relative energies for the 1ee, 1aa and 1eaconformers of 1,4-diazacyclohexane with four water molecules in cluster form and four water

molecules in chain form. Relative energies after removal of hyperconjugative interaction (ELew),

contributions from hyperconjugation (Edel) to the total energy differences for 1ee, 1aa and 1eaconformers of 1,4-diazacyclohexane in four cluster form and four chain form are given in

kcal/mol. BSSE corrected relative energies are given in parenthesis.

4:H2O cluster 4:H2O chain


94

1ee 1aa 1ea 1ee 1aa 1ea

ERel 0.0(0.0) 0.7(0.6) 0.2(0.2) 0.0(0.0) 0.0(0.1) 2.1(2.6)

Elew 0.0 3.4 3.8 0.0 9.7 -6.9

Edel 0.0 -2.7 -3.6 0.0 -9.7 9.0

that the contributions of Elew and Edel energies are smaller with four water molecules compared

to the two water molecules and contributions of both the energies are largely comparable in the

former case (Table 4 & Table 5). Further, to take the advantage of hydrogen bonding within the

water molecules, calculations have been performed with the chain of water and 1,4-

diazacyclohexane conformers (Figure 4). The relative energies calculated with the chain of

water molecules show that the 1ee and 1aa conformers are isoenergetic in this case (Table 4).

Interestingly, the 1ea conformer was found to be much higher in energy than 1ee and 1aaconformers, which is mainly dictated by the unfavored hyperconjugative type interaction energy

(Edel.). To note that both the nitrogen lone pairs are engaged in 1ea while interacting with the

four water chain, however, this is not the case with 1ee and 1aa. Therefore, there is a possibility

that the nitrogen lone pair not engaged in hydrogen bonding can interact with one more water

molecule. Additional calculations performed with five water molecules also showed that 1aa is

3.0 kcal/mol energetically preferred over 1ea conformer (Figure 5).


diazacyclohexane with explicit four water molecules in cluster form and in chain form are given


95

[nitrogen: blue; carbon: grey; oxygen : red; hydrogen : white]. Hydrogen bond-distances are

given in angstroms.

The relative energies of the 1aa and 1ea conformers of 1,4-diazacyclohexane with explicit two

water molecules and four water molecules at other levels of theory are given in table 6.

Table 6. Relative energies of 1ee, 1aa and 1ea conformers of 1,4-diazacyclohexane interacting

with two and four water molecules at MP2/6-311+G** and B3LYP/6-31G* level of theory.

Energies are in kcal/mol.

1aa 1eaERel (kcal/mol) 0.0 2.9

Figure 5 B3LYP/6-31+G* optimized structures of the 1ee, 1aa and 1ea conformers of 1,4-

diazacyclohexane with explicit 5 water molecules and their relative electronic energies in

kcal/mol are given [nitrogen: blue; carbon: grey; oxygen : red; hydrogen : white]. Hydrogen

bond-distances are given in angstroms.

A.3.1.2.4. Ab initio Molecular Dynamics Simulation (AIMD)DFT calculations with four water molecules showed that the clustered water interacting with 1,4-

diazacyclohexane conformers are energetically less stable than the corresponding situations

1ee 1aa 1ea

MP2/6-311+G** 2:H2O 0.0 5.8 2.0

4:H2O cluster 0.0 1.3 0.5

4:H2O chain 0.0 0.2 2.0

B3LYP/6-31G* 2:H2O 0.0 4.9 1.7

4:H2O cluster 0.0 0.4 0.1

4:H2O chain 0.7 0.0 3.5


96

where water molecules form a chain. Therefore, it appears that four water molecules would

prefer to interact with 1ee, 1aa and 1ea conformers while taking advantage of more number of

hydrogen bonding i.e., in the chain form. To examine the orientations of four water molecules in

the chain form observed in DFT calculations with time—ab initio molecular dynamic simulations

(AIMD) were performed at B3LYP/6-31G* level using the Atom-Centered Density Matrix

Propagation (ADMP) method. The AIMD simulations performed for 100 fs showed that the

orientations of water molecules are largely unperturbed in each case. The total energy vs. the

time step plots are given in Figure 6 for 1ee, 1aa and 1ea conformers. The snapshots with the

maximum fluctuations of water molecules in the time trajectory marked as black are also given

in Figure 6. Comparing the snapshots taken for each conformer it appears that there are minor

perturbations in the orientations of water molecules with 1,4-diazacyclohexane.

Figure 6. B3LYP/6-31G* trajectories for the interaction of 1ee, 1aa, 1ea conformers of 1,4-

diazacyclohexane with four water in chain form with AIMD/ADMP simulations. Snapshots of the


97

conformers for each case are given at specific time marked in black in the time trajectory

[nitrogen: blue; carbon: grey; oxygen: red; hydrogen: white]. Hydrogen bond-distances are given

in angstroms.

B. Conformational Analysis of 1-oxa-3-aza-cyclohexane1-oxa,3-aza-cyclohexane (Scheme 2) is the origin of many important drugs34 and

polymeric/chemically curable resins.35 Cyclophosphamide, a synthetic alkylating agent

chemically related to the nitrogen mustards with antineoplastic and immunosuppressive

activities is a derivative of 1-oxa,3-aza-cyclohexane (Scheme 3). In the liver, cyclophosphamide

is converted to the active metabolites aldophosphamide and phosphoramide mustard, which

bind to DNA, thereby inhibiting DNA replication and initiating cell death.34 Carballeira et al.

reported that the conformational behaviour of the N-C-O type systems depends on the

combination of steric and stereoelectronic effects and hydrogen bond-type interactions.21a

However, the influence of solvent effect on the conformational behavior of 1-oxa,3-aza-

cyclohexane is not well understood.

Axial (2a) Equatorial (2e)

Scheme 2

Scheme 3. Cyclophosphamide

In this section, we have examined the conformational behavior of 1-oxa,3-aza-cyclohexane

(Scheme 2) in the gas and aqueous phase. The solvent study has been performed both with

implicit solvent continuum model and explicit solvent molecules. We have examined the stability

N O

H

H

H

H

H

HH

H

H12

13

1410

7

153

9

118

5

6

12

4

N OH

H

H

H

H H

H

H

H2

3

4

5

6

7

89

10

11

121314

15

1

O

P NHN

Cl

Cl

O


98

of conformers of 1,4-diazacyclohexane with two and four water molecules. Natural bond orbital

analysis (NBO) was performed to obtain the hyperconjugative and steric contributions towards

the stability of 1,4-diazacyclohexane in the gas and solvent phase.

B.3.1.1. Computational DetailsSimilar theoretical methods have been used for the conformational analysis of 1-oxa-3-aza-

cyclohexane [2]. The structures are fully optimized using B3LYP/6-31+G* level.37,38 As non-

bonding interactions are present single point calculations at M05-2X/6-311+G** have been

performed.53 NBO calculations were carried out at the same level of theory.41-43

The solvation effect was calculated at M05-2X/6-311+G** level employing the Polarizable

Continuum (PCM) solvent model44 and CPCM solvent model.54 For explicit interactions between

the solute and solvent, water has been considered as solvent molecules. NBO analyses are

performed for the different solvated geometries involving two and four water molecules. All

calculations were carried out with the Gaussian 03 suite of programs.46 According to the NBO

method, the total SCF energy (Etot) can be decomposed in two terms. The Lewis energy (ELew)

is associated with the localized Hartree Fock (HF) wave function (corresponding essentially to a

Lewis structure, although its interpretation is not direct), and is obtained by zeroing all the orbital

interactions, that is deleting the off-diagonal elements of the Fock matrix. The delocalization

energy (Edel) corresponding to all the possible interactions between orbitals, is calculated as:-

Edel = Etot - Elew

B.3.1.2. Results and DiscussionsB.3.1.2.1. Conformational Analysis in the gas phase and implicit solvent modelThe 1-oxa-3-azacyclohexane [2] was optimized in two different conformations differed in the

orientations of the N-H bonds: axial (2a) and equatorial (2e) positions (scheme 2). The

optimized geometries of axial and equatorial conformers showed that 2a is relatively more

stable in gas as well as in continuum solvent phase, similar to the results reported by

Carballeira et al.21a The relative energies in gas and solvent phase and the energetic

contribution from the NBO model of 2a and 2e at M05-2X/6-311+G(d,p) are given in table 7. In

the gas phase calculations, the NBO decomposition energies suggest that the Elew energy does

not contribute much towards the stability of the axial conformer of [2], however, the

hyperconjugative type interaction energy (E2) for 2a is much lower than 2e, which corresponds

to the overall stability of the axial conformer (2a) than the equatorial conformer (2e) by 3.4

kcal/mol. The dipole moments of the conformers are also included in table 7. The dipole

moment calculated for 2a is relatively lower than the corresponding 2e, which is in agreement


99

with the previous reports that the most stable conformers in the gas phase correspond with the

lower dipole.49,55

The preference for the axial conformer of [2] is decreased by ~ 0.8 kcal in water with the solvent

continuum PCM model. Other solvation model like CPCM employed in the present study

showed similar trend in the stability of the conformers of [2]. The calculated results suggest that

the conformer with larger anomeric interactions is destabilized by the solvent effect. The

presence of polar solvent causes in reduction of the anomeric effect20 and this is observed for

the conformers of [2]. The Elew in the solvent phase calculations showed a better stability for the

equatorial conformer (Table 7), which opposes the VSEPR theory. According to VSEPR theory,

the lp-lp repulsion is higher than the lp-bp repulsion. However, the hyperconjugative type

interaction energy (E2) in 2a is lower than the 2e (Scheme 2), which corresponds to the overall

stability of the axial conformer in the solvent phase (Table 7).

The NBO calculations performed at M05-2X/6-311+G(d,p)//B3LYP/6-31+G* level of theory at

PCM solvation model showed higher hyperconjugative Interaction energies (E2) for the nN-σ*C-O

and nN-σ*C-C interactions of 2a (16.77 and 7.56 kcal/mol) due to the presence of nitrogen lone

pair antiperiplanar to the C-O bond and C-C bonds, respectively (Scheme 1 and Table 8). Such

hyperconjugative interaction energies are weaker in the case of 2e as the nitrogen lone pair is

antiperiplanar to the C-H bonds (Scheme 1). The calculated hyperconjugative Interaction

Energies (E2) for nN-σ*C-H interactions are 8.71 & 8.38 kcal/mol, respectively (Table 8).

Therefore, it appears that the hyperconjugative interaction is mainly responsible for the higher

stability of the axial conformer of [2], as other interactions are comparable in both the axial and

equatorial conformers (Table 8).

Selected geometrical parameters are listed in Table 9. The bonds which are in antiperiplanar

position to the lone pairs of Nitrogen are elongated and thus exhibits the anomeric effect.5-10,56

The angles containing these bonds are also widened (Scheme 1 and Table 9) as observed with

the anomeric systems.

Table 7: M05-2X/6-311+G(d,p)//B3LYP/6-31+G* relative energies (ERel) for the conformers of 1-

oxa-3-azacyclohexane in gas and aqueous phase. Relative energies after removal of

hyperconjugative interaction (ELew), contributions from hyperconjugation (Edel) to the total energy

differences and dipole moment for 2a and 2b conformers in the gas phase are given. Energies

are in kcal/mol.

M05-2X/6-

311+G(d,p)

2a 2e


100

ERel (gas) 0.0 3.4

Elew(gas) 0.0 0.3

Edel(gas) 0.0 3.1

ERel (water) PCM 0.0 2.6

Elew(PCM) 0.0 -3.4

Edel(PCM) 0.0 6.0

ERel (water) CPCM 0.0 2.6

Elew(CPCM) 0.0 -3.4

Edel(CPCM) 0.0 6.0

Dipole moment (gas) 1.5199 2.2811

Table 8: Hyperconjugative Interaction Energies (E2) (in kcal/mol) calculated at M05-

2X/6311+G**//B3LYP/6-31+G* for 2a and 2e in PCM solvent model.

Donor

(lp)

Acceptor

(σ*)

2a 2e

N13 C1-C2 7.56 1.10

N13 C2-H5 2.85 8.71

N13 C2-H6 0.85 1.57

N13 C3-H9 2.36 8.38

N13 C3-H10 0.94 1.57

N13 C3-O15 16.77 4.11

O15 C1-C4 6.08 5.90

O15 C3-H9 6.19 6.27

O15 C3-H10 2.96 3.26

O15 C3-N13 9.26 9.59

O15 C4-H11 6.84 6.67

O15 C4-H12 2.99 3.03

Table 9. Selected B3LYP/6-31+G* Geometrical Parameters for 2a and 2e (bond lengths in

angstroms, and bond angles in degrees)


101

2a 2e

C2-H5 1.097 1.106

C2-H6 1.093 1.093

C3-H9 1.099 1.110

C3-H10 1.089 1.091

O15-C3 1.433 1.411

C1-C2 1.537 1.531

N13-C3-O15 114.460 110.692

N13-C2-C1 112.271 108.059

N13-C3-H9 108.239 112.066

N13-C3-H10 110.104 109.425

N13-C2-H5 107.514 112.088

N13-C2-C6 108.847 109.049

The influence of dielectric constant of solvent on the N-C-O system was noticed, however, the

influence of hydrogen bonding of polar solvent molecules with the conformers is absent in such

continuum model calculations. Therefore, it is important to examine the effect of hydrogen

bonding of solvent molecules with 2a and 2e and the stability of such hydrogen bonded

conformers. In the present study, we have considered different orientations of two and four

water molecules with the conformers.

B.3.1.2.2. Conformational analysis of 1-oxa-3-azacyclohexane [2] with two watermoleculesFigure 7 and Figure 8 shows the interactions of two water molecules with 2a and 2e conformers

respectively and their corresponding relative energies and NBO data are given in table 10 and

table 11. The water molecules can interact with the conformers in associated manner or can

interact individually.

Four different geometries have been calculated with two water molecules interacting with the 2aconformer. The calculated results show that 2a-1 and 2a-2 are energetically comparable and

lower than the other calculated geometries. (Figure 7 and Table 10) In the case of 2a-1, the

nitrogen and oxygen anomeric equatorial lone-pairs are involved in the intermolecular hydrogen

bonding with the water molecules, whereas, in 2a-2, such anomeric lone-pairs are free to

stabilize the system. The water molecules are oriented in associative manner via hydrogen

bonding (Figure 7). The NBO calculations show that the stronger delocalization energy (Edel) is

present in 2a-2 compared to 2a-1 as the lone pairs are involved in the hydrogen bonding with

the water molecules in the later case. The contribution of steric component calculated with the


102

lewis energy (Elew) is much higher for 2a-2 and compensates the stabilization gained with the

delocalization energy, resulting the similar energies for 2a-1 and 2a-2. The other geometries

(2a-3 and 2a-4) calculated with 2 water molecules seem to suggest the stability is governed by

the interplay of steric and electronic interactions (Figure 7 and Table 10).

2a-1 2a-2

2a-3 2a-4Figure 7. B3LYP/6-31+G* optimized structures of the 2a conformer of 1-oxa-3-aza-cyclohexane

with explicit two water molecules are given [nitrogen: blue; carbon: grey; oxygen : red; hydrogen

: white]. Hydrogen bond-distances are given in angstroms.

Table 10: The relative stability (ERel) of the different geometries of the conformers 2a interacting

with two water molecules and the corresponding ELew and Edel are given in kcal/mol. The

hydrogen bonding distances are given in Å. The overall relative energies (ERel) comparing 2aand 2e geometries interacting with two water molecules are given in parenthesis ( ).

Geometries ERel ELew Edel

2a-1 0.0 (0.3) 0.0 0.0

2a-2 0.0 (0.3) 17.1 -17.1

2a-4 0.7 1.7 -1.0

2a-5 3.0 0.4 2.6

1.912.38

1.922.

091.86


103

The interactions of 2 water molecules with the 2e conformer have also been calculated at the

same level of theory (Figure 8). The calculated results show that 2e-1 is more stable than other

geometries with other orientation of water molecules (Table 11). Importantly, the interaction

pattern of water molecules with 2e is similar, however, the arrangement of hydrogen bonding

between the water molecules are different in these cases (Figure 8). The NBO calculations

suggest that the delocalization energy is lower in the case of 2e-1 compared to 2e-2 and shows

slightly the better stability in the former case (Table 11).

The contributions of steric component are lower for 2e-3 and 2e-4, however, the involvement of

the lone pairs in the hydrogen bonding with water molecules reduces the total hyperconjugative

interaction energy (Edel) and results in higher in energy than 2e-1. Furthermore, the total

hyperconjugative interaction energy (Edel) governs the stability of 2e-3 than 2e-4. The individual

NBO analysis show a stronger hyperconjugative interaction energy between Nlp-σ*C2-H5 and Nlp-

σ*C2-H6 for 2e-3 (9.10 kcal/mol and 9.16 kcal/mol respectively) than 2e-4 (7.58 kcal/mol and 7.79

kcal/mol, respectively).

2e-1 2e-2

2e-3 2e-4Figure 8. B3LYP/6-31+G* optimized structures of the 2e conformer of 1-oxa-3-aza-cyclohexane

with explicit two water molecules are given [nitrogen: blue; carbon: grey; oxygen : red; hydrogen


1.93 1.89


104

Table 11: The relative stability (ERel) of the different geometries of the conformers 2e interacting

with two water molecules and the corresponding ELew and Edel are given in kcal/mol. The



2e-1 0.0 (0.0) 0.0 0.0

2e-2 0.4 -1.1 1.5

2e-3 2.4 -3.2 5.6

2e-4 6.1 -4.0 10.1

Overall, the calculated results suggest that 2e-1 is the most stable geometry with 2 water

molecules (Table 10 & Table 11). This result is different from the gas phase and continuum

model calculations (Table 7). The hydrogen bonding interaction between the water molecules

and anomeric lone-pairs of 2 attenuates the anomeric effect and hence the stability order was

found to be different in these cases.

B.3.1.2.3. Conformational Analysis of 1-oxa-3-azacyclohexane [2] with four watermoleculesThe study was further extended with four water molecules. The possible interactions of 4 water

molecules with 2a and 2e conformers are given in figure 9 and figure 10, respectively. The

relative energies are given in table 12 and table 13, respectively.

The increasing number of water molecules enhances the possibility of intermolecular hydrogen

bonding within them and also interacts with the different possible sites of conformers 2a and 2e.The interaction of 2a conformer with 4 water molecules gives rise to six different geometries

(Figure 9). The calculated results suggest that 2a-5 is the most stable geometry in this case.

The stability of 2a is dependent on the interplay of Lewis energy (ELew) and the delocalization

energy (Edel) (Table 12). These results show that the hydrogen bonding of the anomeric lone-

pairs of 2a with water molecules greatly attenuates the anomeric effect and hence affects the

stability of 1-oxa-3-azacyclohexane conformers.


105

2a-5 2a-6 2a-7

2a-8 2a-9 2a-10Figure 9. B3LYP/6-31+G* optimized structures of the 2a conformer of 1-oxa-3-aza-cyclohexane

with explicit four water molecules are given [nitrogen: blue; carbon: grey; oxygen : red; hydrogen


Table 12: The relative stability (ERel) of the different geometries of the conformers 2a interacting

with four water molecules and the corresponding ELew and Edel are given in kcal/mol. The



2a-5 0.0 (0.0) 0.0 0.0

2a-6 1.8 -0.6 2.4

2a-7 2.5 4.2 -1.7

2a-8 6.6 -24.8 31.4

2a-9 4.1 -18.8 22.9

2a-10 2.7 -8.3 11.0

Five geometries have been optimized for the 2e conformer with four water molecules (Figure

10). The calculated results show that the stability of 2e conformer with 4 water molecules is

greatly influenced by the Lewis energy (ELew), which swamped the delocalization energy (Edel)

1.99

1.99

1.94


106

(Table 13). 2e-5 was predicted to be the most stable structure in this series. Comparing the

overall results, it appears that 2a-6 is the most stable with 4 water molecules (Table 12 & 13),

which is in agreement with the calculated gas phase and continuum model results.

2e-5 2e-6 2e-7

2e-8 2e-9Figure 10. B3LYP/6-31+G* optimized structures of the 2e conformer of 1-oxa-3-aza-

cyclohexane with explicit four water molecules are given [nitrogen: blue; carbon: grey; oxygen:

red; hydrogen : white]. Hydrogen bond-distances are given in angstroms.

Table 13. The relative stability (ERel) of the different geometries of the conformers 2e interacting

with four water molecules and the corresponding ELew and Edel are given in kcal/mol. The



2e-5 0.0 (2.4) 0.0 0.0

2e-6 2.6 26.1 -23.5

2e-7 4.5 1.0 3.5

2e-8 0.4 13.4 -13.0

1.78

1.78

2.26


107

2e-9 3.5 -5.8 9.3

3.1.2. ConclusionsThis section demonstrates the conformational stability of 1,4-diazayclohexane and 1-oxa-3-aza-

cyclohexane in gas phase, implicit and explicit solvent molecules. The stability of conformers

was found to be interplay of steric, dipolar repulsions and hyperconjugative interactions for such

stereoelectronic systems. The NBO analysis suggests that the anomeric effect weakens with

the interaction of water molecules.

In the case of 1,4-diazayclohexane [1], the solvent continuum model (PCM) with water predicted

the similar conformational stability: 1ee >1aa > 1ea as observed with the gas phase

calculations, though the preference for 1ee is reduced in solvent medium. The explicit water

molecules, however, showed the change in the conformational stability order of 1,4-

diazacyclohexane conformers compared to gas and continuum model results. The chain of

water molecules around 1ee, 1ea, 1aa conformers are more stable than the cluster form of

water molecules. In the chain form, the conformers 1ee and 1aa are isoenergetic and are

expected to be equally populated in the polar solvents like water, which is different from the gas

phase results. Ab initio molecular dynamics study showed the minor perturbation in the

orientation of water molecules and no dramatic changes was observed during the simulation

with 1,4-diazacyclohexane conformers.

In the case of 1-oxa-3-aza-cyclohexane [2], the solvent continuum models showed the axial

conformer 2a to be more stable than the equatorial one 2e with less preference than the gas

phase results. The explicit water molecules however, differed in stabilizing the conformers---2

water molecules predicted the stability of 2e over 2a conformer of 1-oxa-3-aza-cyclohexane.

The 4 water molecules predicted the similar stability of [2] as obtained with the gas phase and

continuum model calculations. Overall, the stability of such stereoelectronic systems is

governed by the interplay of steric, dipolar repulsions and hyperconjugative interactions of the

systems interacting with the number of water molecules participating in the process.


108

References1. Roberts, J. D. Acc. Chem. Res. 2006, 39, 889.

2. Luibrand, R. T.; Taigounov, I. R.; Taigounov, A. A. J. Org. Chem. 2001, 66, 7254.

3. H. Sachse, Ber. Dtsch. Chem. Ges. 1890, 23, 1363.

4. S. Wolfe, Acc. Chem. Res. 1972, 5, 102.

5. G.R. Thatcher, J. Ed. The Anomeric Effect and Associated Stereoelectronic Effects ACS Symposium

Series. No. 539 American Chemical Society: Washington, DC, 1993.

6. E. Juaristi, G. Cuevas, Tetrahedron 1992, 48, 5019.

7. A. J. Kirby, The Anomeric Effect and Related Stereoelectronic Effects at Oxygen. Springer: Berlin,

1983.

8. P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry. Wiley: New York, 1983.

9. G.A. Jeffrey, J.A. Pople, J.S. Binkley, S. Vishveshwara, J. Am. Chem. Soc. 1978,100, 373.

10. R.U. Lemieux, In Molecualr Rearrangements; De Mayo, P., Ed. Interscience Publishers: New York,

1964, p 709.

11. S. David, O. Eisenstein, W.J. Hehre, L. Salem, R. Hoffmann, J. Am. Chem. Soc. 1973, 95, 3806.

12. U. Salzner, P.v.R. Schleyer, J. Org. Chem. 1994, 59, 2138 (and references cited therein).

13. L. Schleifer, H. Senderowitz, P. Aped, E. Tartakovsky, B. Fuchs, Carbohydr. Res. 1990, 206 21.

14. B. Fuchs, A. Ellencweig, E. Tartakovsky, P. Aped, Angew. Chem. Int. Ed. Engl. 1986, 25, 287.

15. H. Senderowitz, P. Aped, B. Fuchs, Tetrahedron 1993, 49, 3879.

16. H. Senderowitz, B. Fuchs, J. Mol. Struct.: THEOCHEM 1997, 395, 123.

17. O. Reany, I. Goldberg, S. Abramson, L. Golender, B. Ganguly, B. Fuchs, J. Org. Chem. 1998, 63,

8850.

18. E. Kleinpeter, F. Taddei, P. Wacker, Chem. Euro. J. 2003, 9, 1360.

19. I.V. Alabugin, J. Org. Chem. 2000, 65, 3910.

20. I. Tvarosˇka, J.P. Carver, J. Phys. Chem. B 1997, 101, 2992.

21. (a) Carballeira, L.; Juste, I. P. J. Org. Chem. 1997, 62, 6144. (b) Lemieux, R. U. In Molecular

Rearrangements; De Mayo, P., Ed.; Interscience Publishers: New york, 1964; p. 709.

22. L. Goodman, R.R. Sauers, J. Chem. Theory Comput. 2005, 1, 1185.

23. K.B. Wiberg, Acc. Chem. Res. 1996, 29, 229.

24. K.B. Wiberg, M.A. Murcko, K.E. Laidig, P.J. MacDougall, J. Phys. Chem. 1990, 94, 6956.

25. M.P. Freitas, R. Rittner, J. Phys. Chem. A 2007, 111, 7233.

26. C. Van Alsenoy, K. Slam, J.D. Ewbank, L.Schafer, J. Mol. Struct. 1998, 136, 77.

27. L. Radom, W.A. Lathan, W.J. Hehre, J.A. Pople, J. Am. Chem. Soc. 1973, 95, 693.

28. D.D. Corte, C. W. Schläpfer, C. Daul, Theor. Chem. Acc., 2000, 105, 39.

29. J.S. Muray, P.C. Redfern, J.S. Seminario, P. Politzer, J. Phys. Chem., 1990, 94, 2320.

30. A. Singh, B. Ganguly, J. Phys. Chem. A 2007, 111, 9884 and references within.

31. U. Salzner, J. Org. Chem., 1995, 60, 986.


109

32. M. Fermeglia, M. Ferrone, A. Lodi, S. Pricl, Carbohydrate Polymers, 2003, 53, 15.

33. (a) Aroua, M. K.; Salleh, R. M. Chem. Eng. Technol. 2004, 27, 65. (b) Speyer, D. ; Maurer, G. J.

Chem. Eng. Data. 2011, 56, 763.

34. (a) Takimoto, C. H.; Calvo, E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman, L.

D.; Camphausen, K. A.; Hoskins, W. J. (Eds) Cancer Management: A Multidisciplinary Approach. 11

E.d. 2008. (b) Popp, F. D. J. Med. Chem. 1966, 9, 270. (c) Camerman, N.; Camerman A. J. Am.

Chem. Soc., 1973, 95, 5038. (d) Ludeman, S. M.; Zon, G. J. Med. Chem., 1975, 18, 1251.

35. (a) Schreiber, H. Patent No. EP0178414 B1, 1988. (b) Schreiber, H. Patent No. US4607091 A, 1986.

(c) Schreiber, H. Patent No. USRE32745 E, 1988.

36. Becke, A. D. J. Chem. Phys.1993, 98, 5648.

37. Lee, C. T.; Wang, W. T.; Parr, R. G. Phys. Rev. B 1988, 37, 785.

38. Locke, J. M.; Crumbie, R. L.; Griffith, R.; Bailey, T. D.; Boyd, S.; Roberts, J. D. J. Org. Chem. 2007,

72, 4156.

39. Goodman, L.; Gu, H.; Pophristic, V. J. Phys. Chem. A 2005, 109, 1223.

40. Kolocouris, A. J. Org. Chem. 2009, 74, 1842.

41. Carpenter, J. E.; Weinhold, F. J. Mol. Struct.: THEOCHEM 1988, 169 41.

42. Reed, A. E.; Weinhold, F. J. Chem. Phys. 1983, 78, 4066.

43. A. E. Reed, L. A. Curtiss, F. Weinhold, Chem. Rev. 1988, 88, 899.

44. (a) S. Miertus, E. Scrocco, J. Tomasi, Chem. Phys. 1981, 55, 117. (b) M. Cossi, V. Barone, R.

Cammi, J. Tomasi, Chem. Phys. Lett. 1996, 255, 327. (c) B. Mennucci, J. Tomasi, J. Chem. Phys.

1997, 106, 5151.

45. S.F. Boys, F. Bernardi, Mol. Phys. 1970, 19, 553.

46. M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, J.A.

Montgomery Jr., T. Vreven, K.N. Kudin, J.C. Burant, J.M. Millam, S.S. Iyengar, J. Tomasi, V. Barone,

B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G.A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.

Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X.

Li, J.E. Knox, H. P. Hratchian, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E.

Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, P.Y. Ayala, K. Morokuma,

G.A. Voth, P. Salvador, J.J. Dannenberg, V.G. Zakrzewski, S. Dapprich, A.D. Daniels, M.C. Strain, O.

Farkas, D.K. Malick, A.D. Rabuck, K. Raghavachari, J.B. Foresman, J.V. Ortiz, Q. Cui, A.G. Baboul, S.

Clifford, J. Cioslowski, B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R.L. Martin, D.J.

Fox, T. Keith, M.A. Al-Laham, C.Y. Peng, A. Nanayakkara, M. Challacombe, P.M.W. Gill, B. Johnson,

W. Chen, M. W. Wong, C. Gonzalez, J.A. Pople, Gaussian (Revision E.01), Inc., Wallingford CT, 2004.

47. (a) H.B. Schlegel, J.M. Millam, S.S. Iyengar, G.A. Voth, A.D. Daniels, G.E. Scuseria, M. J. Frisch, J.

Chem. Phys. 2001, 114, 9758. (b) S.S. Iyengar, H.B. Schlegel, J.M. Millam, G.A. Voth, G.E. Scuseria,

M.J. Frisch, J. Chem. Phys. 2001, 115, 10291. (c) H.B. Schlegel, S.S. Iyengar, X. Li, J.M. Millam, G.A.

Voth, G.E. Scuseria, M.J. Frisch, J. Chem. Phys. 2002, 117, 8694.


110

48. Møller C.; Plesset, M. S. Phys Rev 1934, 46, 618.

49. C. L. Perrin, K.B. Armstrong, M.A. Fabian, J. Am. Chem. Soc. 1994, 116, 715.

50. (a) C.J. Cramer, J. Org. Chem. 1992, 57, 7034. (b) R. Montagnani, J. Tomasi, Int. J. Quanta. Chem.

1991, 39, 851.

51. L. Carballeira, I. Pérez-Juste, J. Comput. Chem. 2000, 21, 462.

52. (a) C. H. Hu, M. Shen, H.F. Schaefer III, J. Am. Chem. Soc. 1993, 115, 2923. (b) V. Baronel, C.

Adamo, F. Lelj, J. Chem. Phys. 1995, 102, 364.

53. Zhao, Y.; Schultz, N. E.; Truhlar, D. G. J. Chem. Theory and Comput. 2006, 2, 364.

54. (a) Barone, V.; Cossi, M. J. Phys. Chem. 1997, 102, 1995. (b) Cossi, M.; Rega, N.; Scalmani, G.;

Barone, V. J. Comp. Chem. 2003, 24, 669.

55. (a) Perrin, C. L.; Young, D. B. Tetrahedron Lett. 1995, 36, 7185. (b) Wiberg, K. B.; Murcko, M. A. J.

Chem. Phys. 1987, 91, 3616.

56. (a) Riddel, F. G.; Williams. F. G. Tetrahedron Lett. 1971, 2073. (b) Blackbume, I. D.; Katritzky, A. R.;

Read, D. M.; Chivers, P. J.; Crabb, T. A. J. Chem. Soc., Perkin Trans. II 1976, 418. (c) Chive, P. J.;

Crabb, T. A. Tetrahedron 1970, 26, 3369. (d) Katritzky, A. R.; Brito-Palma, F. M. S.; Baker, V. J. J.

Chem. Soc., Perkin Trans. II 1980, 1739. (e) Katritzky, A. R.; Baker, V. J.; Brito-Palma, F. M. S.;

Ferguson, I.; Angiolini, J. L. J. Chem. Soc., Perkin Trans. II 1980, 1746. (f) Jones, R. A. Y.; Katritzsky,

A. R.; Snarey. M. J. Chem. Soc. B 1970, 131. (g) Katritzsky, A. R.; Baker, V. J.; Ferguson, I. J.; Pate,

R. C. J. Chem. Soc., Perkin Trans. II 1979, 143. (h) Armarego, W. L. F.; Jones. R. A. Y.; Katritzsky, A.

R.; Read, D. M.; Scattergood, R. Aust. J. Chem. 1975, 28, 2323. (i) Armarego, W. L. F.; Kobayishi, T.

J. Chem. Soc. C 1971, 1912.

Π-Facial Selectivity Chapter 3.2

111

3.2. Development of new computational approach to predict the π-facialselectivity of sterically unbiased olefins with different electrophiles and theinfluence of solvation on the stereoselectivity3.2.1. IntroductionThe origin of π-face diastereoselection has been a subject of intense debate for a few decades

and still an active field of research.1-8 Induction of face selectivity in nucleophilic and

electrophilic additions to the olefinic group through remote electronic perturbation is an elegant

approach towards stereoselective bond formation. This has been an active research since

Cram’s model6 predicted the facial selectivity of nucleophilic addition to alpha-chiral aldehydes

and ketones. It is now well recognized that long range electronic effects can play decisive roles

in determining π-facial selectivity. However, precise nature of these effects and how exactly

they engender stereo-differentiation during electrophilic addition is still a challenge, despite

devising and investigating many experimental probes and invoking a variety of theoretical

models.9 Several theoretical models involving geometric, orbital distortions, steric, torsion,

stereoelectronic and electrostatic effects have been developed to rationalize face selective

reactions in organic synthesis.7,10 One of the hyperconjugative models, the Cieplak effect focus

on the hyperconjugative interactions between an electron-donor σ-bond, antiperiplanar to an

electron-acceptor (σ*) antibonding orbital.7 The role of electrostatic interactions, Felkin-Anh

model, transition state model, desymmetrization of the л-orbital, pre-complexation model, cation

complexation model11(k,l),12(j,k,l,n]) etc. constitute some of the other attempts put forward to

rationalize the face selectivities.10(a-d),11 The semi-quantitative semi-empirical MNDO model was

developed to predict the л-face selectivity for the nucleophilic addition to sterically unbiased

ketones, which segregates the importance of orbital and electrostatic effects.12(d),13 However,

the various electronic factors responsible for the л-face selectivity in electrophilic additions to

sterically unbiased alkenes has received only limited attention.14(e,f,n,o),9(g),15 In a conformationally

unconstrained substrate, the geometric and electronic effects might be operative, however, in

isosteric systems, the electronic effects might govern the stereoselectivity. The role of orbital

interactions and electrostatic interactions could be important in the electrophilic addition to steric

unbiased systems; however, the computational approach available in the literature is unable to

segregate such effect. Therefore, we have developed a computational approach to delineate the

orbital and electrostatic interactions to rationalize the observed л-face selectivity for isosteric

systems with electrophiles of varied nature. Experimental results for the π-facial selectivity of

5,6-cis,exo-disubstituted bicyclic[2.2.2]oct-2-enes (1, Scheme 1) (bearing electron-withdrawing


112

groups) with electrophiles showed the syn face preference for the addition of m-CPBA, while

anti face preference for the cycloaddition of diazomethane. The high syn selectivity observed in

epoxidation (with m-CPBA) of 1 can be rationalized by the Cieplak model. However, dominance

of an anti attack in the reactions of diazomethane is in contrast with the predictions based on

the Cieplak theory.14g

In this section, we have discussed the origin of reversal of facial selectivity of peracid and

diazomethane with 1 employing a newly developed model for the approach of electrophiles to

the olefinic systems that segregates electrostatic component from the orbital effects. The study

was then extended to evaluate л-face selectivity in other sterically unbiased olefins like endo

substituted 7-isopropylidenenorbornanes (2); 2,3-endo,endo-7-methylenenorbornanes (3); 5-

exo-bicyclo[2.1.1]hexane (4); 4-substituted 9-methylenenorsnoutanes (5) and 2,5-disubstituted

adamantanes (6) during addition of different electrophiles like m-chloroperbenzoic acid (m-

CPBA), chlorocarbene (:CCl2), diborane (B2H6) and Hydrochloric acid (HCl) (Scheme 2 and

Scheme 3) with the developed model.

5,6-cis,exo-disubstitutedbicyclic[2.2.2]oct-2-enes1 syn antiX = CN, Y= m-CPBA 95 5X-X = OCOO, Y= m-CPBA 96 4X = CN, Y= CH2N2 31 69

X-X = OCOO, Y= CH2N2 38 62

Scheme 1. Experimental results for the π-facial selectivity of 5,6-cis,exo-disubstituted

bicyclic[2.2.2]oct-2-enes

X

X

H HANTI SYN ANTI SYN

X

HHANTI SYN

X

CH3H3C

X

H HANTI SYN ANTI SYN

X

H H

32 5 6

a: X = CN; b: X = COOMe; c: X = CH2CH3; d: X = F; e: X = CH3

16

5 43

2

7

8

4

32

1

6 5

7

68

1

7

2

4

17

4

13

3

5

14

356

62 8

5

1

89 2

10 11

9

4


113

Scheme 2. Sterically unbiased olefins

m-CPBA Dichlorocarbene

B B

H

HH H

H H

Diborane Hydrogen Chloride

Scheme 3. Electrophiles

Earlier reports suggested that the origin of face selectivities observed in polycyclic systems 1-6with different electrophiles can be rationalized through orbital effects and the role of electrostatic

effect is less important to control the face selectivities in such systems,14(c,e,f,g,h,n)]. In the case of

4, the diastereofacial selection was reported to be controlled by the interplay of electrostatic and

Cieplak type orbital effects.14(n) However, a direct comparison of the electrostatic and orbital

models was not available in these cases as reported for the nucleophilic addition to the carbonyl

groups.12(a,d) Herein, we disclose the results of a computational study to gauge the role of

electrostatic and orbital interactions directly, employing the response of substrates 1-6 (Scheme

1 and Scheme 2) towards different electrophiles (Scheme 3) and discern their relative

importance to explain the experimentally observed face selectivities. The structural diversity of

substrates 1-6, harboring both endo- and exo-cyclic double bonds and substitution patterns was

expected to provide an intriguing testing bed for our model and the approach of the

electrophiles.

The density functional and ab initio calculations revealed that π-facial selectivity can be

controlled by the atom centres of an electrophile which remains after the bond formation and

also which is not directly involved in the bond formation while interacting with substrates. The

MESP analysis was performed in selected cases to examine the efficacy of electrostatic effects

in explaining the observed diastereoselectivites in sterically unbiased olefins.

Employing this computational approach to rationalize the face selectivity of 5-Fluoro-2-

methyleneadamantane (6d, scheme 2) with per-acid, the computed results could not predict the

correct selectivity in this case. Therefore, the apparent failure prompted us to examine the

stereoselectivity of this reaction further. The role of medium (i.e., solvent) was found to be

crucial in this case to predict the correct selectivity. It is well-known that different reactions can

be affected by the medium. Solvents can change both the equilibrium constants and reaction


114

rates.16 The effect of solvent on the stereoselectivity have been described by organic chemists,

and in particular examples of solvent-dependent face selectivity have been discussed.17 The

calculated results identify asymmetric distortional contributions to the transition state geometries

in the solvent medium to predict the correct selectivity. The distortion-interaction model

qualitatively rationalized the selectivities calculated in gas and solvent phase.18,19 The

asymmetric distortions in the л-face of 5-Fluoro-2-methyleneadamantane (6d) in solvent

environment were also observed with Ab Initio Molecular Dynamics (AIMD) calculations. It

appears that the ground state distortion contributions constitute the component of the transition

state differential for this reaction in solvent. Ground state distortions using AIMD simulations

suggest that the syn face is relatively more accessible for the electrophile (per-acid) compared

to the anti-face. Marcus theory accommodates this result owing to the fact that more distortional

asymmetry contributions reactant pass through a lower barrier to arrive the product compared to

the less distorted reactant to arrive the diastereomeric product.20 Furthermore, the opening of

syn-face in AIMD simulations suggest that the reaction rate of this face will be influenced by the

easy access of the electrophile (per-acid) than the other (anti) face.21

A. Development of the Model and its ApplicationA.3.2.1. Computational DetailsAll the substrates, electrophiles and the transition state geometries for the syn and anti addition

of these systems were fully optimized with B3LYP/6-31G* level of theory.22 B3LYP/6-31G* level

has been used in previous π-facial studies.11(k,l),12(o,t),23(c) The importance of computational

methods and models to qualitatively predict the π-facial selectivity of nucleophilic addition to

sterically unbiased ketones has been reported.12(p) The relative energies calculated with

B3LYP/6-31G* level were also corrected with zero point vibrational energies (ZPVE). Scheme 4

and Scheme 5 shows the model transition state geometries for the addition of various

electrophiles to the substrates 1-6. The harmonic vibrational frequencies were computed to

determine the minima and the first order saddle points in each case. Additionally, MP2/6-31G*

calculations24 were performed using B3LYP/6-31G* optimized geometries to calculate the

energy differences for syn- and anti- addition of electrophiles to the above mentioned

substrates. The solvent calculations for 1 has been performed with PCM continuum model.25

To segregate the electrostatic effects from orbital effects, the charge model derived to explain

the face selectivity of 5,6-cis,exo-disubstituted bicyclic[2.2.2]oct-2-enes was employed in all

cases. The electrophile modeled with point charge (PC) to examine the reactivity of the

acetaldehyde enolate has been reported.26 It is important to emphasize that the charge model is

not identical to the use of molecular electrostatic potential maps (MESP). The latter method is a


115

more direct approach to examine the electrostatic effects and has indeed been successfully

applied for a number of studies of regiochemical and facial selectivities in conjunction with both

ab initio and semiempirical methods.27 However, the present procedure incorporates an

additional effect. Since the wave functions are recomputed in the presence of the test charge,

electronic reorganization within the substrate due to the approaching reagent is taken into

account. Thus, the model includes polarization effects. The electrostatic interactions were

modeled with the CHelpG charges28 of the specific atom of the electrophiles obtained in the

transition state calculations and placing them at the calculated distance (d) as shown in Scheme

4. The atoms modeled for the charge calculations in different electrophiles are those which

remain in the final products. In the case of dichlorocarbene (:CCl2) addition to these substrates,

there is a possibility of attack from both ends of the double bond, as shown in I and II (Scheme

5). In I, the charge on the carbon atom of :CCl2 and in II the charge of chlorine atoms are used

to perform the charge model calculations. For convenience, performic acid was considered as a

model for m-CPBA.29 In case of performic acid, the charge calculations are performed by

removing the electrophile and adding the charge in place of the O4 oxygen atom. For diborane

(B2H6) addition, the charge of the hydrogen (H4) is taken in each case. In the case of

diazomethane (CH2N2), the CHelpG charge of the nitrogen atom (N2), which is not involved in

the bond formation with the substrate is taken for the charge model calculations. For HCl

addition, charge on the Hydrogen atom (H2) is taken to evaluate the electrostatic effect. ChelpG

charges were derived from electrostatic potentials using a grid based method as suggested by

Breneman and Wiberg.30 All calculations were done by the Gaussian 03 suite of programs.31

The MESP is calculated using eq (1) where ZA is the charge on nucleus A, located at RA and

ρ(r') is the electron density.32

( ) = | − | − ( ′) ′| ′ − | … … … … … … … (1)In general, electron dense regions are expected to show high negative MESP whereas electron

deficient regions are characterized by positive MESP.33 The most negative valued point (Vs,min)

in electron rich regions and the most positive values point (Vs,max)34 can be obtained from the

MESP topography calculation.35

A.3.2.2. Results and DiscussionA.3.2.2.1. Development of the modelFacial selectivity for the electrophilic addition to 5,6-cis,exo-disubstituted bicyclic[2.2.2]oct-2-

enes [1] was experimentally reported by Gandolfi et al.14(g) The diasterereotopic faces of 1 is

both sterically and torsionally unbiased. Gandolfi et al. used different electrophiles and the exo


116

substituted bicyclic[2.2.2]oct-2-enes to examine the π-facial selectivity. High syn selectivity was

observed for the epoxidation of 1 bearing electron withdrawing group such as X = –CN (1a) and

X-X = –OCOO- (1b) in agreement with Cieplak’s theory, but anti selectivity was observed for

diazomethane addition which could not be explained. To investigate the observed difference in

the selectivities of 1 with m-CPBA and diazomethane, we have performed density functional and

ab inito calculations with B3LYP/6-31G* and MP2/6-31G* levels of theory using the Gaussian

03 suite of programs. Performic acid was considered as a model for m-CPBA.36 The respective

transition states for syn- and anti- additions of performic acid and diazomethane to 1a and 1bare located at B3LYP/6-31G* level (Table 1). MP2/6-31G* single point calculations were also

performed to compare the relative energies with B3LYP/6-31G* optimized transition state

geometries of syn- and anti- addition of electrophiles to 1a and 1b. Additionally, solvent effect

was considered on the transition states by performing PCM continuum model calculations.25

Dichloromethane was used as a solvent for performic acid addition to 1a and 1b, whereas,

diethyl ether was employed for diazomethane addition as performed experimentally. The

butterfly transition states have been located for the addition of performic acid to the olefinic

double bonds of 1a and 1b.37 The transition states calculated for the 1,3-dipolar cycloaddition of

diazomethane to 1a and 1b are concerted in nature similar to earlier reports.38 The calculations

suggest that the approach of performic acid to 1a and 1b is energetically preferred from the syn-

face compared to the corresponding anti-face in excellent agreement to the observed results

(Table 1). Solvent phase calculations also reproduced the syn selectivity though the energetic

preferences were reduced compared to the gas phase results. The anti selectivity with

diazomethane for 1a and 1b was also borne out in the transition state energy differences at

B3LYP and MP2 levels of theory (Table 1). Solvent calculations were also in agreement with the

gas phase results. Based on Cieplak model, the electron withdrawing groups (X=CN 1a and X-X

= OCOO 1b) substituted to 1 should dictate the syn approach of electrophiles. The syn

selectivity predicted with performic acid in the transition state calculations is in the line of

agreement with Cieplak model, however, the anti selectivity predicted for the approach of

diazomethane towards 1a and 1b is in contrary to this model. The apparent failure of

hyperconjugative effects in sterically unbiased 1a and 1b to explain the stereoselectivity with

diazomethane suggests that other factors are important to dictate the selectivity in this case.

The electrostatic effects of remote substituents suggested to be important on the

stereoselectivities of nucleophilic additions on bicyclic systems.8,39e Here, in this case to

evaluate the electrostatic effects we have located the position of an electrophile and place the

ChelpG charge (Scheme 4) that can have a significant influence on the stereoselectivity


117

Analyzing the CHelpG charges,40 it has been found that the performic acid oxygen (O4)

participates in the bond formation bears a considerable negative charge on it, whereas, the

nitrogen atom (N2) not involved in the bond formation with 1a and 1b of diazomethane bears a

large positive charge (Figure 1). Figure 1 also shows the most interactive site of the

electrophiles, B3LYP/6-31G(d) computed electrostatic potentials Vs(r) on the surface of

performic acid and diazomethane i.e. the negative potential Vs,min on O4 (-100.46 kJ/mol),

whereas, positive potential Vs,max on N2 (76.18 kJ/mol). The analysis with the electrostatic

charges is also given in table 1, which corroborates with the experimental results of 1.

‘A’ is the electrostaticcharge on the atom

Calculation done by placing thecharge at the same position of theatom in the transition state.

Scheme 4.

Figure 1. The CHelpG charges at B3LYP/6-31G(d) of performic acid and diazomethane are

given here. The computed B3LYP/6-31G(d) Vs,min and Vs,max on the electrostatic isopotential

surface34 in kJ/mol for performic acid and diazomethane are shown in italics. The locations of

Vs,min and Vs,max are given in Å.

Table 1. The B3LYP/6-31G* relative energies calculated for syn- and anti- transition states (TS)

of 1a and 1b with performic acid and diazomethane in gas and solvent phase (in parentheses)

in kJ/mol. The ZPVE corrected energies for the TS are in bold. Single point MP2/6-31G* relative


118

energies (kJ/mol) are shown here. Bond lengths are in (Å). The relative energies (in kJ/mol)

derived with charge model is also shown here. [Nitrogen: blue; carbon: grey; oxygen: red;

hydrogen: white].

1a(syn) 1a(anti) 1b(syn) 1b(anti)

B3LYP/

6-31G*

TS 0.0(0.0)

0.010.9(5.4)

11.70.0(0.0)

0.011.3 (8.4)

11.8Charge

on O4

0.0 10.0 0.0 12.0

MP2/

6-31G*

TS 0.0(0.0) 13.0(6.7) 0.0(0.0) 14.7(10.9)

Charge

on O4

0.0 9.5 0.0 11.9

1a(syn) 1a(anti)1b(syn) 1b(anti)

B3LYP/

6-31G*

TS 3.3(4.8)

3.00.0(0.0)

0.00.2(1.3)

0.50.0(0.0)

0.0Charge

on N2

3.9 0.0(0.0) 0.8 0.0(0.0)

MP2/

6-31G*

TS 2.9(4.6) 0.0(0.0) 0.8(0.6) 0.0(0.0)

Charge

on N2

4.8 0.0(0.0) 0.7 0.0(0.0)

A.3.2.2.2. Application of the model to other systemsIn this section, we have also shown that the newly developed electrostatic charge model very

aptly predicted the π-face selectivity for different electrophilic interaction to sterically unbiased


119

olefins like endo substituted 7-isopropylidenenorbornanes (2); 2,3-endo,endo-7-

methylenenorbornanes (3); 5-exo-bicyclo[2.1.1]hexane (4); 4-substituted 9-

methylenenorsnoutanes (5) and 2,5-disubstituted adamantanes (6). The optimized geometries

of the olefins 2-6 do not reveal constituent features which can be correlated with the observed

face selectivity in the corresponding electrophilic additions. In particular, the alkene unit is

essentially planar. The sum of the angles around the corresponding carbon atom does not

deviate by more than ~1º from 360º. The presence of endo substituents in 2-6 does not lead to

significant tilt of the alkene bridge toward either side of the rings. The alkene unit in these

compounds is also nearly eclipsed with the bridgehead hydrogen atoms. Hence, ground state

distortions and torsional interactions during the formation of the transition structures cannot be

implicated for the face selectivity in these substrates. Scheme 5 shows the transition state

geometries and the specific atom and position to place the ChelpG charge.

Scheme 5: ‘*’ denotes the atom on which the CHelpG charge is placed in the charge model

calculation using the transition state geometries.

A.3.2.2.2.1. Endo-substituted 7-Isopropylidenenorbornanes (2).Electrophilic addition to 2 was earlier reported by Mehta et al.14(e) The observed preferences

were explained by ab initio and semiempirical MO calculations. The calculated results

suggested that the diastereoselectivites were primarily due to orbital effects. The calculations

performed in the present study with performic acid and dichlorocarbene, however showed that

electrostatic interactions can also explain the observed selectivity for 2 (Table 2). Endo-cyano-7-

isopropylidenenorbornanes [2a (X = -CN)] and endo-carbomethoxy-7-

isopropylidenenorbornanes [2b (X = -COOMe)] have been considered for the calculations. The

B3LYP/6-31G* optimized butterfly transition state geometries have been located for the addition

of performic acid to the olefinic double bonds of 2a (X = -CN) and 2b (X = -COOMe).23 In this

study, the transition state energy differences showed syn preferences and were found to be in

good agreement with the experimentally observed results for 2a (X = -CN) and 2b (X = -

COOMe) with m-CPBA. These transition state calculations involve the orbital and electrostatic

contributions and hence to delineate these electronic factors additional calculations are


120

required.12(d),28(a) In the present study, the calculations performed with the relative ChelpG

charges taken from the respective transition states for oxygen atoms (O4) for performic acid and

placed at its location yields the syn-face preference compared to the anti-face in 2a (X = -CN)

and 2b (X = - COOMe), respectively. The MP2/6-31G* calculations also supported the

B3LYP/6-31G* results (Table 2). The direct comparison of transition states and charge models

reveals that the electrostatic effect alone can also explain the face selectivity for endo-

substituted 7- isopropylidenenorbornanes (2). The importance of electrostatic agreement with

observed preference for the addition of m-CPBA interaction was also observed in

stereoselective epoxidation of α-cyclogeranyl systems and cis-disubstituted cyclobutenes.41

Transition state energies determined with the B3LYP/6-31G* level for :CCl2 additions to 2 are

also consistent with the observed selectivities. Since the least motion path for the addition of

carbene to an olefin is a forbidden pathway,42 the transition structure is highly unsymmetrical. In

effect, the carbene forms a bond to one of the olefinic carbon atoms with a C-C-C angle of

about 90º. The chlorine atoms are tilted towards the other carbon, which has a planar

coordination characteristic of a carbocation. In view of the unsymmetrical nature of the olefins,

two sets of first order saddle points, characterized by a closer approach of the carbene to C7 or

C8 (Scheme 2), were obtained for the syn- as well as anti-facial additions. The :CCl2 attack at C7

was found to be stable by ~4 kJ/mol than the corresponding attack at C8. The transition state

energies showed a clear preference for the syn-face attack of :CCl2 at C7 in 2a (X = -CN) and 2b(X = -COOMe), respectively. Nonetheless, the corresponding attack at C8 also showed the

similar preference for the :CCl2 addition to 2a (X = -CN) and 2b (X = -COOMe) (Table 3). The

calculations performed with the relative CHelpG charges taken from the respective transition

states for carbon atoms (C1) for :CCl2 and placed at its location in C7 and on chlorine atoms (Cl2 & Cl 3) for C8 transition states yields the syn-face preference (Table 2 Table 3). The charge

calculated results showed larger syn preference with C8 atom than C7 atom. Direct comparison

of transition states and charge calculations seem to indicate that the orbital contributions are

less important for the preferential attack of m-CPBA and :CCl2 to 2. Similar charge model

calculations have been performed for :CCl2 addition to polycyclic dioxa systems, respective

charges at their transition state positions.15 Moreover, single calculations have been performed

with 6-31+G*, 6-311G** and 6-311+G** basis sets at B3LYP and MP2 levels for 2 with performic

acid to examine the effect of basis set on the relative energy preferences. It appears that the

relative energy preferences are independent of basis set (Table 4).43

Table 2. The B3LYP/6-31G* relative energies [including zero point vibrational energy-corrected

values in parenthesis ( )] for syn- and anti- transition states (TS) of 2a (X = -CN) and 2b (X = -


121

COOMe) with performic acid and dichlorocarbene (kJ/mol). Single point MP2/6-31G* relative


derived with charge model is also shown here [Carbon: grey; Nitrogen: blue; Oxygen: red;

Hydrogen: white; Chlorine: green].

2a(syn) 2a(anti) 2b (syn) 2b (anti)

B3LYP/

6-31G*

TS 0.0 (0.0) 5.4 (5.0) TS 0.0 (0.0) 3.6 (4.0)

Charge

on O4

0.0 2.9 Charge

on O4

0.0 2.1

MP2/6-31G* TS 0.0 6.3 TS 0.0 4.2

Charge

on O4

0.0 2.9 Charge

on O4

0.0 1.7

Experiment 77% 23% 62% 38%

2a (syn) 2a (anti) 2b (syn) 2b (anti)

B3LYP/

6-31G*

TS 0.0 (0.0) 4.6 (5.2) TS 0.0 (0.0) 3.8 (4.0)

Charge

on C1

0.0 0.3 Charge

on C1

0.0 0.4

MP2/6-31G* TS 0.0 4.6 TS 0.0 3.8

Charge

on C1

0.0 0.1 Charge

on C1

0.0 0.2

Experiment 78% 22% 60% 40%


122


values in parenthesis ( )] for syn- and anti- transition states (TS) of 2a (X = -CN) and 2b (X= -

COOMe) with dichlorocarbene (kJ/mol). Bond lengths are in (Å). The relative energies (in kJ/mol)

derived with charge model is also shown here. [Nitrogen: blue; Carbon: grey; Hydrogen: white;

Chlorine: green].

Table 4. : Relative energies for syn- and anti- transition states (TS) for 1a (X = -CN) and 1b (X = -

COOMe) with performic acid with different basis sets (kJ/mol).

B3LYP/6-31+G* B3LYP/6-311G(d,p) B3LYP/6-311+G(d,p)

syn anti syn anti syn anti

2a TS in kJ/mol 0.0 4.2 0.0 3.8 0.0 4.2

Cl2

Cl3

2a syn

Cl3

Cl2

2a anti

TS 0.0 (0.0) 2.6 (2.7)

Charge on Cl 2

& Cl 3

0.0 (0.0) 1.9 (1.9)

Cl3

Cl2

2b syn

Cl3

Cl2

2b anti

TS 0.0 (0.0) 2.2 (2.3)

Charge on Cl 2&

Cl 3

0.0 (0.0) 2.3 (2.3)


123

2b TS in kJ/mol 0.0 2.9 0.0 3.8 0.0 2.8

MP2/6-31+G* MP2/6-311G(d,p) MP2/6-311+G(d,p)


2a TS in kJ/mol 0.0 4.4 0.0 5.6 0.0 4.9

2b TS in kJ/mol 0.0 3.5 0.0 3.4 0.0 3.2

A.3.2.2.2.2. 2,3-endo,endo-7-methylenenorbornanes (3)Electronic control of electrophilic additions to 2,3-endo,endo-7-methylenenorbornanes (3) was

also reported by Mehta et .al.14(c) The π-facial selectivity was tuned through remote substituents.

The endo-substituted ethyl groups [3c (X = -CH2CH3)] directed the addition of m-CPBA, B2H6

and oxymercuration preferentially from the anti-face, whereas, the ester groups directed the

same electrophiles from the syn-face of 3b (X = -COOMe). These results can be explained by

Cieplak hyperconjugative model.7(a,b) To delineate the electronic factors responsible for the face

selectivity of 3, transition state and charge model calculations have been performed. The

transition state calculations for the addition of performic acid to 3c (X = CH2CH3) showed syn-

preference at both B3LYP/6-31G* and MP2/6-31G* levels of theory (Table 5) which is in

contrary to the observed preferences. However, the charge calculations predicted a clear anti

preference at both levels of theory. Going from 3c (X = -CH2CH3) to 3b (X= COOMe), the

transition state results showed the syn preference at B3LYP/6-31G* and MP2/6-31G* levels of

theory. Employing the similar charge model calculations applied for 1, the syn-face preference

was obtained at both B3LYP and MP2 levels of theory for 3b (X = -COOMe) in agreement with

the observed results.

Furthermore, the electrophilic addition of B2H6 was modeled with endo-substituted 7-

methylenenorbornanes 3c (X = -CH2CH3) and 3b (X = -COOMe). The transition state

geometries for the B2H6 addition to the double bond of 3c (X = -CH2CH3) and 3b (X = -COOMe)

are similar to that of hydroboration of alkenes.44 The B2H6 addition to double bond is an early

one and the B…H bond is significantly broken in the transition state geometries. The transition

state geometries located for B2H6 addition to 3c (X = - CH2CH3) are given in Table 5. In the case

of 3c (X = -CH2CH3), transition state and charge model calculations predicted the anti

preference for the hydroboration with B2H6 in good agreement with the observed trend (Table

5). The charge of H4 was placed to calculate the electrostatic interactions between 3c, 3b and

diborane. MESP isosurface also showed the Vs,max on the H4 hydrogen atom (Figure 2). The

preferential addition of B2H6 to 3c can possibly be dictated by the electrostatic effect. The

calculated energy differences for 3b (X = -COOMe) showed the syn-preference for the

hydroboration in agreement with the observed results. However, the CHelpG charges taken


124

from the respective transition states for hydrogen atoms (H4) for B2H6 (Scheme 5) and placed at

its location yields the anti-face preference, which are not in agreement with the observed

results. These results indicate that the orbital contributions seem to be important to control the

face selectivity for the hydroboration of 3b (X = -COOMe). B3LYP calculations seem to

underestimate the non-covalent interactions, in particular dispersive interactions, hence

additional calculations have been carried out with M052X functional.45 This DFT functional is

considered to be a better model for non-covalent interactions. The single point calculations

performed with M052X/6-31G* showed the similar energetic preference for both 2 and 3 as

observed with the B3LYP and MP2 levels (Table 6).


values in parenthesis ( )] for syn- and anti- transition states (TS) of 3c (X = -CH2CH3) and 3b (X

= -COOMe) with performic acid and diborane (kJ/mol). Single point MP2/6-31G* relative


derived with charge model is also shown here [Carbon: grey; Oxygen: red; Hydrogen: white;

Boron: pink].

3c (syn) 3c (anti)3b (syn) 3b (anti)

B3LYP/6-

31G*

TS 0.0 (0.0) 0.1 (0.1) TS 0.0 (0.0) 6.3 (5.9)

Charge

on O4

1.3 0.0 Charge

on O4

0.0 3.8

MP2/6-

31G*

TS 0.0 0.8 TS 0.0 7.5

Charge

on O4

1.3 0.0 Charge

on O4

0.0 2.9

Experiment 30% 70% 74% 26%


125

3c (syn) 3c (anti) 3b (syn) 3b (anti)

B3LYP/6-

31G*

TS 2.5 (1.4) 0.0 (0.0) TS 0.0 (0.0) 4.6 (4.6)

Charge

on H4

3.8 0.0 Charge

on H4

7.1 0.0

MP2/6-

31G*

TS 2.5 0.0 TS 0.0 3.8

Charge

on H4

5.4 0.0 Charge

on H4

8.0 0.0

Experiment 38% 62% 59% 41%

H4

B2H6

Figure 2. The B3LYP/6-31G* computed Vs,max is shown on the molecular electrostatic potential

(MESP) isosurface in kJ/mol for diborane. The location of Vs,max is given in Å.

Table 6. M052X/6-31G* relative energies for syn- and anti- transition states (TS) of 2a (X = -

CN), 2b (X = -COOMe) with performic acid and dichlorocarbene; 3c (X = -CH2CH3), 3b (X = -

COOMe) with performic acid and diborane (kJ/mol).

syn anti

2a (performic acid) 0.0 5.8

2b (performic acid) 0.0 4.1

2a (dichlorocarbene) 0.0 4.3

2b (dichlorocarbene) 0.0 3.7

3c (performic acid) 0.0 0.2


3c (diborane) 2.5 0.0

3b (diborane) 0.0 5.7

A.3.2.2.2.3. 5-exo-substituted-2-methylenebicyclo[2.1.1]hexane (4)The electrophilic additions to 2-methylenebicyclo[2.1.1]hexane systems (4) have been

examined.14(n) The experimental and computational studies showed that the face selectivity in


126

this system is modulated through the interplay of electrostatic and Cieplak-type orbital effects

whose involvement has been gleaned through MESP topographical analysis and bond density

calculations. We have examined the addition of performic acid, B2H6 and :CCl2 to 5-exo-cyano-

2-methylenebicyclo[2.1.1]hexane 4a (X = -CN) and 5-exo-carbomethoxy-2-

methylenebicyclo[2.1.1]hexane 4b (X = -COOMe), respectively. Both (-CN and -COOMe)

substituted groups should give syn selectivity according to Cieplak-type hyperconjugative effect.

However, the diastereoselectivity depends on the electrophiles used with these substrates. The

epoxidation through performic acid addition occurs preferentially from the syn-face, whereas,

the diborane and dichlorocarbene additions give anti selectivity in contrary to the Cieplak effect.

Transition state and charge model calculations predict the syn selectivity for the m-CPBA

addition to 4a (X = -CN) and 4b (X = -COOMe), respectively. These results clearly show that the

selectivity can be governed by electrostatic effects. Turning to B2H6 addition to 4b (X = -

COOMe), the charge model calculations predicts the anti selectivity in agreement with the

observed results (Table 7), which further corroborates the importance of electrostatic effect in

controlling the face selectivity for 4. Interestingly, the :CCl2 additions to 4a (X = -CN) and 4b (X

= -COOMe) gives anti selelctivity.14(n) In this case, the transition state and charge model

calculations predicted the syn selectivity in contrary to the observed results, except the MP2

charge model calculation which showed the agreement with observed trend for 4b (X = -

COOMe) (Table 7). To note that the transition states are located for 4a (X = -CN) and 4b (X = -

COOMe) with :CCl2, while attacking at C2 position of the substrates (Scheme 2). Attempts failed

to achieve the favored transition states, while attacking at C7 position of 4a (X= -CN) and 4b (X

= -COOMe) substrates (Scheme 2). We have been able to locate a constrained transition state

for 4b (X = -COOMe) with :CCl2 at C7 position (Table 8). This result revealed that the transition

states predicts the syn selectivity, whereas, the charge model gives the anti selectivity as

observed experimentally.


values in parenthesis ( )] for syn- and anti- transition states (TS) of 4a (X = -CN) and 4b (X = -

COOMe) with performic acid, diborane and dichlorocarbene (kJ/mol). Single point MP2/6-31G*

relative energies (kJ/mol) are shown here. Bond lengths are in (Å). The relative energies (in

kJ/mol) derived with charge model is also shown here [Carbon: grey; Nitrogen: blue; Oxygen:

red; Hydrogen: white; Boron: pink; Chlorine: green].


127

4a (syn) 4a (anti)4b (syn) 4b (anti)

B3LYP/6-

31G*

TS 0.0 (0.0) 1.7 (1.8) TS 0.0 (0.0) 2.1 (1.9)

Charge

on O4

0.0 2.1 Charge on

O4

0.0 1.7

MP2/6-31G* TS 0.0 2.5 TS 0.0 2.9

Charge

on O4

0.0 2.1 Charge on

O4

0.0 1.3

Experiment 64% 36% 56% 44%

4b (syn) 4b (anti)

B3LYP/6-

31G*

TS 0.0 (0.0) 2.1 (2.2)

Charge

on H4

1.3 0.0

MP2/6-31G* TS 0.0 1.7

Charge

on H4

0.8 0.0

Experiment 66% 34%


128

4a (syn) 4a (anti) 4b (syn) 4b (anti)

B3LYP/6-

31G*

TS 0.0 (0.0) 2.7 (2.8) TS 0.0 (0.0) 2.5 (2.4)

Charge

on C1

0.0 0.4 Charge

on C1

0.0 0.4

MP2/6-31G* TS 0.0 3.8 TS 0.0 3.3

Charge

on C1

0.0 0.8 Charge

on C1

0.8 0.0

Experiment 45% 55% 47% 53%


values in parenthesis ( )] for syn- and anti- transition states (TS) of 4b (X= -COOMe) with

dichlorocarbene (kJ/mol). Bond lengths are in (Å). The relative energies (in kJ/mol) derived with

charge model is also shown here. [Carbon: grey; Oxygen: red; Hydrogen: white; Chlorine: green;].

Cl3Cl2

4b (syn)

Cl2

Cl3

4b (anti)

TS 0.0 (0.0) 8.8 (8.7)

Charge on Cl 2 & Cl 3 11.6 (11.6) 0.0 (0.0)

A.3.2.2.2.4. 4-substituted 9-methylenenorsnoutanes (5).Face selectivity in electrophilic additions to 4-substituted 9-methylenenorsnoutanes 5 has been

reported.14(h) The combined experimental and computational studies reveal that the face

selectivity is primarily governed by through-bond interactions. The MESP topological analysis


129

and semi-empirical calculations ruled out the importance of electrostatic interactions in

governing the face selectivity for substituted 9- methylenenorsnoutanes. We have examined the

factors responsible for the face selectivity of 9-methylenenorsnoutanes employing the transition

state and charge model calculations. The calculations have been performed with ester-

substituted 9-methylenenorsnoutanes [5b (X = -COOMe)] as a representative case. The :CCl2attack at C9 (Scheme 2) was found to be stable by ~14 kJ/mol than the corresponding attack at

C10 in [5b (X = -COOMe)] (Table 9). The transition state energies showed the preference for

syn-face attack of :CCl2 at C9 and C10 positions with 5b (X = -COOMe) (Scheme 2). The

electrostatic interactions modeled with the previously described ChelpG charge model also

explained the observed selectivity of 5b (X = -COOMe) (Table 9). The similar analysis

performed to examine the addition of performic acid to 5b (X = -COOMe) also suggests that the

electrostatic interaction can alone govern the observed face selectivity (Table 10).


values in parenthesis ( )] for syn- and anti- transition states (TS) of 5b (X= -COOMe) with


charge model is also shown here. [Carbon: grey; Oxygen: red; Hydrogen: white; Chlorine:

green;].

Cl2

Cl3

5b (syn)

Cl2

Cl3

5b (anti)

TS 0.0 (0.0) 2.3 (2.3)

Charge on Cl 2 & Cl 3 0.0 (0.0) 1.7 (1.7)


130

Table 10. The B3LYP/6-31G* relative energies [including zero point vibrational energy-

corrected values in parenthesis ( )] for syn- and anti- transition states (TS) of 5b (X = -COOMe)

with performic acid and dichlorocarbene (kJ/mol). Single point MP2/6-31G* relative energies

(kJ/mol) are shown here. Bond lengths are in (Å). The relative energies (in kJ/mol) derived with

charge model is also shown here [Carbon: grey; Oxygen: red; Hydrogen: white; Chlorine:

green].

5b (syn) 5b (anti)

B3LYP/6-

31G*

TS 0.0 (0.0) 1.7 (1.0)

Charge on

O4

0.0 14.2

MP2/6-31G* TS 0.0 1.3

Charge on

O4

0.0 14.2

Experiment 66% 34%

5b (syn) 5b (anti)

B3LYP/6-

31G*

TS 0.0 (0.0) 0.8 (0.6)

Charge on

Cl 2 & Cl 3

0.0 2.1

MP2/6-31G* TS 0.0 0.2

Charge on 0.0 1.3


131

Cl 2 &Cl 3

Experiment 61% 39%

A.3.2.2.2.6. 5-substituted-2-methyleneadamantane (6).le Noble et al. experimentally observed that 5-fluoro-2-methyleneadamantane [6d (X = -F)]

shows syn selectivity on electrophilic addition with dichlorocarbene.14(a) Moreover,

hydrochlorination of 5-fluoro-2-methyleneadamantanes 6 with different substituents showed

syn-face selectivity in each case.14(f) The substituents varied from electron donating group such

as methyl to electron withdrawing such as fluoro- and cyano- groups for hydrochlorination

reaction. Adcock et al. emphasized the importance of hyperconjugation as a dominant factor

governing the diastereoselectivity of the hydrochlorination of 5-substitued-2-

methyleneadamantane.14(f) Additionally, they emphasized that the -CH3 substituent acts as an σ-

electron withdrawing group. We have employed the transition state and charge model

calculations for the electrophilic addition of dichlorocarbene and hydrochloric acid with 5-

substitued-2-methyleneadamantane. Markovnikov’s rule of addition of hydrochloride to alkenes

is favourable than anti markovnikov addition. A detailed study has been reported on the

transition state geometries of HCl addition to alkenes.46 The H…Cl bond breaks away and C…H

bond forms in the rate determining step for the addition of HCl to alkenes. We have modeled the

transition states for HCl addition to 6 similar to that of rate determining steps for such additions.

The calculated results for the addition of :CCl2 to 6d (X = -F) are given in Table 11. The

transition state calculations predict the syn selectivity for the addition of :CCl2 to the

energetically preferred C11 carbon position (Scheme 2) of 6d as observed experimentally. The

:CCl2 attack at C11 (Scheme 2) was found to be stable by ~14 kJ/mol than the corresponding

attack at C2 for 6d (X = -F) (Table 11 and Table 12). Furthermore, the charge model calculations

also predicted the syn selectivity for :CCl2 addition to 6d.

To rationalize the observed selectivity for the addition of HCl to cyano substituted 2-

methyleneadamantane [6a (X = -CN)] and methyl substituted 2-methyleneadamantane [6e (X =

-CH3)], transition state and charge model calculations have been employed. The calculated

results show that the addition of HCl to 6a (X = -CN) and 6e are syn preferred as observed

experimentally (Table 13).14(f) The charge model calculations performed with the CHelpG of

hydrogen atom of HCl also predicted the syn selectivity in both cases (Table 14). Therefore, it

appears that the π-facial addition of HCl to 6a and 6e is electrostatcially controlled.


corrected values in parenthesis ( )] for syn- and anti- transition states (TS) of 6d (X= -F) with



132

charge model is also shown here. [Carbon: grey; Oxygen: red; Hydrogen: white; Chlorine:

green;].

6d syn 6d anti

TS 0.0 (0.0) 0.2 (0.6)

Charge on C1 0.7 (0.7) 0.0 (0.0)


corrected values in parenthesis ( )] for syn- and anti- transition states (TS) of 6d (X = -F) with

dichlorocarbene (kJ/mol). Single point MP2/6-31G* relative energies (kJ/mol) are shown here.

Bond lengths are in (Å). The relative energies (in kJ/mol) derived with charge model is also

shown here [Carbon: grey; Fluorine: sky-blue; Hydrogen: white; Chlorine: green].

6d (syn) 6d (anti)

B3LYP/6-31G* TS 0.0 (0.0) 0.4 (0.5)

Charge on

Cl 2 & Cl 3

0.0 2.1

MP2/6-31G* TS 0.0 0.8

Charge on

Cl 2 & Cl 3

0.0 0.5

Experiment 60% 40%


corrected values in parenthesis ( )] for syn- and anti- transition states (TS) of 6a (X = -CN) and

6e (X = -CH3) with hydrochloric acid (kJ/mol). Single point MP2/6-31G* relative energies


133

(kJ/mol) are shown here. Bond lengths are in (Å). The relative energies (in kJ/mol) derived with

charge model is also shown here [Carbon: grey; Nitrogen: blue; Hydrogen: white; Chlorine:

green].

The Enthalpy corrected relative energies for the TS of different electrophilic additions at

B3LYP/6-31G* level of theory are given in Table 13.

Table 14. B3LYP/6-31G* relative energies with enthalpy correction for syn- and anti- transition

states (TS) for the different substrates 1-6 (kJ/mol).

syn anti



1a (diazomethane) 2.9 0.0

1b (diazomethane) 0.1 0.0





3c (performic acid) 0.0 0.1


3c (diborane) 1.7 0.0

6a (syn) 6a (anti) 6e (syn) 6e (anti)

B3LYP/6-

31G*

TS 0.0 (0.0) 1.3 (0.9) TS 0.0 (0.0) 1.7 (1.1)

Charge

on H2

0.0 7.5 Charge

on H2

0.0 2.1

MP2/6-31G* TS 0.0 2.1 TS 0.0 0.7

Charge

on H2

0.0 11.7 Charge

on H2

0.0 2.9

Experiment 87% 13% 56% 44%


134









6d (dichlorocarbene) 0.0 0.5

6a (Hydrochloric acid) 0.0 1.0

6e (Hydrochloric acid) 0.0 1.2

The apparent failure of the model to predict the face selectivity of 5-Fluoro-2-

methyleneadamantane (6d) with m-CPBA prompted us to examine the stereoselectivity of this

reaction further. The role of the medium is observed to be important in this case.

B. Influence of solvation on the stereoselectivityB.3.2.1. Computational MethodsB.3.2.1.1. DFT CalculationsThe substrates, electrophiles and the transition state geometries of 6d, 5b and 1b are fully

optimized with B3LYP/6-31G* level of theory22 in both gas and solvent phase with PCM

continuum model.25 Dichloromethane is used as a solvent for the calculations (Є = 8.93). The

harmonic vibrational frequencies were computed to determine the minima and the first order

saddle points in each case. The saddle points are confirmed with a single imaginary frequency.

Single point calculations are performed with MP2/6-31G*24 and B3LYP/aug-ccpVDZ47 level of

theory on both the gas and solvent phase optimized geometries. All calculations are performed

with the Gaussian 03 suite of programs.30 The electrostatic interactions are modeled with the

CHelpG charges27 of the specific atom of the electrophiles obtained in the transition state

calculations and placing them at the calculated distance (d) as shown in Scheme 6. The atoms

modeled for the charge calculations in different electrophiles are those which remain in the final

products. As performic acid showed similar results like m-CPBA for 6d, it has been considered

as a model for m-CPBA for 5b and 1b.28 The charge model calculations are performed by

removing the electrophile and adding the charge in place of the O4 oxygen atom. The distortion-

interaction model is used to analyze the energy barriers. This model consists of activation

energy (ΔE‡), distortion energy (ΔE‡strain) and interaction energy (ΔE‡

int) and is calculated for the

gas and solvent phase geometries using the equation:


135

Scheme 6B.3.2.1.2. Molecular Dynamics SimulationsThe Molecular Dynamics calculations are performed with DMol3 software in Material Studio

(version 4.1) of Accelrys Inc.48 The geometries 6d, 5b and 1b are first fully optimized with local

spin density approximation with Perdew-Wang correlational (LDA/PWC)49 employing the density

functional program DMol3 in Material Studio (version 4.1) of Accelrys Inc.48 We used DND

double numerical basis sets which is comparable to the 6-31G* basis set. All the MD

simulations for 6d, 5b and 1b in gas and with solvent molecules are performed in periodic

boundary condition with a cubic box of 20 Å size, with canonical NVT ensemble and the system

temperature is kept at around 300 K using Nosé-Hoover chain thermostat.50 Six solvent

molecules (CH2Cl2) are placed at the two faces in equal distribution inside the periodic box i.e.

three on each side to observe the solvent effect. The simulation consisted of a 2 ps NVT

dynamics with a fixed time step of 0.8 fs.

B.3.2.2. Results and DiscussionB.3.2.2.1. DFT study

In the present study, we have performed gas phase transition state calculations for 6d with

performic acid at B3LYP/6-31G(d) level of theory. Charge model calculation was also invoked,

by replacing the electrophile with the ChelpG point charge of O4 at its position in the transition

state (Table 15). The gas phase TS and the charge model results showed anti selectivity for the

interaction of performic acid with 6d which is not in concurrence to the experimentally observed

results.14a,f The calculations have also been performed with m-CPBA as an electrophile, and the

results are similar to that obtained with performic acid (Table 15 and Table 16). Transition

states calculated with solvent continuum model (PCM) using Dichloromethane (DCM) predicted

that syn-face attack is preferred by 0.8 kJ/mol compared to anti-face attack, which is in


136

qualitative agreement with the experimental results (Table 15). Single point energies calculated

with B3LYP/aug-ccpVDZ and MP2/6-31G* levels of theory also showed similar trends in

selectivity in gas and solvent phase (Table 15).

To examine the influence of solvent on the face selectivity of reference compounds 5b and 1b,

additional calculations have been performed. The relative energies of the TS structures

calculated for 5b and 1b with performic acid at both gas and solvent phase at B3LYP/6-31G*,

B3LYP/aug-ccpVDZ and MP2/6-31G* level of theory are given in table 17. The transition state

(TS) at the gas phase and the charge model calculations of 5b and 1b with performic acid

predicts syn-face selectivity, which is in agreement with the observed experimental results.

Moreover, the solvent phase transition state calculation also showed the syn-face selectivity in

both cases. The relative free energies for 6d interacting with performic acid in gas phase also

showed anti preference, while syn face is preferred in the solvent phase (Table 18). Similar

results are observed for 5b and 1b interacting with performic acid in gas as well as solvent

phase calculated at B3LYP/6-31G* level of theory (Table 17).

Other solvation models like CPCM,51 COSMO52 employed in the present study showed the very

similar trend in predicting the syn-face selectivity (Table 19).

Table 15. B3LYP/6-31G* optimized syn and anti transition state geometries of 6d with performic

acid in gas and solvent phase and their relative energies are given in kJ/mol. Single point

B3LYP/aug-ccpvdz and MP2/6-31G* relative energies (kJ/mol) are also shown. Solvent phase

energies are given in parenthesis ( ). Distances of the gas phases/(solvent phase) are in (Å).

[Carbon: grey; Fluorine: sky-blue; Oxygen: red; Hydrogen: white].

O4

6d syn

O4

6d anti

B3LYP/6-31G* TS 0.7 (0.0) 0.0 (0.8)

B3LYP/aug-ccpVDZ TS 0.7 (0.0) 0.0 (0.6)

MP2/6-31G* TS 0.4 (0.0) 0.0 (1.1)

B3LYP/6-31G* Charge

on O41.3 0.0

Experiment 66% 34%


137

Table 16. B3LYP/6-31G* optimized syn and anti transition state geometries of 6d with m-CPBA

in gas and solvent phase and their relative energies are given in kJ/mol. Single point

B3LYP/aug-ccpvdz and MP2/6-31G* relative energies (kJ/mol) are also shown here. Solvent

phase energies are given in parenthesis ( ). Distances of the gas phases/(solvent phase) are in

Å. [Carbon: grey; Fluorine: sky-blue; Oxygen: red; Hydrogen: white; Chlorine: green].

6dm-CPBA (syn) 6dm-CPBA (anti)

B3LYP/6-31G* TS 0.6 (0.0) 0.0 (0.9)

B3LYP/6-31G* Charge on O4 0.5 0.0


MP2/6-31G* TS 0.5 (0.0) 0.0 (0.9)

Experiment 66% 34%

LDA/PWC/DND/COSMO TS 0.0 7.8

Table 17. B3LYP/6-31G* optimized syn and anti transition state geometries of 5b and 1b with

performic acid in gas and solvent phase and their relative energies are given in kJ/mol. Single

point B3LYP/aug-ccpvdz and MP2/6-31G* relative energies (kJ/mol) are also shown. Solvent

phase energies are given in parenthesis ( ). Distances of the gas phases/(solvent phase) are in

(Å). [Carbon: grey; Fluorine: sky-blue; Oxygen: red; Hydrogen: white].

O4

5b syn

O4

1.98 (2.06)

5b anti

B3LYP/6-31G* TS 0.0 (0.0) 1.5 (1.1)


MP2/6-31G* TS 0.0 (0.0) 1.3 (1.2)


138

B3LYP/6-31G* Charge

on O40.0 14.2

Experiment 66% 34%

1b syn 1b anti

B3LYP/6-31G* TS 0.0 (0.0) 11.5 (8.1)


MP2/6-31G* TS 0.0 (0.0) 14.9 (11.0)

B3LYP/6-31G* Charge

on O40.0 12.0

Experiment 96% 4%

Table 18 The relative free energies of the transition state of I, II and III with performic acid in

gas and solvent phase at B3LYP/6-31G* level of theory

6dHCOOOH 5bHCOOOH 1bHCOOOH


B3LYP/6-31G* (gas) 0.9 0.0 0.0 11.2 0.0 1.2

B3LYP/6-31G* (PCM) 0.0 0.7 0.0 7.0 0.0 0.4

Table 19. Different solvation model like B3LYP/6-31G*/CPCM; LDA/PWC/DND/COSMO

employed on the B3LYP/6-31G*/PCM optimized syn and anti transition state geometries of 6d,

5b and 1b with performic acid and their relative energies are given in kJ/mol. Distances are in Å.

[Carbon: grey; Fluorine: sky-blue; Oxygen: red; Hydrogen: white].

O4

6d (syn)

1.84O4

6d (anti)


139

B3LYP/6-31G*/CPCM TS 0.0 1.1


O4

5b (syn)

O4

2.06

5b (anti)

B3LYP/6-31G*/CPCM TS 0.0 0.6


1b (syn) 1b (anti)

B3LYP/6-31G*/CPCM TS 0.0 7.5


To understand the reason behind the selectivity of 6d we have performed the

distortion/activation model which is an useful tool to understand many chemical reactions and

their related barriers with a fragment based approach.18,19 The distortion/activation model was

employed to account for the stereoselectivity in the 1,3-dipolar cycloaddition of azides to

cyclooctyne systems.53 The model has also shed light on the origin of selectivity of chiral dienes

and achiral dienophiles.18g Deformation from the original structure of the two different reactants

occur when they advance towards each other from infinity to get a better interaction site. In this

model, the activation energy ΔE‡ of the transition state (TS) breaks down into the distortion or

strain energy ΔE‡strain and the interaction energy ΔE‡

int (see eqn (1) and Scheme 7):


140

Reactant

Product

Transition State

ΔE‡strain

ΔE‡int

ΔE‡

Scheme 7. Relationship between activation, distortion, and interaction energies.18,19

The distortion/activation model has been applied to examine the л-face selectivity of 6d with

performic acid in the gas phase and solvent (PCM continuum model) phase at B3LYP/6-31G(d)

level of theory (Table 20). This model deconstructs the activation energy of a reaction into the

distortion energy (the energy required to distort the ground state of the reactants to their TS

geometries) and the interaction energy (the energy between the reactants in the transition

state).18,19 The contributions of distortion energy are important in this case to account for the

observed syn-face selectivity in the solvent phase calculations. The higher activation energy

with the syn-face addition of performic acid to 6d compared to the anti-face in the gas phase is

due to the higher distortional energy in this case (Table 20). The distortion/activation model has

also been applied for the reference systems 5b and 1b in both gas and solvent phase. The

distortion energies calculated for 5b and 1b accounts for the syn-selectivity in both gas and

solvent phase calculations (Table 20).

Table 20. B3LYP/6-31G* calculated activation, distortion and interaction energies of the syn and

anti transition state geometries of 6d, 5b and 1b interacting with performic acid in gas and

solvent phase in kJ/mol are given here. Solvent phase energies are given in parenthesis ( ).

Activation Energy Distortion Energy Interaction Energy

6d (syn) 6d (anti) 6d (syn) 6d (anti) 6d (syn) 6d (anti)

B3LYP/6-31G(d) 41.3

(40.6)

40.6

(41.4)

108.6

(89.6)

107.6

(90.9)

-67.3 (-49.0) -67.0 (-49.5)

5b (syn) 5b (anti) 5b (syn) 5b (anti) 5b (syn) 5b (anti)

B3LYP/6-31G(d) 44.5

(44.3)

46.0

(45.3)

113.4

(94.0)

114.8

(96.1)

-68.9 (-49.7) -68.8 (-50.8)

1b (syn) 1b (anti) 1b (syn) 1b (anti) 1b (syn) 1b (anti)

B3LYP/6-31G(d) 50.7 62.2 117.7 122.5 -67.0 (-50.3) -60.3 (-47.1)


141

(52.4) (60.5) (102.7) (107.6)

These computational results derive the contribution of distortional effect in the transition states

to determine the л-face selectivity of 6d with per acid in DCM. It has been reported that the

distortional contributions associated with reactant ground state constitute the bulk of the

transition state differential for the reactions.21 In the case of 5-Fluoro-2-methyleneadamantane

(6d), it is likely that the distortions of syn and anti-face of 6d is induced in the ground state level,

which can possibly contribute to determine the л-face selectivity. Ground-state induced

differences in transition barriers can be easily understood by the reaction theory.20 As stated by

Marcus, if two products possible from a single reactant have identical energies, the reactant Rwill go through the lower barrier transition state and give the respective product (Scheme 8).

Thus to go to the TS, at first the ground state must be observed. To examine the effect of

ground state towards the selectivity in the gas and solvent phase for 6d, we have performed

molecular dynamics calculations with the substrate molecule. For comparison, we have also

performed MD calculations with the substrates 5b and 1b in both gas and solvent phase.

ETS′′ > ETS

′ so P′ will be the favourable product.

Scheme 8. Asymmetric deformations of reactant (R) giving rise to differences in reaction

barriers (TS′ compared to TS′′), even for conversion to isoenergetic diastereomeric products (P′

and P’’).20

B.3.2.2.2. Molecular Dynamics calculationsAb initio molecular dynamics with NVT ensemble have been performed to examine the

asymmetric distortions of the pi-faces of 6d with explicit solvent molecules (6 DCM molecules)

in a periodic box of 20 Å. Three solvent molecules were placed on each side of the pi-face

(Figure 3). The MD calculations have been performed in the gas phase to compare any

distortions associated with the π-face caused due to the influence of solvent molecules.


142

Figure 3. Snapshot of 6d interacting with the solvent molecules (dichloromethane) initial time.

[Carbon: grey; Fluorine: sky-blue; Hydrogen: white; Chlorine: green].

The molecular dynamics simulations performed for I showed significant difference in the tilting of

exocyclic C2-C11 double bond from its equilibrium position in the presence of solvent molecules.

Such tilting opens the syn or anti face within the stipulated 2 ps. This tilting of the angles can be

registered as defined in scheme 9. “a, b, c” are the midpoints of C1-C3, C8-C10 and C4-C9

respectively. The deviation of angles observed during the MD simulation is between the two

planes containing 2-a-c (syn angle) and 2-a-b (anti angle) points, respectively.

F

H H

1

2

34

567

8 910

11

syn angleanti angle a

b c

Scheme 9. The angles calculated for 6d in gas and solvent phase is due to the tilting of the C2

carbon from the plane. The angle is between the two planes, one containing C2 and the 1, and

the other containing 1 and 2 (or 1 and 3).

The distributions of syn and anti angles (Scheme 9) in the presence of explicit solvent

molecules are given in Figure 4. The histogram presented in the figure clearly shows that the

distributions of the angle variation in presence of solvent are wider for the syn-face of (6d)

compared to the corresponding anti-face. The frequency of opening of syn angle (scheme 9) is

in the range of angle 120° to 140°, whereas the occurrence of such distribution of angles is


143

relatively less in the anti case (Scheme 9 & Figure 4). This result suggests that syn face is more

distorted in the ground state in solvent and can presumably raise the ground state energy.

Consequently, the activation barrier would reduce to arrive the transition state with the

electrophile, compared to the corresponding anti-face attack of the same electrophile.18-21 The

geometries at different time steps have been given in figure 5.

110 115 120 125 130 135 140 145 1500

5

10

15

Freq

uenc

y

Angle

Solvent- anti angle

110 115 120 125 130 135 140 145 1500

5

10

15

Freq

uenc

y

Solvent- syn angle

110 115 120 125 130 135 140 145 1500

5

10Fr

eque

ncy

Gas- anti angle

110 115 120 125 130 135 140 145 1500

5

10

Freq

uenc

y

Gas- syn angle

Figure 4. The distribution of syn and anti angles of exocyclic C2-C11 double bond of 6din the MD study. (i)

Step 250

128.02125.04

Step 1150

133.51116.61

Step 1500

132.54114.86

Step 2501

128.00123.42

Step 1050

130.64121.07

Solvent = CH2Cl2

(ii)Figure 5. Snapshots of 6d, at different time scale showing the angle deviation of the double

bond resulting in the opening of the syn and anti faces in presence of solvent molecules. The

solvent molecules are not shown here for clarity. The angles are given in degree. [Carbon: grey;

Fluorine: sky-blue; Hydrogen: white;].

The MD simulations performed to account for the distributions of syn and anti angles of olefinic

systems 5b and 1b in solvent molecules are given in Figure 6 (a,b). The variation in the angles

of syn- and anti-л face of 5b is similar on either side over 2 ps. However, the distributions of

opened syn- л face for III is relatively lower than the corresponding anti-π face (Figure 6b).

These calculated results suggest that the asymmetric distortions in the ground state of 5b and

1b as a constituent of the bulk transitional state differential for the reaction with per-acid in

minimal in these cases. The role of orbital and electrostatic effects are important to govern the


144

π-face selectivity for 5b and 1b as reported in earlier reports.4t,5g,o The snapshots at regular

intervals for 5b and 1b in presence of solvent molecules are given in figure 7.

110 115 120 125 130 135 140 145 1500

5

10

15

Freq

uenc

y

Angles

Solvent anti angle

110 115 120 125 130 135 140 145 1500

5

10

Freq

uenc

y

Solvent syn angle

110 115 120 125 130 135 140 145 1500

5

10

Freq

uenc

y

Gas anti angle

110 115 120 125 130 135 140 145 1500

5

10

Freq

uenc

y Gas- syn angle

a

110 115 120 125 130 135 140 145 1500

5

10

15

Freq

uenc

y

Angle

Solvent- anti angle

110 115 120 125 130 135 140 145 1500

5

10

Freq

uenc

y

Solvent- syn angle

110 115 120 125 130 135 140 145 15005

101520

Freq

uenc

y

Gas- anti angle

110 115 120 125 130 135 140 145 1500

5

10

Freq

uenc

y

Gas- syn angle

bFigure 6. The distribution of syn and anti angles of (a) exocyclic C9-C10 double bond of

5b and (b) C2-C3 double bond of 1b in the MD study.

Gas phase

Step 250 Step 1050 Step 1150 Step 1500 Step 2501

127.37124.21119.84133.90 135.74115.01

124.40 124.54126.95123.65

Solvent = CH2Cl2

Step 250 Step 1050 Step 1150 Step 1500 Step 2501

123.98126.27 125.30 123.38 126.24 123.38 128.17 124.41127.94122.33

(i)

(ii)


145

(i)

121.20 119.76 123.44 118.79 122.30 117.67 120.34 123.11 120.66 117.39

Solvent = CH2Cl2

Step 250 Step 1050 Step 1150 Step 1500 Step 2501(ii)Figure 7. Snapshots of 5b and 1b, at different time scale showing the angle deviation of the

double bond resulting in the opening of the syn and anti faces of 5b and 1b in presence of

solvent molecules. Solvent Molecules are omitted for better view. The angles are given in

degree. [Carbon: grey; Oxygen: red; Hydrogen: white].

The distortions associated with the syn- and anti–face of (6d) with solvent molecules seem to

arise due to more flexibility in this cyclic structure compared to (5b) and (1b). The C-C σ bonds

[C2-C3, C6-C7 in 5b; C5-C6, C7-C8 in 1b] in the bicyclic systems (5b) and (1b) are not present

in (6d) and hence the olefinic л-bond can perturb more easily in (6d) than the former ones. The

distortions of the л-bond from the equilibrium position on either syn or anti-face can be

influenced by hyperconjugative stabilization from the vicinal C-C σ orbitals. The NBO analysis

performed using the most distorted syn and anti face geometries of (6d) taken from AIMD

simulations shows that the interactions are relatively better when the syn-face is more open

compared to the anti-face (Figure 8). The solvent influenced the distortion in the л-face of 6d,

which is coincidently favored by the orbital interactions.

2

3

11

4

1

8 10 9

7 6 5

E (2) = 6.88 kcal/mol2

3

11

4

1

8 10 9

567

E (2) = 5.28 kcal/mol

Figure 8. The hyperconjugative interaction energies (E2 in kcal/mol) from the NBO analysis for

the maximum open syn or anti face of 6d in the ground state MD calculations.

3.2.2. ConclusionIn this section, we have developed a new model to delineate the face selectivity of sterically

unbiased alkenes with varied electrophiles. The effect of electrostatic and polarization


146

interactions is exclusively modeled using CHelpG charge of a specific atom taken from the

transition state calculations. It has also been observed that the atom centre of an electrophile,

which is not directly involved in the bond formation, contributes towards the face selectivity. The

model has been observed to predict the face selectivity of different olefins with electrophiles, but

failed for a case where the experimental results of syn selectivity of л-facial selectivity of 5-

Fluoro-2-methyleneadamantane with per acid could not be explained with the electrostatic

charge model. The transition state and the electrostatic charge model calculations in the gas

phase predicted the anti selectivity. The incorporation of solvent (dichloromethane) in the

transition state calculations predicted the syn-selectivity as observed in experimental results.

The difference in predicting the selectivity in the gas and solvent phase arises due to the

distortional effects in the transition states. The distortion/activation model accounts for the

correct selectivity in solvent for 5-Fluoro-2-methyleneadamantane (6d) with per acid. The

molecular dynamics calculations (AIMD) performed for the substrate molecule (6d) with explicit

DCM molecules suggest that the distortion is likely to be possible in the ground state of the

substrate molecule. Such distortions in the ground-state can induce the difference in transition

barriers that is explained by the reaction theory.20 The calculations performed for 4-carboxylate-

9-methylenenorsnoutanes (5b) and 5,6-cis,exo-disubstituted bicyclic[2.2.2]oct-2-enes (1b)

suggested that the face selectivities in these cases are governed by orbital and electrostatic

effects and the solvent and the ground state distortion effects are not important. The face

selectivity of 5-Fluoro-2-methyleneadamantane (6d) with per-acid appears to be a special case,

where the role of solvent overrides the electronic effects.


147

References1. (a) Klunder, A. J. H.; Volkers, A. A.; Zwanenburg, B. Tetrahedron 2009, 65, 2356. (b) Ruano, J. L.

G.; Alonso, M.; Cruz, D.; Fraile, A.; Martı´n, M. R.; Peromingo, M. T.; Tito, A.; Yuste, F. Tetrahedron

2008, 64, 10546. (c) Kobayashi, S.; Semba, T.; Takahashi, T.; Yoshida, S.; Dai, K.; Otani, T.;

Saito, T. Tetrahedron 2009, 65, 920. (d) Soteras, I.; Lozano, O.; Escolano, C.; Orozco, M.; Amat,

M.; Bosch,J.; Luque, F. J. J. Org. Chem. 2008, 73, 7756. (e) Lam, Y.-h.; Cheong, P. H.-Y.; Mata, J.

M. B.; Stanway, S. J.; Gouverneur, V.; Houk, K. N. J. Am . Chem. Soc. 2009, 131, 1947. (f) Cruz,

D. C., Yuste, F., Martı´n, M. R., Tito, A., Ruano, J. L. G. J. Org. Chem. 2009, 74, 3820.(g) Catak,

S.; Celik, H.; Demir, A. S.; Aviyente, V. J. Phys. Chem. A 2007, 111, 5855. (h) Berardi, R.; Cainelli,

G.; Galletti, P.; Giacomini, D.; Gualandi, A.; Muccioli, L.; Zannoni, C. J. Am. Chem. Soc. 2005, 127,

10699. (j) Bhargava, G.; Ananda, A.; Mahajan, M. P.; Saito, T.; Sakai, K.; Medhi, C. Tetrahedron

2008, 64, 6801. (k) Illa, O.; Bagan, X.; Baceiredo, A.; Branchadell, V.; Ortuño, R. M. Tetrahedron:

Asymmetry 2008, 19, 2353. (l) Suzuki, Y.; Kaneno, D.; Miura, M.; Tomoda, S. Tetrahedron Lett.

2008, 49, 4223.

2. (a) Lu, T.; Song, Z.; Hsung, R. P. Org.Lett. 2008, 10, 541. (b) Mehta, G.; Singh, R. S.; Balanarayan,

P.; Gadre, S. R. Org. Lett. 2002, 4, 2297.(c) Yadav, V. K.; Ganesh Babu K.; Balamurugan R.

Tetrahedron Lett. 2003, 44, 6617. (d) Mehta, G.; Singh, S. R.; Gagliardini, V.; Priyakumar, U. D.;

Sastry, G. N. Tetrahedron Lett. 2001, 42, 8527.

3. Li, H.; le Noble; Reel, W. J. Trav. Chim. Pays-Bas 1992, 111, 199.

4. (a) For reviews on diastereoselection, see a thematic issue: Chem. Rev. 1999, 99, 1069. (b) Mehta

G.; Chandrasekhar, J. Chem. Rev. 1999, 99, 1437.

5. (a) Cheung, C. K.; Tseng, L. T.; Lin, M. –h.; Silver, J. E.; le Noble, W. J. J. Am. Chem. Soc. 1986,

108, 1598. (b) Mehta, G.; Khan, F. A. J. Am. Chem. Soc. 1990, 56, 3229. (c) Mehta, G.; Khan, F. A.

Tetrahedron Lett. 1992, 33, 3065. (d) Okada, K.; Tomita, S.; Oda, M. Tetrahedron Lett. 1986, 33,

3065. (e) Halterman, R. L.; McEvoy, M. A. J. Am. Chem. Soc. 1990, 112, 6690. (f) di Maio, G.;

Migneco, L. M.; Vecchi, E. Tetrahedron 1990, 46, 6053.

6. (a) Cram, D. J.; Abd Elfahez, F. A. J. Am. Chem. Soc. 1952, 74, 5828. (b) Dauben, W. G.; Fonken,

G. J.; Noyce, D. S. J. Am. Chem. Soc. 1956, 78, 2579.

7. (a) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540. (b) Cieplak, A. S. Chem. Rev. 1999, 99,

1265.

8. (a) Ganguly, B.; Chandrasekhar, J.; Khan, F. A.; Mehta, G. J. Org. Chem. 1993, 58, 1734. (b)

Yadav, V. K.; Balamurugan, R. J. Org. Chem. 2002, 67, 587. (c) Yadav , V. K. J. Org. Chem., 2001,

66, 2501-2502.

9. (a) Inagaki, S.; Fujimoto, H.; Fukui, K. J. Am. Chem. Soc. 1976, 98, 4054. (b) Paquette, L. A.;

Hertel, L. W.; Gleiter, R.; Bo¨hm, M. J. Am. Chem. Soc. 1978, 100, 6510. (c) Hertel, L. W.;

Paquette, L. A. J. Am. Chem. Soc. 1979, 101, 7620. (d) Mazzocchi, P. H.; Stahly, B.; Dodd, J.;

Rondan, N. G.; Domelsmith, L. N.; Roseboom, M. D.; Caramella, P.; Houk, K. N. J. Am. Chem.


148

Soc. 1980, 102, 6482. (e) Kahn, S. D.; Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 663. (f) Ishida,

M.; Beniya, Y.; Inagaki, S.; Kato, S. J. Am. Chem. Soc. 1990, 112, 8980. (g) Wu, Y. –D.; Li, Y.; Na,

J.; Houk, K. N. J. Org. Chem. 1993, 58, 4625. (h) Rza, A.; Savaskan, Y. S. Indian Journal of

Chemistry. Sect.B: Organic Chemistry, including medical chemistry 2006, 45, 1722.

10. (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 9, 2199. (b) Chérest, M.; Felkin, H.

Tetrahedron Lett. 1968, 9, 2205. (c) Anh, N. T. Tetrahedron 1973, 29, 3227. (d) Anh, N. T.;

Eisenstein, O. Nouv. J. Chim. 1977, 1, 61. (e) Paquette, L. A.; Hertel, L. W.; Gleiter, R.; Bo¨hm, M.

C.; Beno, M. A.; Christoph, G. G. J. Am. Chem. Soc. 1981, 103, 7106. (f) Fujita, M.; Ishizukaa, H.;

Ogura, K. Tetrahedron Lett. 1991, 32, 6355. (g) Fujita, M.; Ishida M.; Manako, K.; Sato, K.; Ogura,

K. Tetrahedron Lett. 1993, 34, 645. (h) Jones, G. R.; Vogel, P. J. Chem. Soc., Chem. Commun.

1993, 769. (i) Ohwada, T.; Tsuji, M.; Okamoto, I.; Shudo, K. Tetrahedron Lett. 1996, 37, 2609. (j)

Kobayashi, T.; Miki, K.; Nikaeen B.; Ohta, A. J. Chem. Soc., Perkin Trans. 1, 2001, 1372. (k).

Kobayashi, T.; Tsujuki, T.; Tayama, Y.; Uchiyama, Y. Tetrahedron 2001, 57, 9073. (l) Catak, S.;

Celik, H.; Demir, A. S.; Aviyente, V. J. Phys. Chem. A 2007, 111, 5855.

11. (a) Dauben, W. G.; Fonken, G. J.; Noyce, D. S. J. Am. Chem. Soc. 1956, 78, 2579. (b). Kahn, S.

D.; Pau, C. F.; Hehre, W. J. J. Am. Chem. Soc. 1986, 108, 7396. (c) Chamberlin, A. R.; Mulholland

Jr., R. L.; Kahn, S. D.; Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 672. (d) Meyers, A. I.; Strurgess,

M. A. Tetrahedron Lett. 1988, 29, 5339. (e) Meyers, A. I.; Wallace, R. H. J. Org. Chem. 1989, 54,

2509. (f) Vedejs, E.; Dent III, W. H. J. Am. Chem. Soc. 1989, 111, 6861. (g) Wu, Y.-D.; Houk, K. N.;

Florez, J.; Trost, B. M. J. Org. Chem. 1991, 56, 3656. (h) Chao, T. M.; Hehre, W. J., Kahn, S. D.

Pure Appl. Chem. 1991, 63, 283. (i) Fujita, M.; Ishizuka, H.; Ogura, K. Tetrahedron Lett. 1991, 32,

6355. (j) Paquette, L. A.; Underiner, T. L.; Gallucci, J. C. J. Org. Chem. 1992, 57, 86. (k) Yadav, V.

K.; Balamurugan, R. J. Org. Chem. 2002, 67, 587. (l) Yadav, V. K.; Gupta, A; Balamurugan, R. J.

Org. Chem. 2006, 71, 4178.

12. (a) Caramella, P.; Rondan, N. G.; Paddon-Row, M. N.; Houk, K. N. J. Am. Chem. Soc. 1981, 103,

2438. (b) Mehta, G.; Khan, F. A. J. Am. Chem. Soc. 1990, 112, 6140. (c) Coxon, J. M.; McDonald,

D. Q. Tetrahedron Lett. 1992, 33, 651. (d) Ganguly, B.; Chandrasekhar, J.; Khan, F. A.; Mehta, G.

J. Org. Chem. 1993, 58, 1734. (e) Franck, R. W.; Kaila, N.; Blumenstein, M.; Geer, A.; Huang, X. L.;

Dannenberg, J. J. J. Org. Chem. 1993, 58, 5335. (f) Mehta, G.; Khan, F. A.; Ganguly, B.;

Chandrasekhar, J. J. Chem. Soc., Perkin. Trans. 2 1994, 2275. (g) Mehta, G.; Ravikrishna, C.;

Ganguly, B.; Chandrasekhar, J. J. Chem. Soc., Chem. Commun. 1997, 75. (h) Gung, B. W. Chem.

Rev. 1999, 99, 1377. (i) Yadav, V. K. J. Org. Chem. 2001, 66, 2501. (j) Yadav, V. K.; Sriramurthy,

V. Tetrahedron 2001, 57, 3987. (k) Mehta, G.; Singh, S. R.; Gagliardini, V.; Priyakumar, U. D.;

Sastry, G. N. Tetrahedron Lett. 2001, 42, 8527. (l) Marchand, A. P.; Coxon, J. M. Acc. Chem. Res.

2002, 35, 271. (m) Mehta, G.; Gagliardini, V.; Priyakumar, U. D.; Sastry, G. N. Tetrahedron Lett.

2002, 43, 2487. (n) Mehta, G.; Singh, S. R.; Priyakumar, U. D.; Sastry, G. N. Tetrahedron Lett.

2003, 44, 3101. (o) Yadav, V. K.; Babu, K. G.; Balamurugan, R.; Tetrahedron Lett. 2003, 44, 6617.


149

(p) Priyakumar, U.D.; Sastry, G. N.; Mehta, G. Tetrahedron, 2004, 60, 3465. (q) Soteras, I.; Lozano,

O.; Escolano, C.; Orozco, M.; Amat, M.; Bosch, J.; Luque, F.-J. J. Org. Chem. 2008, 73, 7756. (r)

Kobayashi, S.; Semba, T.; Takahashi, T.; Yoshida, S.; Dai, K.; Otani, T.; Saito, T. Tetrahedron

2009, 65, 920. (s) Lam, Y.-h.; Cheong, P. H.-Y.; Mata, J. M. B.; Stanway, S. J.; Gouverneur, V.;

Houk, K. N. J. Am. Chem. Soc. 2009, 131, 1947. (t) Chakrabarty, K.; Gupta, S. N.; Roy, S.; Das, G.

K. J. Mol. Struct.: THEOCHEM 2010, 951, 1.

13. (a) Mazzocchi, P. H.; Stahly, B.; Dodd, J.; Rondan, N. G.; Domelsmith, L. N.; Rozeboom, M. D.;

Caramella, P.; Houk, K. N. J. Am. Chem. Soc. 1980, 102, 6482. (b) Wu, Y. –D.; Houk, K. N. J. Am.

Chem. Soc. 1987, 109, 908. (c) Wu, Y. -D.; Tucker, J. A.; Houk, K. N. J. Am. Chem. Soc. 1991,

113, 5018. (d) Paddon-Row, M. N.; Wu, Y. -D.; Houk, K. N. J. Am. Chem. Soc. 1992, 114, 10638.

(e) Coxon, J. M.; Houk, K. N.; Luibrand, R. T. J. Org. Chem. 1995, 60, 418.

14. (a) Srivastava, S.; le Noble, W. J. J. Am. Chem. Soc. 1987, 109, 5874. (b) Arjona, O.; de la Pradilla,

R. F.; Pita-Romero, I.; Plumet, J.; Viso, A. Tetrahedron 1990, 46, 8199. (c) Mehta, G.; Khan, F. A.

J. Chem. Soc., Chem. Commun. 1991, 18. (d) Broughton, H. B.; Green, S. M.; Rzepa, H. S. J.

Chem. Soc., Chem. Commun. 1992, 998. (e) Mehta G.; Khan, F. A.; Gadre, S. R.; Shirsat, R. N.;

Ganguly, B.; Chandrasekhar, J. Angew. Chem. Int. Ed. Engl. 1994, 33, 1390. (f) Adcock, W.;

Cotton, J.; Trout, N. A. J. Org. Chem. 1994, 59, 1867. (g) Gandolfi, R.; Amade, M. S.; Rastelli, A.;

Bagatti, M. Tetrahedron Lett. 1996, 37, 1321. (h) Mehta G.; Ravikrishna, C.; Gadre, S. R.; Suresh,

C. H.; Kalyanaraman, P.; Chandrasekhar, J. J. Chem. Soc., Chem. Commun. 1998, 975. (i)

Ohwada, T. Chem. Rev. 1999, 99, 1337. (j) Kaselj, M.; Chung, W. -S.; le Noble, W. J. Chem. Rev.

1999, 99, 1387. (k) Mehta, G.; Chandrasekhar, J. Chem. Rev. 1999, 99, 1437. (l) Mehta, G.; Uma,

R. Acc. Chem. Res. 2000, 33, 278. (m) Igarashi, H.; Sakamoto, S.; Yamaguchi, K.; Ohwada, T.

Tetrahedron Lett. 2001, 42, 5257. (n) Mehta G.; Singh, S. R.; Balanarayan, P.; Gadre, S. R. Org.

Lett. 2002, 4, 2297.

15. Chao, I.; Shih, J. H.; Wu, H. -J. J. Org. Chem. 2000, 65, 7523.

16. C. Reichardt, Solvents and Solvent Effects in Organic Chemistry, 3rd ed.; Wiley-VCH: Weinheim,

Germany, 2003.

17. (a) S. Roland and P. Mangeney, Eur. J. Org. Chem. 2000, 611; (b) G. Cainelli, D. Giacomini and P.

Galletti, Eur. J. Org. Chem. 1999, 61; (c) M. T. Crimmins and A. L. Choy, J. Am. Chem. Soc. 1997,

119, 10237. [d] R. W. Murray, M. Singh, B. L. Williams, H. M. Moncrieff, Tetrahedron Lett. 1995, 36,

2437; (e) T. Saito, M. Kawamura, J. Nishimura, Tetrahedron Lett. 1997, 38, 3231; (f) P. Wipf, J.-K.

Jung, Angew. Chem. Int. Ed. Engl. 1997, 36, 764; (g) G. Cainelli, D. Giacomini, F. Perciaccante,

Tetrahedron: Asymmetry 1994, 5, 1913; (h) S. E. Denmark, N. Nakajima, O. J.-C. Nicaise, J. Am.

Chem. Soc. 1994, 116, 8797; (i) M. T. Reetz, S. Stanchev, H. Haning, Tetrahedron 1992, 48, 6813;

(j) R. Berardi, G. Cainelli, P. Galletti, D. Giacomini, A. Gulandi, L. Muccioli, C. Zannoni, J. Am.

Chem. Soc. 2005, 127, 10699.


150

18. (a) W.-J. van Zeist and F. M. Bickelhaupt, Org. Biomol. Chem. 2010, 8, 3118; (b) D. H. Ess, G. O.

Jones, and K. N. Houk, Org. Lett. 2008, 10, 1633; (c) G. O. Jones and K. N. Houk, J. Org. Chem.

2008, 73, 1333; (d) Y. Lan, S. E. Wheeler, K. N. Houk, J. Chem. Theory Comput. 2011, 7, 2104; (e)

I. Fernández, F. M. Bickelhaupt, F. P. Cossío, Chem. Eur. J. 2009, 15, 13022; (f) D. H.; Ess and

Houk, K. N. J. Am. Chem. Soc. 2008, 130, 10187; (g) S. Agopcan, N. Çelebi-Ölçüm, M. N. Üçışık,

A. Sanyal and V. Aviyente, Org. Biomol. Chem. 2011, 9, 8079; (h) F. Schoenebeck, D, H. Ess, G.

O. Jones and K. N. Houk, J. Am. Chem. Soc. 2009, 131, 8121; (i) C. G. Gordon, J. L. Mackey, E.

M. Sletten and Houk, K. N. J. Am. Chem. Soc. 2012, 134, 9199.

19. (a) F. M. Bickelhaupt, J. Comput. Chem. 1999, 20, 114; (b) D. J. Mitchell, S H. B. Schlegel, S.

Shaik and S. Wolfe, Can. J. Chem. 1985, 63, 1642; (c). C. Y. Legault, Y. Garcia, C. A. Merlic and K.

N. Houk, J. Am. Chem. Soc., 2007, 129, 12664.

20. (a) R. A. Marcus, Pure & Appl. Chem. 1997, 69, 13. (b) R. F. Grote and J. T. Hynes, J. Chem.

Phys. 1980, 73, 2715. (c). S. H. Northrup and J. T. Hynes, J. Chem. Phys. 1980, 73, 2700. (d). R.

V. Kolakowski and L. J. Williams, Nat. Chem. 2010, 2, 303.

21. M. Trautz, Z. Anorgan. Chem. 1916, 96, 1; (b) W. C. M. Lewis, J. Chem. Soc. 1918, 113, 471.

22. (a) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab initio Molecular Orbital Theory,

Wiley Interscience, New York, 1986. (b) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.

(c) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.

23. (a) Bartlett, P. D. Rec. Chem. Prog. 1950, 11, 47. (b) Bach, R. D.; Glukhovtsev, M. N.; Gonzales, C.

J. Am. Chem. Soc. 1998, 120, 9902. (c) Houk, K. N.; Washington, I. Angew. Chem., Int. Ed. 2001,

40, 4485. (d) Freccero, M.; Gandolfi, R.; Amadè, M. S.; Rastelli, A. J. Org. Chem. 2002, 67, 8519.

24. Møller, C.; Plesset, M. S. Phys. Rev. 1934, 46, 618.

25. (a) Tomasi, J.; Persico, M. Chem. Rev. 1994, 94, 2027. (b) Tomasi, J.; Mennucci, B.; Cammi, R.

Chem. Rev. 2005, 105, 716.

26. Contreras, R.; Domingo, L. R.; Andre´s, J.; Pe´rez, P.; Tapia, O. J. Phys. Chem. A 1999, 103, 1367.

27. (a) Kahn, S. D.; Pau, C. F.; Overman, L. E.; Hehre, W. J. J. Am. Chem. Soc. 1986, 108, 7381. (b)

Kahn, S. D.; Hehre, W. J. J. Am. Chem. Soc. 1986, 108, 7399. (c) Sjoberg, P.; Politzer, P. J. Phys.

Chem. 1990, 94, 3959.

28. (a) Tsuzuki, S.; Uchimaru, T.; Tanabe, K.; Yliniemela, A. J. Mol. Struct.: THEOCHEM 1996, 365,

81. (b) Rozas, I. Int. J. Quant. Chem. 1997, 62, 477. (c) Martin, F.; Zipse, H. J. Comput. Chem.

2005, 26, 97. (d) Reddy, M. R.; Erion, M. D.; Agarwal, A.; Viswanadhan, V. N.; Mcdonald, D. Q.;

Still, W. C. J. Comput. Chem. 1998, 19, 769.

29. (a) Singleton, D. A.; Merrigan, S. R.; Liu, J.; Houk, K. N. J. Am. Chem. Soc. 1997, 119, 3385. (b)

Marchand, A. P.; Ganguly, B.; Shukla, R.; Krishnudu, K.; Kumar, V. S.; Watson, W. H.; Bodige, S.

G. Tetrahedron 1999, 55, 8313.

30. Breneman, C. M.; Wilberg, K. B. J. Comput. Chem. 1990, 11, 361.


151

31. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.;

Montgomery Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi,

J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.;

Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;

Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.;

Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;

Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J.

J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck,

A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;

Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox,

D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;

Johnson, B.; Dhandapani Sadasivam, Birney Page S6 Benzothiet-2-one Chen, W.; Wong, M. W.;

Gonzalez, C.; and Pople, J. A.; Gaussian, Inc., Wallingford CT, 2004.

32. P. Politzer, J. S. Murray Reviews in Computational Chemistry (Eds: In: K. B. Lipkowitz, D. B. Boyd),

VCH Publishers, New York, 1991, vol 2. Ch. 7.

33. (a) R. K. Pathak and S. R. Gadre, J. Chem. Phys., 1990, 93, 1770. (b) T. Brinck, J. S. Murray and

P. Politzer. Mol. Phys., 1992, 76, 609. (c) J. S. Murray and P. Politzer, J. Mol. Struct. (Theochem),

1998, 425, 107.

34. (a) P. Politzer, J. S. Murray and F. A. Bulat, J. Mol. Model. 2010, 16, 1731. (d) Bulat, F. A.; Brink,

T.; Toro-Labbe, A.; Politzer, P. A.; Murray, J. S. J. Mol. Model. 2010, 16, 1679.

35. (a) G. Trogdon, J. S. Murray, M. C. Concha, P. Politzer, J Mol Model 2006, 13, 313. (b) P.

Politzer, In Chemical Applications of Atomic and Molecular Electrostatic Potentials; (Eds: P.

Politzer, D. G. Truhlar), Plenum, New York, 1981. (c) J. S. Murray and P. Politzer, Chem. Phys.

Lett., 1988, 152, 364. (d) M. Haeberlein, J. S. Murray, T. Brinck and P. Politzer, Can. J. Chem.,

1992, 70, 2209. (e) J. M. Wiener, M. E. Grice, J. S. Murray, P. Politzer, J. Chem. Phys. 1996, 104,

5109.

36. (a) Singleton, D. A.; Merrigan, S. R.; Liu, J.; Houk, K. N. J. Am. Chem. Soc. 1997, 119, 3385. (b)

Marchand, A. P.; Ganguly, B.; Shukla, R.; Krishnudu, K.; Kumar, V. S. Tetrahedron 1999, 55, 8313.

37. a) Bartlett, P. D. Rec. Chem. Prog. 1950, 11, 47. (b) Bach, R. D.; Glukhovtsev, M. N.; Gonzales, C.

J. Am. Chem. Soc. 1998, 120, 9902. (c) Houk, K. N.; Washington, I. Angew. Chem. Int. Ed. 2001,

40, 2001. (d) Freccero, M.; Gandolfi, R.; Amadè, M. S.; Rastelli, A. J. Org. Chem. 2002, 67, 8519.

38. (a) Huisgen, R. J. Org. Chem. 1968, 33, 2291. (b) Nguyen, J. T.; Chandra, A. K.; Sakai, S.;

Morokuma, K. J. Org. Chem. 1999, 64, 65. (c) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2008,

130, 10187

39. Paddon-Row, M. N.; Wu, Y.-D.; Houk, K. N. J. Am. Chem. Soc. 1992, 114, 10638.


152

40. (a) Martin, F., Zipse, H. J. Comput. Chem. 2005, 26: 97–105. (b) Rozas, I., Int. J. Quantam Chem.

1997, 62, 477-487. (c) Tsuzuki, S., Uchimaru, T., Tanabe, K., Yliniemela, A. J. Mol. Struct.

(Theochem) 1996, 365, 81.

41. (a) Freccero, M.; Gandolfi, R.; Amadè, M. S. Tetrahedron 1999, 55, 11309. (b) Washington, I.;

Houk, K. N. Angew. Chem., Int. Ed. 2001, 40, 4485.

42. (a) Hoffmann, R. J. Am. Chem. Soc. 1968, 90, 1475. (b) Hoffmann, R. W.; Hauel, N.; Landmann,

B.; Chem. Ber. 1983, 116, 389. (c) Houk, K. N.; Rondan, N. G. Mareda, J. Tetrahedron 1985, 41,

1555.

43. Gadre, S. R.; Kulkarni, S. A.; Suresh, C.H.; Shrivastava, I. H. Chem. Phys. Letters 1995, 239, 273.

44. Wang, X.; Li, Y.; Wu, Y. –D.; Paddon-Row, M. N.; Rondan, N. G.; Houk, K. N. J. Org. Chem. 1990,

55, 2601.

45. Zhao, Y.; Schultz, N. E.; Truhlar, D. G. J. Chem. Theory Comput. 2006, 2, 364.

46. (a) Suresh, C. H.; Koga, N.; Gadre, S. R. J. Org. Chem. 2001, 66, 6883. (b) Burda, J. V.; Murray, J.

S.; Toro-Labbe´, A.; Gutie´rrez-Oliva, S.; Politzer, P. J. Phys. Chem. A 2009, 113, 6500.

47. T. H., Dunning, Jr., J. Chem. Phys. 1989, 90, 1007.

48. (a) B. Delley, J. Chem. Phys. 1990, 92, 508; (b) B. Delley, J. Phys. Chem. 1996, 100, 6107; (c) B.

Delley, J. Chem. Phys. 2000, 113, 7756; (d) Materials Studio DMOL3 Version 4.1, Accelrys Inc.,

San Diego, USA..

49. J. P. Perdew and Y. Wang, Phys. Rev. B 1986, 33, 8800.

50. (a) S. Nose, J. chem. Phys. 1984, 81, 511; (b) W. G. Hoover, Phys. Rev. A 1985, 31, 1695.

51. (a) V. Barone, M. Cossi, J. Phys. Chem. A, 1998, 102, 1995. (b) M. Coddi, N. Rega, G. Salmani, V.

Barone J. Comp. Chem. 2003, 24, 2003.

52. (a) A. Klamt, G. Schüürmann, J. Chem. Soc., Perkin Trans. 2 1993, 799. (b) J. Tomasi, M. Perisco,

Chem. Rev. 1994, 94, 2027.

53. F. Schoenebeck, D. H. Ess, G. O. Jones and K. N. Houk, J. Am. Chem. Soc. 2009, 131, 8121.

effect of solvation on the conformational behavior of...

Documents