Intrinsic conformational characteristics of alpha,alpha-diphenylglycine

Quantum mechanical calculations at the B3LYP/6-31+G(d,p) level have been used to investigate the intrinsic conformational preferences of alpha,alpha-diphenylglycine, a simple alpha,alpha-dialkylated amino acid bearing two phenyl substituents on the alpha-carbon, in both the gas phase and aqueous solution. Nine minimum energy conformations have been characterized for the N-acetyl-N'-methylamide derivative within a relative energy range of about 9 kcal/mol. The relative stability of these structures is largely influenced by specific backbone...side chain and side chain...side chain interactions that can be attractive (N-H...pi and C-H...pi) or repulsive (C=O...pi). On the other hand, comparison with the minimum energy conformations calculated for alpha-aminoisobutyric acid, in which the two phenyl substituents are replaced by methyl groups, revealed that the bulky aromatic rings of alpha,alpha-diphenylglycine induce strain in the internal geometry of the peptide. Finally, a set of force-field parameters for classical Molecular Mechanics calculations was developed for the investigated amino acid. Molecular Dynamics simulations in aqueous solutions have been carried out to validate the parameters obtained.     

The molecular and crystal structure of tert-butyl Nalpha-tert-butoxycarbonyl-L-(S-trityl)cysteinate and the conformation-stabilizing function of weak intermolecular bonding

The title compound, C31H37NO4S [systematic name: (R)-tert-butyl-2-[(tert-butoxycarbonyl)amino]-3-(tritylsulfanyl)propanoate] is an L-cysteine derivative with three functions: NH2, COOH and SH, blocked by protecting groups tert-butoxycarbonyl, tert-butyl and trityl, respectively. The main chain of the molecule adopts the extended, nearly all-trans C5 conformation with the intramolecular N-H...O=C hydrogen bond. The urethane group is not involved in any intermolecular hydrogen bonding. Only weak intermolecular hydrogen bonds and hydrophobic contacts are observed in the crystal structure. These are C-H...O hydrogen bonds and CH/pi interactions with donor...acceptor distances, C...O ca. 3.5 A and C...C ca. 3.7 A, respectively. The first type of interaction links phenyl H-atoms and carbonyl groups. The second type of interaction is formed between a methyl group of the tert-butyl fragment and a trityl phenyl ring. The resulting molecular conformation in the crystal is very close to an ab initio minimum energy conformer of the isolated molecule. The extended C5 conformation of the main peptide chain is the same and there is slight discrepancy in the disposition of trityl phenyl rings. Their small dislocation creates the possibility of forming the entire network above of extensive, specific, weak intermolecular interactions; these constrain the molecule and permit it to retain the minimum energy C5 conformation of its main chain in the solid state. In contrast, in n-hexane solution, where such specific interactions cannot occur, only a small population of the molecules adopts the extended C5 conformation.     

Proton-coupled electron transfer versus hydrogen atom transfer in benzyl/toluene,methoxyl/methanol,and phenoxyl/phenol self-exchange reactions

Degenerate hydrogen atom exchange reactions have been studied using calculations, based on density functional theory (DFT), for (i) benzyl radical plus toluene, (ii) phenoxyl radical plus phenol, and (iii) methoxyl radical plus methanol. The first and third reactions occur via hydrogen atom transfer (HAT) mechanisms. The transition structure (TS) for benzyl/toluene hydrogen exchange has C(2)(h)() symmetry and corresponds to the approach of the 2p-pi orbital on the benzylic carbon of the radical to a benzylic hydrogen of toluene. In this TS, and in the similar C(2) TS for methoxyl/methanol hydrogen exchange, the SOMO has significant density in atomic orbitals that lie along the C-H vectors in the former reaction and nearly along the O-H vectors in the latter. In contrast, the SOMO at the phenoxyl/phenol TS is a pi symmetry orbital within each of the C(6)H(5)O units, involving 2p atomic orbitals on the oxygen atoms that are essentially orthogonal to the O.H.O vector. The transferring hydrogen in this reaction is a proton that is part of a typical hydrogen bond, involving a sigma lone pair on the oxygen of the phenoxyl radical and the O-H bond of phenol. Because the proton is transferred between oxygen sigma orbitals, and the electron is transferred between oxygen pi orbitals, this reaction should be described as a proton-coupled electron transfer (PCET). The PCET mechanism requires the formation of a hydrogen bond, and so is not available for benzyl/toluene exchange. The preference for phenoxyl/phenol to occur by PCET while methoxyl/methanol exchange occurs by HAT is traced to the greater pi donating ability of phenyl over methyl. This results in greater electron density on the oxygens in the PCET transition structure for phenoxyl/phenol, as compared to the PCET hilltop for methoxyl/methanol, and the greater electron density on the oxygens selectively stabilizes the phenoxyl/phenol TS by providing a larger binding energy of the transferring proton.     

Rotational isomerism—22: An nmr study of oh..π bonding and the conformations of benzyl alcohol and derivatives

The conformations of benzyl alcohol, the ortho and para nitro and methoxy derivatives and benzyl methyl ether have been investigated by NMR in CCL₄ and DMSO solutions. The ³J(CH.OH) and ²J(H.C.H) couplings (the latter via the ²J(H.C.D)coupling)and the OH chemical shift (in DMSO and ∞ dil^XXX as conformational probes. The δ_∞ (OH) for ROH (R = Me, Et, iPr) is also given.The results provide no support for the existence of an intramolecular H-bond in benzyl akohol The endo conformation of the OH proton (anti to a CH proton) is favoured by ca. 1 kcal mole^?1 over the exo conformation (H anti to phenyl) and these conformers are responsible for the separate OH frequencies observed in the IR spectrum. The results do not support an extreme conformation of the phenyl ring (C.C.C.O dihedrals of 0 or 90°) but are consistent with either an 6?0° conformation of the phenyl ring or a freely rotating model. In ortho nitrobenzyl alcohol intramolecular H-bonding is present, but in ortho methoxy benzyl alcohol little or no bonding to the substituent occurs.     

Nonadiabatic effects on peptide vibrational dynamics induced by conformational changes

Quantum dynamical simulations of vibrational spectroscopy have been carried out for glycine dipeptide (CH(3)-CO-NH-CH(2)-CO-NH-CH(3)). Conformational structure and dynamics are modeled in terms of the two Ramachandran dihedral angles of the molecular backbone. Potential energy surfaces and harmonic frequencies are obtained from electronic structure calculations at the density functional theory (DFT) [B3LYP/6-31+G(d)] level. The ordering of the energetically most stable isomers (C(7) and C(5)) is reversed upon inclusion of the quantum mechanical zero point vibrational energy. Vibrational spectra of various isomers show distinct differences, mainly in the region of the amide modes, thereby relating conformational structures and vibrational spectra. Conformational dynamics is modeled by propagation of quantum mechanical wave packets. Assuming a directed energy transfer to the torsional degrees of freedom, transitions between the C(7) and C(5) minimum energy structures occur on a sub-picosecond time scale (700...800 fs). Vibrationally nonadiabatic effects are investigated for the case of the coupled, fundamentally excited amide I states. Using a two state-two mode model, the resulting wave packet dynamics is found to be strongly nonadiabatic due to the presence of a seam of the two potential energy surfaces. Initially prepared adiabatic vibrational states decay upon conformational change on a time scale of 200...500 fs with population transfer of more than 50% between the coupled amide I states. Also the vibrational energy transport between localized (excitonic) amide I vibrational states is strongly influenced by torsional dynamics of the molecular backbone where both enhanced and reduced decay rates are found. All these observations should allow the detection of conformational changes by means of time-dependent vibrational spectroscopy.     

Conformational analysis of a cyclopropane analogue of phenylalanine with two geminal phenyl substituents

Quantum mechanical methods have been used to investigate the intrinsic conformational preferences of 1-amino-2,2-diphenylcyclopropanecarboxylic acid (c(3)Dip), a cyclopropane analogue of phenylalanine bearing two phenyl substituents on the same beta-carbon. Geometries, energies, and frequencies were calculated on the N-acetyl-N'-methylamide derivative at the HF and B3LYP levels using the 6-31G(d), 6-311G(d), and 6-31+G(d,p) basis sets. Four minimum energy conformations were characterized: axial C(7), equatorial C(7), right-handed helix, and polyproline II. Analysis of the whole results, which are fully consistent with available experimental data, indicates that c(3)Dip tends to promote gamma-turn conformations.     

On the consequences of side chain flexibility and backbone conformation on hydration and proton dissociation in perfluorosulfonic acid membranes

The flexibility of the side chain and effects of conformational changes in the backbone on hydration and proton transfer in the short-side-chain (SSC) perfluorosulfonic acid fuel cell membrane have been investigated through first principles based molecular modelling studies. Potential energy profiles determined at the B3LYP/6-31G(d,p) level in the two pendant side chain fragments: CF(3)CF(-O(CF(2))(2)SO(3)H)-(CF(2))(7)-CF(-O(CF(2))(2)SO(3)H)CF(3) indicate that the largest CF(2)-CF(2) rotational barrier along the backbone is nearly 28.9 kJ mol(-1) higher than the minimum energy staggered trans conformation. Furthermore, the calculations reveal that the stiffest portion of the side chain is near to its attachment site on the backbone, with CF-O and O-CF(2) barriers of 38.1 and 28.0 kJ mol(-1), respectively. The most flexible portion of the side chain is the carbon-sulfur bond, with a barrier of only 8.8 kJ mol(-1). Extensive searches for minimum energy structures (at the B3LYP/6-311G(d,p) level) of the same polymeric fragment with 4-7 explicit water molecules reveal that the perfluorocarbon backbone may adopt either an elongated geometry, with all carbons in a trans configuration, or a folded conformation as a result of the hydrogen bonding of the terminal sulfonic acids with the water. These electronic structure calculations show that the fragments displaying the latter 'kinked' backbone possessed stronger binding of the water to the sulfonic acid groups, and also undergo proton dissociation with fewer water molecules. The calculations point to the importance of the flexibility in both the backbone and side chains of PFSA membranes to effectively transport protons under low humidity conditions.     

Prevalence of the alkyl/phenyl-folded conformation in benzylic compounds C6H5CH2-X-R (X=O,CH2, CO,S, SO,SO2): significance of the CH/pi interaction as evidenced by high-level ab initio MO calculations

Ab initio MO calculations were carried out to examine the conformational energies of various benzylic compounds C(6)H(5)CH(2)XR (X=O, CH(2), CO, S, SO, SO(2); R=CH(3), C(2)H(5), iC(3)H(7), tC(4)H(9)) at the MP2/6-311G(d,p)//MP2/6-31G(d) level. Rotamers with R/Ph in gauche relationship are generally more stable than the R/Ph anti rotamers. In these stable geometries, the interatomic distance in the interaction of alpha- or beta-CH in the alkyl group and the ipso-carbon atom of the phenyl ring is short. The computational results are consistent with experimental data from supersonic molecular jet spectroscopy on 3-n-propyltoluene and NMR and crystallographic data on structurally related ketones, sulfoxides, and sulfones. In view of this, the alkyl/phenyl-congested conformation of these compounds has been suggested to be a general phenomenon, rather than an exception. The attractive CH/pi interaction has been suggested to be a dominant factor in determining the conformation of simple aralkyl compounds.     

Ab initio study of the substituent effects on the relative stability of the E and Z conformers of phenyl esters. Stereoelectronic effects on the reactivity of the carbonyl group

Equilibria between the Z (tau1= 0 degrees) and E (tau1= 180 degrees) conformers of p-substituted phenyl acetates 4 and trifluoroacetates 5 (X = OMe, Me, H, Cl, CN, NO2) were studied by ab initio calculations at the HF/6-31G* and MP2/6-31G* levels of theory. The preference for the Z conformer, DeltaE(HF), was calculated to be 5.36 kcal mol(-1) and 7.50 kcal mol(-1) for phenyl acetate and phenyl trifluoroacetate (i.e., with X = H), respectively. The increasing electron-withdrawing ability of the phenyl substituent X increases the preference of the Z conformer. An excellent correlation with a negative slope was observed for both series between DeltaE of the E-Z equilibrium and the Hammett sigma constant. By using an appropriate isodesmic reaction, it was shown that electron-withdrawing substituents decrease the stability of both conformers, but the effect is higher with the E conformer. Electron-withdrawing phenyl substituents decrease the delocalization of the lone pair of the ether oxygen to the C=O antibonding orbital (nO--> pi*C=O) in both the E and Z forms and in both series studied; this effect is higher in the E conformer than in the Z conformer. The nO --> pi*C=O electron donation has a minimum value with tau1= 90 degrees and a maximum value with tau1= 0 degrees (the Z conformer), the value with tau1= 180 degrees (the E conformer) being between these two values, obviously due to steric hindrance. The effects of the phenyl substituents on the reactivity of the esters studied are discussed in terms of molecular orbital interactions. ED/EW substituents adjust the availability of the pi*C=O antibonding orbital to interact with the lone pair orbital of the attacking nucleophile and therefore affect the reactivity: EW substituents increase and ED substituents decrease it. Excellent correlations were observed between the rate coefficients of nucleophilic acyl substitutions and pi*C=O occupancies of the ester series 4 and 5.     

Establishing effective simulation protocols for beta- and alpha/beta-peptides. II. Molecular mechanical (MM) model for a cyclic beta-residue

All-atom molecular mechanical (MM) force field parameters are developed for a cyclic beta-amino acid, amino-cyclo-pentane-carboxylic acid (ACPC), using a multi-objective evolutionary algorithm. The MM model is benchmarked using several short, ACPC-containing alpha/beta-peptides in water and methanol with SCC-DFTB (self consistent charge-density functional tight binding)/MM simulations as the reference. Satisfactory agreements are found between the MM and SCC-DFTB/MM results regarding the distribution of key dihedral angles for the tetra-alpha/beta-peptide in water. For the octa-alpha/beta-peptide in methanol, the MM and SCC-DFTB/MM simulations predict the 11- and 14/15-helical form as the more stable conformation, respectively; however, the two helical forms are very close in energy (2-4 kcal/mol) at both theoretical levels, which is also the conclusion from recent NMR experiments. As the first application, the MM model is applied to an alpha/beta-pentadeca-peptide in water with both explicit and implicit solvent models. The stability of the peptide is sensitive to the starting configuration in the explicit solvent simulations due to their limited length ( approximately 10-40 ns). Multiple ( approximately 20 x 20 ns) implicit solvent simulations consistently show that the 14/15-helix is the predominant conformation of this peptide, although substantially different conformations are also accessible. The calculated nuclear Overhauser effect (NOE) values averaged over different trajectories are consistent with experimental data, which emphasizes the importance of considering conformational heterogeneity in such comparisons for highly dynamical peptides.     

Conformational origin of glassy-state relaxation and ductility in aromatic polycarbonates

A new two-state conformational transition is proposed to explain the large, low-temperature mechanical loss peak seen in glassy polycarbonates. Restricted Hartree Fock ab initio calculations at the 6–31G7 level for diphenyl carbonate (DPC), a key model compound of bisphenol-A polycarbonate, reveal two inequivalent trans-trans carbonate-ring conformations both of which will exist in solution, melt or glassy states. These calculations appear to be the first high level ones (with full geometry optimization) reported for DPC, and the findings are consistent with earlier ab initio results for phenyl formate and other smaller model compounds and also with single-crystal X-ray data for DPC and oligomers. In addition to a trans-trans conformer of DPC with both phenyl rings on the same side of the carbonate unit (called the ‘syn’ conformer) which is seen in the crystalline state of DPC, an ‘anti’ conformer of lower energy is found, which has its two phenyl rings located on opposite sides of the plane of the carbonate unit. Analysis of these calculated ground state geometries and energies as well as experimental single crystal X-ray results indicates that the ‘anti’ conformer has the lowest energy in the gas phase and solution, while the ‘syn’ conformation is stabilized relative to the ‘anti’ in the bulk, probably because of aromatic ring interactions between neighbour chain segments. In the glassy state of either DPC or polycarbonate, one expects a nearly random mixture of ‘syn/anti’ conformers, and the prominent low-temperature mechanical loss peak observed in many polycarbonates is consistent with a molecular level two-state process consisting of ‘syn/ anti’ carbonate conformer conversions. These conformational transitions must involve rotation and translation of both the carbonate units and, most importantly, the neighbouring phenyl groups. The possible influence of these conformational changes and the accompanying correlated molecular motions on polymer ductility and ageing is briefly discussed.     

Noncovalent interactions between cytosine and SWCNT: curvature dependence of complexes via pi...pi stacking and cooperative CH...pi/NH...pi

Fragments of C24H12, adapted from a variety of armchair [(n,n), (n = 5, 7, and 8)] and zigzag [(m,0) (m = 8, 10, and 12)] single-walled carbon nanotube (SWCNT), are used to model corresponding SWCNTs with different diameters and electronic structures. The parallel binding mainly through pi...pi stacking interaction, as well as the perpendicular binding via cooperative NH...pi and CH...pi between cytosine and the fragments of SWCNT have been extensively investigated with a GGA type of DFT, PW91LYP/6-311++G(d,p). The eclipsed tangential (ET) conformation with respect to the six-membered ring of cytosine and the central ring of SWCNT fragments is less stable than the slipped tangential (ST) conformation for the given fragment; perpendicular conformations with NH2 and CH ends have higher negative binding energy than those with NH and CH ends. At PW91LYP/6-311++G(d,p) level, two tangential complexes are less bound than perpendicular complexes. However, as electron correlation is treated with MP2/6-311G(d,p) for PW91LYP/6-311++G(d,p) optimized complexes, it turns out there is an opposite trend that two tangential complexes become more stable than three perpendicular complexes. This result implies that electron correlation, a primary source to dispersion energy, has more significant contributions to the pi...pi stacking complexes than to the complexes via cooperative NH...pi and CH...pi interactions. In addition, it was found for the first time that binding energies for two tangential complexes become more negative with increasing nanotube diameter, while those for three perpendicular complexes have a weaker dependence on the curvature; i.e., binding energies are slightly less and less negative. The performance of a novel hybrid DFT, MPWB1K, was also discussed.     

Two polymorphs of 2,5‐dichloro‐3,6‐bis(dibenzylamino)‐p‐hydroquinone with flexible dibenzylamino groups

We obtained two conformational polymorphs of 2,5‐dichloro‐3,6‐bis(dibenzylamino)‐p‐hydroquinone, C₃₄H₃₀Cl₂N₂O₂. Both polymorphs have an inversion centre at the centre of the hydroquinone ring (Z′ = ), and there are no significant differences between their bond lengths and angles. The most significant structural difference in the molecular conformations was found in the rotation of the phenyl rings of the two crystallographically independent benzyl groups. The crystal structures of the polymorphs were distinguishable with respect to the arrangement of the hydroquinone rings and the packing motif of the phenyl rings that form part of the benzyl groups. The phenyl groups of one polymorph are arranged in a face‐to‐edge motif between adjacent molecules, with intermolecular C—H…π interactions, whereas the phenyl rings in the other polymorph form a lamellar stacking pattern with no significant intermolecular interactions. We suggest that this partial conformational difference in the molecular structures leads to the significant structural differences observed in their molecular arrangements.     

Solution structure, dimerization, and dynamics of a lipophilic alpha/3(10)-helical, C alpha-methylated peptide. Implications for folding of membrane proteins.

The solution structure and the dimerization behavior of the lipophilic, highly C(alpha)-methylated model peptide, mBrBz-Iva(1)-Val(2)-Iva(3)-(alphaMe)Val(4)-(alphaMe)Phe(5)-(alphaMe)Val(6)-Iva(7)-NHMe, was studied by NMR spectroscopy and molecular dynamics simulations. The conformational analysis resulted in a right-handed 3(10)/alpha-helical equilibrium fast on the NMR time scale with a slight preference for the alpha-helical conformation. The NOESY spectrum showed intermolecular NOEs due to an aggregation of the heptapeptide. In addition, temperature-dependent diffusion measurements were performed to calculate the hydrodynamic radius. All these findings are consistent with an antiparallel side-by-side dimerization. The structure of the dimeric peptide was calculated with a simulated annealing strategy. The lipophilic dimer is held together by favorable van der Waals interactions in the sense of a bulge fitting into a groove. The flexibility of the helical conformations concerning an alpha/3(10)-helical equilibrium is shown in a 3 ns molecular dynamics simulation of the resulting dimeric structure. Both overall helical structures of each monomer and the antiparallel mode of dimerization are stable. However, transitions were seen of several residues from a 3(10)-helical into an alpha-helical conformation and vice versa. Hence, this peptide represents a good model in which two often-discussed aspects of hierarchical transmembrane protein folding are present: i <-- i + 3 and i <-- i + 4 local H-bonding interactions cause a specific molecular shape which is then recognized as attractive by other surrounding structures.     

Empty level structure in phenyl and benzyl isocyanates

The energies of the lowest-lying anion states of phenyl (C6H5N=C=O) and benzyl (C6H5CH2N=C=O) isocyanates have been determined experimentally in the gas phase for the first time using electron transmission spectroscopy (ETS), and their localization properties have been evaluated using HF/6-31G, MP2/6-31G*, and B3LYP/6-31G* calculations. The lowest-lying anion state of phenyl isocyanate, mainly of benzene ring character but with some contribution also from the N=C=O pi-system, lies at significantly higher energy than that of other benzenes substituted by pi-functionals, such as benzaldehyde or styrene. The scaling with the use of suitable empirical equations of the virtual orbital energies (VOEs) for orbitals with predominantly pi*(ring) character calculated for the neutral-state molecules leads to vertical attachment energies (VAEs) which closely correspond to those determined experimentally, whereas those calculated for the predominantly pi*(CO) and pi*(NC) orbitals (3rd and 4th LUMO, respectively) are significantly different from the corresponding measured values notwithstanding the fact that the calculations reproduce the shortening of the N=C and C=O double bonds.     

Conformational studies on (17alpha,20Z)-21-(X-Phenyl)-19-norpregna-1, 3,5(10),20-tetraene-3,17beta-diols using 1D and 2D NMR spectroscopy and GIAO calculations of (13)C shieldings

Differences in agonist responses of the novel estrogen receptor ligands (17alpha,20Z)-(p-methoxyphenyl)vinyl estradiol (1), (17alpha, 20Z)-(o-alpha,alpha,alpha-trifluoromethylphenyl)vinyl estradiol (2), and (17alpha,20Z)-(o-hydroxymethylphenyl)vinyl estradiol (3) led us to investigate their solution conformation. In competitive binding assay studies, we observed that several phenyl-substituted (17alpha, 20E/Z)-(X-phenyl)vinyl estradiols exhibited significant estrogen receptor binding, but with variation (RBA (1) = 20; RBA (2) = 23; RBA (3) = 140 where estradiol RBA = 100) depending on the phenyl substitution pattern. Because the 17alpha-phenylvinyl substituent interacts with the key helix-12 of the ligand binding domain, we considered that differences in the preferred conformation of 1-3 could account for their varying binding affinity. 2D NMR experiments at 500 MHz allowed the complete assignment of the (13)C and (1)H spectra of 1-3. The conformations of these compounds in solution were established by 2D and 1D NOESY spectroscopy. A statistical approach of evaluating contributing conformers of 1-3 from predicted (13)C shifts correlated quite well with the NOE data. The 17alpha substituents of 1 and 2 exist in similar conformational equilibria with some differences in relative populations of conformers. In contrast, the 17alpha substituent of 3 exists in a different conformational equilibrium. The similarity in solution conformations of 1 and 2 suggests they occupy a similar receptor volume, consistent with similar RBA values of 20 and 23. Conversely, the different conformational equilibria of 3 may contribute to the significant binding affinity (RBA = 140) of this ligand.     

Experimental and Theoretical Conformational Analysis of 5‐Benzylimidazolidin‐4‐one Derivatives – a ‘Playground’ for Studying Dispersion Interactions and a ‘Windshield‐Wiper’ Effect in Organocatalysis

The PF₆ salts of 5‐benzyl‐1‐isopropylidene‐ and 5‐benzyl‐1‐cinnamylidene‐3‐methylimidazolidin‐4‐ones 1 (Scheme) with various substituents in the 2‐position have been prepared, and single crystals suitable for X‐ray structure determination have been obtained of 14 such compounds, i.e., 2 – 10 and 12 – 16 (Figs. 2–5). In nine of the structures, the Ph ring of the benzyl group resides above the heterocycle, in contact with the cis‐substituent at C(2) (staggered conformation A ; Figs. 1–3); in three structures, the Ph ring lies above the iminium π‐plane (staggered conformation B ; Figs. 1 and 4); in two structures, the benzylic C? C bond has an eclipsing conformation ( C ; Figs. 1 and 5) which places the Ph ring simultaneously at a maximum distance with its neighbors, the CO group, the N?C‐π‐system, and the cis‐substituent at C(2) of the heterocycle. It is suggested by a qualitative conformational analysis (Fig. 6) that the three staggered conformations of the benzylic C? C bond are all subject to unfavorable steric interactions, so that the eclipsing conformation may be a kind of ‘escape’. State‐of‐the‐art quantum‐chemical methods, with large AO basic sets (near the limit) for the single‐point calculations, were used to compute the structures of seven of the 14 iminium ions, i.e., 3, 4 / 12, 5 – 7, 13 , and 16 (Table) in the two staggered conformations, A and B , with the benzylic Ph group above the ring and above the iminium π‐system, respectively. In all cases, the more stable computed conformer (‘isolated‐molecule’ structure) corresponds to the one present in the crystal (overlay in Fig. 7). The energy differences are small (≤2 kcal/mol) which, together with the result of a potential‐curve calculation for the rotation around the benzylic C? C bond of one of the structures, 16 (Fig. 8), suggests that the benzyl group is more or less freely rotating at ambident temperatures. The importance of intramolecular London dispersion (benzene ring in ‘contact’ with the cis‐substituent in conformation A ) for DFT and other quantum‐chemical computations is demonstrated; the benzyl‐imidazolidinones 1 appear to be ideal systems for detecting dispersion contributions between a benzene ring and alkyl or aryl CH groups. Enylidene ions of the type studied herein are the reactive intermediates of enantioselective organocatalytic conjugate additions, Diels–Alder reactions, and many other transformations involving α,β‐unsaturated carbonyl compounds. Our experimental and theoretical results are discussed in view of the performance of 5‐benzyl‐imidazolidinones as enantioselective catalysts.     

Conformational preferences of alpha-substituted proline analogues

DFT calculations at the B3LYP/6-31+G(d,p) level have been used to investigate how the replacement of the alpha hydrogen by a more sterically demanding group affects the conformational preferences of proline. Specifically, the N-acetyl-N'-methylamide derivatives of L-proline, L-alpha-methylproline, and L-alpha-phenylproline have been calculated, with both the cis/trans isomerism of the peptide bonds and the puckering of the pyrrolidine ring being considered. The effects of solvation have been evaluated by using a Self-Consistent Reaction Field model. As expected, tetrasubstitution at the alpha carbon destabilizes the conformers with one or more peptide bonds arranged in cis. The lowest energy minimum has been found to be identical for the three compounds investigated, but important differences are observed regarding other energetically accessible backbone conformations. The results obtained provide evidence that the distinct steric requirements of the substituent at C (alpha) may play a significant role in modulating the conformational preferences of proline.