Enantiomeric Conformations Research Articles

Molecular structure and conformation of triphenylsilane from gas-phase electron diffraction and theoretical calculations, and structural variations in H4−n SiPh n molecules (n = 1–4)

The molecular structure of triphenylsilane has been investigated by gas-phase electron diffraction and theoretical calculations. The electron diffraction intensities from a previous study (Rozsondai B, Hargittai I, J Organomet Chem 334:269, 1987) have been reanalyzed using geometrical constraints and initial values of vibrational amplitudes from calculations. The free molecule has a chiral, propeller-like equilibrium conformation of C3 symmetry, with a twist angle of the phenyl groups τ = 39° ± 3°; the two enantiomeric conformers easily interconvert via three possible pathways. The low-frequency vibrational modes indicate that the three phenyl groups undergo large-amplitude torsional and out-of-plane bending vibrations about their respective Si–C bonds. Least-squares refinement of a model accounting for the bending vibrations gives the following bond distances and angles with estimated total errors: rg(Si–C) = 1.874 ± 0.004 A, 〈rg(C–C)〉 = 1.402 ± 0.003 A, 〈rg(C–H)〉 = 1.102 ± 0.003 A, and ∠aC–Si–H = 108.6° ± 0.4°. Electron diffraction studies and MO calculations show that the lengths of the Si–C bonds in H4−nSiPhn molecules (n = 1–4) increase gradually with n, due to π → σ*(Si–C) delocalization. They also show that the mean lengths of the ring C–C bonds are about 0.003 A larger than in unsubstituted benzene, due to a one hundredth angstrom lengthening of the Cipso–Cortho bonds caused by silicon substitution. A small increase of r(Si–H) and decrease of the ipso angle with increasing number of phenyl groups is also revealed by the calculations.

4-Oxocyclohexaneacetic acid: catemeric hydrogen bonding and spontaneous resolution of a single conformational enantiomer in an achiral ∊-keto acid

The asymmetric unit of the title compound, C8H12O3, consists of a single conformational enanti­omer, which aggregates in the catemeric acid-to-ketone hydrogen-bonding mode [O⋯O = 2.682 (4) Å and O—H⋯O = 172 (6)°]. Four hydrogen-bonding chains of translationally related mol­ecules pass through the cell orthogonal to the 43 screw axis along c, alternating in the 110 and the 10 direction, with alignment with respect to this axis of + + − −. Successive chains are rotated by 90° around the c axis. One C—H⋯O=C close contact, involving the carboxyl group, exists.

ChemInform Abstract: Substrate-Leaving Group Control of the Enantioselectivity in the Palladium-Catalyzed Asymmetric Allylic Substitution of 4-Alkyl-1- vinylcyclohexyl Derivatives.

The strong influence of the nature of the leaving group in allylic derivatives in their enantioselective Pd-catalyzed substitution by nucleophile is reported. Analysis of the stereochemical course of the Pd-catalyzed substitution of achiral trans-4-tert-butyl-1-vinylcyclohexyl derivatives with nucleophiles indicates the enantioselective step to be oxidative addition of the allylic substrate onto the chiral Pd complex. The asymmetric induction may be understood as the reuslt of the selection by the chiral Pd catalyst between two reactive enantiomeric conformations of the allylic substrate and, hence, was shown to be strongly dependent upon reaction conditions and especially upon the nature of the substrate leaving group

ChemInform Abstract: Sulfoxides as Chiral Complexation Agents. Conformational Enantiomer Resolution and Induced Circular Dichroism of Bilirubins.

Abstract Bilirubin-IXα, the end product of porphyrin metabolism in mammals and the neurotoxic yellow-orange pigment of jaundice, exhibits a strong tendency to fold like a book into either of two interconverting enantiomeric conformations, which are further stabilized by intramolecular hydrogen bonding. Bilirubin exhibits optical activity in R-(-)-ethylmethylsulfoxide solvent, as seen by moderately strong bisignate circular dichroism Cotton effects (Δϵmax452=+10.9,Δϵmax404=-4.5), and in dichloromethane solution in the presence of 2M R-(+)-methyl-p-tolylsulfoxide its circular dichroism spectrum (Δϵ463max=+11.2,Δϵ412max=-7.1) is comparably strong. As observed earlier for chiral recognition of bilirubin by optically active amines and serum albumins, the optically active sulfoxide acts as a chiral complexation agent to induce an asymmetric transformation of bilirubin, whose bisignate circular dichroism spectra are characteristic of an exciton splitting arising from interaction of the two component dipyrrinone chromophores.

ChemInform Abstract: Chirality and Stereogenicity: The Importance of Conformational Chirality in the Classification of Stereoisomers

Abstract As we have recently shown, the elements of chirality are not defined in the Cahn, Ingold and Prolog classification leading to imprecisions in the assignment and designation of chiral stereoisomers not involving a centre of chirality. Similarly, conformational chirality was not satisfactorily treated in the classification resulting in its underestimation. A recently published scheme of stereoisomer classification as well as many textbooks on organic chemistry, neglect or improperly treat conformational enantiomers and diastereoisomers. The scheme is corrected to include the latter group of stereoisomers.

ChemInform Abstract: Conformational Studies by Dynamic NMR. Part 48. Conformational Preferences and Stereomutational Processes of the Rotational Enantiomers of Hindered Naphthylimines and Imonium Salts

A number of 1-naphthylimines (and some of the corresponding imonium chlorides), having the isopropyl group as a prochiral probe, have been synthesized and their configurations assigned by the combined use of NOE experiments and molecular mechanics calculations. This method also provides reliable information about the conformations adopted in solution. The existence of diastereotopic methyl groups in the isopropyl moiety indicates the presence of conformational enantiomers, due to the rotation about the naphthyl–imino bond in nonplanar conformers. The barriers for the stereomutation of such enantiomeric forms have been determined by line-shape analysis of the temperature-dependent 1H or 13C signals of the prochiral probe. Molecular mechanics calculations have also helped in suggesting which is the preferred stereomutation pathway and in predicting the existence of a derivative having configurationally stable enantiomers. Such a compound has been synthesized and is found to display the predicted property (atropisomerism), in that the two enantiomers can be separated.

ChemInform Abstract: Transoid, Ortho, and Gauche Conformers of n-Si4Cl10: Raman and Mid-IR Matrix-Isolation Spectra.

Calculations at the HF/6-31G*, MP2(FC)/6-31G*, and B3LYP/6-31G* levels of theory predict the existence of three pairs of enantiomeric conformers on the potential energy surface of n-Si4Cl10: trans...

(E)-N2-{4-[(E)-2-(4-Chlorobenzoyl)ethenyl]-3-methyl-1-phenyl-1H-pyrazol-5-yl}-N1,N1-dimethylformamidine: polarized molecules within sheets of π-stacked hydrogen-bonded chains

The molecules of the title compound, C(22)H(21)ClN(4)O, are conformationally chiral, and in the space group P2(1)2(1)2(1) each crystal contains only one conformational enantiomer. The intramolecular dimensions provide evidence for polarization of the electronic structure. Molecules are linked by a single C-H...pi(arene) hydrogen bond into chains, which are themselves weakly linked into sheets by an aromatic pi-pi stacking interaction.

Molecular Simulations of Photoaddition Selectivity and Chirality in Challenging Photochemical Reactions

Abstract The origins of cycloaddition selectivities and chirality controls in particular and challenging photochemical reactions were examined. The profiles of the energies and stereochemical changes of the photoreactions were characterized by molecular simulations using dynamic molecular orbital methods. The photoreactions possess particular factors which are not explained by the frontier molecular orbital (FMO) theory. Particular photoreactions are examined by following the addition selectivities and two chiral controls by use of chiral hosts. (1) Species-(singlet or triplet), peri-, site-, regio-, and stereo-selectivities in the [2 + 2]cycloadditions and [4 + 4]cycloadditions of 2-pyridone (1). (2) Inversion of regioselectivity (hh/ht ratio) by the linkage-length in intramolecular [2 + 2]cycloadditions of α,β-unsaturated furanones 7 and by the alkene ring-size in intermolecular [2 + 2]cycloadditions of cycloalkenecarboxylates 11–13 with 2-cyclohexenone (10). (3) The occurrence of the hydrogen-shift reaction in the [2 + 2]photocycloaddition system between 4-hydoxycoumarin (17) and 3,4-dihydro-2H-pyran (18o). (4) Chiral control of selective [4π]-electrocyclic isomerizations of 1 to photopyridone 20 by hydrogen-bonding of chiral amide hosts 21. The singlet excited state, 1* was inferred to be enantiomeric conformers, 1*(+) and 1*(−), and the complex 1·(l)-21 proceeds to 1*(+)·(l)-21, followed by quenching to (R)-20. (5) Sensational chiral isomerization of (Z)-cyclooctene (28Z) to chiral (E)-cyclooctene (29E) by chiral benzenepolycarboxylates (30). 28Z was inferred to accompany asymmetric 28Z and the diastereomeric exciplexes Ex1 (28Z·30*) and proceeds with chiral isomerization via the one-sided rotation to Ex2 (29E*·30), followed by quenching to chiral 29E. The molecular simulations for the photoreactions by MOPAC-PM5, (PM3 for hydrogen-bonding), UCIS (for singlets), and UB3LYP (for triplets) are found to be successful and show that the origin of the photoreaction selectivities is essentially determined by the first step (TS1) energies and the stereochemistries are dependent on the excited species presented in the Concluding Remarks. We also propose some applications of the molecular simulations.

Enantiodiscrimination of Flexible Cyclic Solutes Using NMR Spectroscopy in Polypeptide Chiral Mesophases: Investigation ofcis-Decalin and THF

The conformational dynamics and orientational behavior of two model cyclic molecules, cis-decalin (cis-dec) and tetrahydrofurane (THF), dissolved in weakly ordering, polypeptidic chiral liquid crystals (CLCs) are theoretically discussed and experimentally investigated using deuterium and carbon-13 NMR spectroscopies. The analysis of enantiomeric and enantiotopic discriminations in these compounds is shown to depend on the rate of conformational exchange regime, slow or fast. The slow exchange regime is illustrated through the case of cis-dec at low temperature (243 K). We show that the deuterium NMR spectra in this regime can be qualitatively and quantitatively interpreted by restricting the conformational pathway of cis-dec to two enantiomeric conformers of C(2)-symmetry. The orientational order parameters of these interconverting enantiomers are calculated by matching the (2)H quadrupolar splittings with calculated conformer structures. The fast exchange regime is investigated through the examples of cis-dec at high temperature (356 K) and THF at room temperature (300 K). The (2)H NMR spectra above the coalescence temperature are analyzed by introducing the concept of "average molecular structure". This fictitious structure allows easily identifying NMR equivalences of solutes dissolved in CLC. However, it cannot be applied to determine consistent orientational order parameters. This study emphasizes that enantiotopic discriminations observed for flexible molecules in the fast exchange regime can be quantitatively interpreted only by considering the orientational order of each conformer.

Helical Polymer of Porphyrin and a Chiral Pd(II) Complex

Saddle-shaped porphyrins such as 1 exist as an equilibrium between enantiomeric conformations. Based on previous studies, the authors hypothesized and showed that addition of a chiral Pd(II) complex would lead to formation of a one-handed helical polymer favoring one enantio­mer.

Five more phases of the structural family [M(H2O)2(15-crown-5)](NO3)2

The structures of five more phases of the structural family of compounds [M(H2O)2(15-crown-5)](NO3)2 have been determined. All of these phases are stable at room temperature or above, but transform to other phases if cooled slowly. All five phase transitions take place without significant damage to the single crystal. The M = Co phase, which has a three-dimensional hydrogen-bonding pattern, is a disordered version of the structure known at room temperature; Z' changes from 2 to (1/2). The other four structures have a two-dimensional hydrogen-bonding pattern, are all modulated variants of the same basic cell (or subcell) and are at least mostly ordered. For M = Mg and Zn the structure found somewhat above room temperature is the Z' = 8 variant found previously for M = Fe. For M = Cu and Ni the Z' = 2 phase found is the same as seen previously for one of the room-temperature polymorphs with M = Mn. There are now two phases and one transition known for each M studied that has a two-dimensional hydrogen-bonding pattern. The changes in the modulation patterns during these transitions are Z' 3 <--> 8 (Mg, Fe, Zn), Z' 3 <--> 2 (Mn, Ni) and Z' 5 <--> 2 (Cu). In all two-dimensional hydrogen-bonded crystals the alternation pattern of conformational enantiomers along the modulation direction becomes more perfect above the phase transition. All stable [M(H2O)2(15-crown-5)](NO3)2 phases whose existence at accessible temperatures is indicated by differential scanning calorimetry (DSC) have now been characterized.

Synthesis, X-ray Crystallographic, and NMR Characterizations of Platinum(II) and Platinum(IV) Pyrophosphato Complexes

A series of mononuclear cis-diamineplatinum(II) pyrophosphato complexes containing ammine (am), trans-1,2-cyclohexanediamine (dach), and 1,2-ethanediamine (en) as the amine ligands were synthesized and characterized by (31)P and (195)Pt NMR spectroscopy. Chemical shifts of (31)P NMR resonances of these completely deprotonated complexes appear at 2.12, 1.78, and 1.93 ppm, indicating a coordination chemical shift of at least 8 ppm. The (195)Pt NMR chemical shifts for the am and dach complexes were observed at -1503 and -1729 ppm. The complexes are highly stable at neutral pH; no aquation due to the release of either phosphate or amine ligands was observed within 48 h. Furthermore, no partial deligation of the pyrophosphate ligand was detected within several days at neutral pH. At lower pH, however, release of a pyrophosphate ion was observed with concomitant formation of a bridged pyrophosphatoplatinum(II) dinuclear complex. The extended crystal structure containing the dach ligand revealed a zigzag chain stacked in a head-to-tail fashion. Moreover, two zigzag chains are juxtaposed in a parallel fashion and supported by additional hydrogen bonds reminiscent of DNA structures where two strands of DNA bases are held by hydrogen bonds. Theoretical calculations support the notion that the two dinuclear units are held together primarily by hydrogen bonds between the amine and phosphate moieties. Platinum(II) pyrophosphato complexes were readily oxidized by hydrogen peroxide to yield cis-diamine-trans-dihydroxopyrophosphatoplatinum(IV) complexes. Two of these complexes, containing am and en, were characterized by X-ray crystallography. Notable structural features include Pt-O (phosphate) bond distances of 2.021-2.086 A and departures from 180 degrees in trans-HO-Pt-OH bond angles, >90 degrees in O-Pt-O, and >90 degrees in cis-N-Pt-N bond angles. The departure in the trans-HO-Pt-OH angle is more pronounced in the 1,2-ethanediamine complex compared to the dach analogue because of the existence of two molecules possessing enantiomeric conformations within the asymmetric unit. (31)P NMR spectra exhibited well-resolved (195)Pt satellites with coupling constants of 15.4 Hz for the ammine and 25.9 Hz for both the 1,2-ethanediamine and trans-1,2-cyclohexanediamine complexes. The (195)Pt NMR spectrum of the ammine complex clearly showed coupling with two equivalent N atoms.

Stereomutation of Conformational Enantiomers of 9-Isopropyl-9-formylfluorene and Related Acyl Derivatives

Low-temperature NMR spectra show that the title compound exists as a pair of conformational enantiomers, generated by the restricted rotation about the C9-Pr (i) bond, the corresponding interconversion barrier being 6.9 kcal mol (-1). This interpretation is supported by theoretical (MM and DFT) calculations and by the experimental determination of the analogous barriers occurring in the related MeC=O and Bu(t)C=O derivatives.

Enantiodiscrimination in Deuterium NMR Spectra of Flexible Chiral Molecules with Average Axial Symmetry Dissolved in Chiral Liquid Crystals: The Case of Tridioxyethylenetriphenylene

Flexible chiral molecules undergoing fast interconversion (on the NMR time scale) between different conformational enantiomers may yield "average" axial species with enantiotopically related sites. Contrary to the situation observed for rigid axial molecules, signals from these enantiotopic sites in NMR spectra recorded in chiral liquid-crystalline solvents can be resolved. In the present work, we studied the deuterium NMR spectra of tridioxyethylenetriphenylene (compound 4) statistically deuterated to 10% in the flexible side chains and dissolved in chiral and achiral lyotropic liquid crystals based on poly(gamma-benzylglutamate). The fast chair-chair flipping of the side chains in 4 on average renders the molecule axially symmetric ( D 3 h ) with pairs of enantiotopic ethylene deuterons. These deuterons exhibit unusually large enantiodiscrimination. To explain this observation, we first describe how the average symmetry of flexible molecules can be derived from the symmetry of the "frozen" conformers and the nature of the averaging process. The procedure is then applied to 4 and used to analyze the NMR results. It is shown that the large enantiodiscrimination in the present case reflects a large difference in the orientational ordering of the conformational enantiomers participating in the interconversion processes as well as a large geometrical factor due to the special shape of the dioxyethylene side groups. (1)H and (13)C NMR spectra of 4 in the same lyotropic liquid crystalline solvent are analyzed to determine its ordering characteristics. Several related cases are also discussed.

Organogold complexes probe a large β-barrel cavity for human serum α 1-acid glycoprotein

Human α 1-acid glycoprotein (AAG) is an acute phase component of the plasma, binding numerous drugs and natural compounds with high-affinity. Using circular dichroism (CD) spectroscopy, strong AAG binding of organogold complexes was found, the molecular size and chemical structure of which differ from known AAG binding agents. The 16-membered Au 2P 4C 8O 2 macrocycles interconvert rapidly between two helical forms and produce enantiomeric conformations which are in dynamic equilibrium in solution. AAG binds preferentially one of the chiral conformers as indicated by strong Cotton effects generated by intramolecular exciton coupling between the pairs of hetercyclic chromophores. Lipophilic nature of the guest molecules suggests the dominant contribution of hydrophobic interactions in the AAG binding. Comparison of the main genetic variants of AAG revealed that both the ‘F1/S’ and ‘A’ variants bind with high-affinity the gold(I) macrocycles ( K a ≈ 10 6 M - 1 ). CD/fluorescence displacement, and fluorescence quenching experiments indicated inclusion of the compounds into the central β-barrel cavity of AAG of which exact tertiary structure is yet unknown. Molecular dimensions of the gold(I) macrocycles (13 × 14 × 14 Å) indicate that the principal ligand binding cavity of both the ‘F1/S’ and ‘A’ variants must be larger compared to the models published to date. Based on these findings, a novel homology model of AAG ‘F1’ variant was constructed using the human neutrophil gelatinase-associated lipocalin as a template. The organogold complexes were successfully docked into the central cavity of this model.

Investigation on the flexibility of chiral tricyclic derivatives

In the perspective of generating libraries for broad screening purposes, the inversion barrier of enantiomeric conformers of various tricyclic compounds, characterized by a seven-membered ring featuring a lactam group with two aromatics condensed at its opposite sides, has been investigated by ab initio calculations and NMR spectroscopy. Solid-state structure characterizations by single-crystal X-ray diffraction have been also carried out. The aim was to assess if moving from ethers to sulfides and sulfones derivatives, causes the racemization barrier to vary. Investigation was also extended to thiolactam congeners. Structural and electronic effects were investigated on the energetics of the inversion process and structure-property relationships evidenced. Results suggest that the ring inversion of the oxo derivatives is easier with respect to the corresponding S/SO2 ones. Also amide molecules have, on the whole, smaller barriers with respect to the corresponding thioamide ones.

Fluxional Additives: A Second Generation Control in Enantioselective Catalysis

The concept of "fluxional additives", additives that can adopt enantiomeric conformations depending on the chiral information in the ligand, is demonstrated in enantioselective Diels-Alder and nitrone cycloaddition reactions. The additive design is modular, and diverse structures are accessible in three steps. Chiral Lewis acids from main group and transition metals show enhancements in enantioselectivity in the presence of these additives.

Four different types of hydrogen bonds observed in 1,2-bis( N-benzenesulfonylamino)benzenes due to conformational properties of the sulfonamide moiety

The crystal structures of 1,2-bis( N-benzenesulfonylamino)benzenes with secondary and/or tertiary sulfonamide groups were determined by X-ray crystallographic analysis. Every Ar-sulfonamide group existed in synclinal conformation in the crystals even though it was secondary or tertiary. Each compound showed different types of hydrogen bonds in the crystal structure. 1,2-Bis( N-benzenesulfonylamino)benzene ( 1) formed two double hydrogen bonds connected to the next molecules, 1-( N-benzenesulfonylamino)-2-( N-benzenesulfonyl- N-methylamino)benzene ( 2) contained double hydrogen bond involved by both the sulfonamide moieties, 1,2-bis( N-4-toluenesulfonylamino)benzene ( 3) had both intra- and intermolecular hydrogen bonds, and 1-( N-methyl- N-4-toluenesulfonylamino)-2-( N-4-toluenesulfonylamino)benzene ( 4) had one double hydrogen bond involved by only one sulfonamide moiety. Sulfonamides 1 and 3 formed infinite arrays of the molecules, and sulfonamides 2 and 4 formed racemic dimer of their conformational enantiomers via the hydrogen bonds.

Structure, Conformation, and Stereodynamics of the Atropisomers of Highly Hindered Benzyl Ethers

Low-temperature and NOE NMR spectra of four of the title compounds indicate that they adopt a synclinal (sc) conformation, in agreement with the prediction of ab initio computations. In the case of the most-hindered derivative (compound 4), the conformation is syn-periplanar (sp), as is also shown by X-ray diffraction. Such stereolabile sp- or sc-atropisomers exist as two conformational enantiomers: the corresponding enantiomerization barriers, covering the range 6.6 to 9.7 kcal mol(-1), could be measured for all the examined compounds. In two cases (compounds 3 and 5), the minor antiperiplanar (ap) atropisomer has been also observed, and the sc to ap interconversion barrier measured (11.7 and 11.9 kcal mol(-1), respectively). In addition, restricted rotation of the isopropyl and tert-butyl substituents has been detected, and the corresponding barriers have been determined.