Gauche Interactions Research Articles

Highly Stereoselective Formation of Cp*IrCl Complexes ofN,N-Dimethylamino Acids

N,N-Dimethylamino acids serve as (N, O)-chelating monoanionic ligands to the prochiral fragment Cp*IrCl. A series of four such complexes and one Rh analog all were formed with diastereoselectivity of ≥50:≤1. The structure of the valine complex 5d (C17H29ClIrNO2) was analyzed at 298 K, from which a cis-arrangement of Cp* and valine side chain (i-Pr) was revealed. Solution NMR studies of 5d, aided by an unusual zero coupling between the two methine protons of the amino acid, showed that the structures in solution and the solid were very similar. The preference for the cis-oriented Cp* and amino acid side chain in 5 is attributed to a maximum number of gauche interactions in the metallacycle and its substituents, especially pronounced for N,N-disubstituted amino acids.

NMR Study of Substituted Bicyclo[3.2.1]octanes

The 1H and 13C NMR spectra of six bromo- and methoxybicyclo[3.2.1]octanes were completely assigned. An axial bromine substituent at C-2 or C-4 results in a 5 ppm upfield shift of C-8 due to the gauche interaction. An equatorial bromine results in an upfield shift of similar magnitude on either C-6 (or C-7) due to a similar gauche interaction but has little effect on the chemical shift of C-8. The 1,4-anti interaction of an axial bromine substituent on carbons C-6 and/or C-7 results in a small upfield shift (0.3 ppm) in parallel to the effect of an equatorial bromine on the chemical shift of C-8. Similarly to the trend observed in bicyclo[2.2.1]heptanes, the substituent effects for 1,4-gauche and 1,4-anti interactions of the methoxy group are larger than for bromine.

Gauche effect and PM3 calculation of open-chain polyphosphorus hydrides

The geometries and the energies of conformers of PnHn + 2 (n = 2−9) have been studied with PM3 method. To test the quality of the semiempirical results, ab initio calculations have been carried out on P3H5. All results of P2H4 and P3H5 with PM3 are consistent with the experimental and ab initio data. According to the analysis of P3H5 and P4H6 results, it is concluded that gauche interaction between adjacent lone electron pairs and gauche interaction between polar P-H bond with adjacent polar P-P bond are important for predicting the stable conformer of open-chain phosphoanes. The calculations of PnHn + 2 (n > 4) give further support to this conclusion. © 1996 John Wiley & Sons, Inc.

Conformationally constrained analogues of diacylglycerol. 12. Ultrapotent protein kinase C ligands based on a chiral 4,4-disubstituted heptono-1,4-lactone template.

Conformationally constrained analogues of diacylglycerol (DAG) built on a 5(-)[(acyloxy)methyl]-5-(hydroxymethyl)tetrahydro-2-furanone template (1, Chart 1) were shown previously to bind tightly to protein kinase C alpha (PK-C alpha) in a stereospecific manner. These compounds, however, racemized readily through rapid acyl migration and lost biological potency. In order to circumvent this problem, the "reversed ester" analogues were designed as a new set of PK-C ligands. This reversal of the ester function produced some new DAG mimetics that are embedded in a C-4 doubly-branched heptono-1,4-lactone template. The reversed ester analogues were impervious to racemization, and their chemically distinct branches facilitated the enantiospecific syntheses of all targets. Compound 2, the simplest reversed ester analogue of 1 (Chart 1), exhibited a 3.5-fold reduction in binding affinity toward PK-C alpha which we attributed to the loss of a stabilizing gauche interaction that caused the ester branch in 2 to be more disordered than in the normal ester 1. However, conversion of the propanoyl branch of 2 into a propenoyl branch restored binding affinity (3 versus 5). As expected, the compounds bound to the enzyme with strict enantioselectivity (3 and 5 versus 4 and 6). Functionalization of the propenoyl-branched compounds as alpha-alkylidene lactones, in a manner which proved successful with the 5(-)[(acyloxy)methyl]-5-(hydroxymethyl)tetrahydro-2-furanone template (9 and 10), produced stable compounds with equivalent ultrapotent binding affinities for PK-C alpha (7 and 8). The additional incorporation of the propenoyl-branched carbonyl into a gamma-lactone ring was performed (11-14) not only to derive a possible additional entropic advantage but also to confirm the spatial disposition of this carbonyl function in the ligand-enzyme complex. Although no additional entropic advantage was derived, the high binding affinities displayed by compounds 11 and 12 helped to establish the correct orientation of the equivalent carbonyl group in PK-C-bound DAG. As expected, these DAG analogues activated PK-C alpha. The most potent agonist, compound 8, stimulated phosphorylation of the alpha-pseudosubstrate peptide, and in primary mouse keratinocytes it caused inhibition of binding of epidermal growth factor with an ED50 of approximately 1 microM. In contrast to the phorbol esters, compound 8 did not induce acute edema or hyperplasia in skin of CD-1 mice, and its pattern of downregulation with several PK-C isozymes was different from that of phorbol 12-myristate 13-acetate (PMA).

Mass spectral study of diastereomers by electron impact

AbstractThe electron impact mass spectra of some diastereomeric dialkyl tartrates and isopropylidine derivatives of dimethyl tartrate show diagnostic differences in the relative abundances of some ions. The differences have been explained based on preferred conformations of these isomers. The configuration of the carbomethoxy groups has been correlated with the configuration of carbomethoxy groups in dimethyl maleate and fumarate. The interaction between the two carbomethoxy groups is relatively larger in conformations where there is a gauche interaction between them. The results could also be correlated with the solution phase conformations of these compounds reported in the literature using nuclear magnetic resonance techniques. The difference, which is small in diastereomeric dimethyl tartrates, is very reproducible and has been confirmed using six different mass spectrometers.

Analysis of the Conformational Nature, Resolvability, and Thermal Racemization of Hetero 2,3-Dispiro Cyclohexanones. The Weighting of Carbonyl/C-X Stabilization Relative to the Electronic Interaction between the Vicinal Electronegative Substituents

A series of hetero 2,3-dispiro cyclohexanones has been prepared. The conformations of the syn and anti isomers were assessed in the solid state, in solution, and in the gas phase (the latter by molecular mechanics calculations). The results are discussed in the light of steric, dipole, and gauche interactions; steric contributions give evidence of controlling ΔG eq . On a different front, the syn/anti pairs were found to interconvert when heated in the presence of a catalytic amount of acid. Three representative examples of these chiral molecules were resolved and complete racemization was observed to result under the conditions of equilibration

Conformational analysis of methylthiazanes: the problem of the methyl-carbon-nitrogen-methyl gauche interaction

The position of conformational equilibria in 2- and 3-methyl-1,4-thiazanes and cis- and trans-2,3-dimethyl-1,4-thiazanes, their N-methyl derivatives, and several of the correSponding sulfoxides and sulfones have been measured. The ΔG o values for the methyl groups are generally in agreement with what one would expect on the basis of known conformational equilibria in methylthianes, methylpiperidines, and N-methylated homologs of the latter; however, the differences in ΔG o between the 2-methyl and N,2-dimethyl homologs are even larger than in the piperidine series

The structural basis of the geminal-dimethyl effect

A systematic analysis of the X-ray structures of cyclohexanes, cylcopentanes and open-chain compounds containing gem.-dimethyl groups has revealed that a static scissor-type deformation at the quaternary C atom is absent. Unexpectedly the CCC bond angles in α-position to the quaternary C atom are significantly larger than the standard values in the unsubstituted reference structures. This distortion is interpreted in terms of gauche interactions. Based on the presently available data for structures containing gem.-dimethyl groups, the structure-reactivity relationship observed by Thorpe and Ingold for this class of compounds, has an origin different from static scissor-like distortions at the quaternary C atom.

The rational design of highly stereoselective boron enolates using transition-state computer modeling: a novel, asymmetric anti aldol reaction for ketones

The design and development of highly enantioselective anti aldol reactions based on computer-aided transition-state modeling is reported. The new chiral boron ligand L=6 was conceived based on its conformational preferences and on minimization of (±) double gauche pentane interactions. Modeling the transition structures for the aldol reaction of Z enolates 1 (L=6) predicted a selectivity which is equal to or slightly lower than that calculated and experimentally tested with L=Ipc (isopinocampheyl) (see Table I)

Influence of gauche interactions on the substituent effects on carbon‐13 chemical shifts in six‐membered ring compounds

Abstract13C NMR spectra of six epimeric substituted 4‐hydroxypiperidines and two corresponding piperidines were recorded. Substituent parameters for equatorial methyl, gem‐dimethyl, equatorial hydroxy and axial hydroxy groups were calculated from the 13C chemical shifts of these compounds and several other six‐membered ring compounds. The effects of nearby substituents on these parameters were examined. It is concluded that the magnitude and even the sign of the α effect is modified by the presence of nearby substituents. It was found that gauche interactions play an important role in determining the magnitude of the α effect. However, the β effect is not influenced by the nearby substituents except for the gem‐dimethyl group. The magnitude of the γ effect is almost independent of the nearby substituents.

Conformational analysis of 1-Y, 2-Z-Cyclohexanes ( Y = OH, OMe, F, Cl, Br and I; Z= SMe, SOMe and SO 2Me): Study of the Z/Y gauche interactions

The conformational study of the title compounds is reported. The configurational assignment of the epimeric sulfoxides was based on the relationship between the stereochemistry of the sulfinyl group and the chemical shifts of the neighboring nuclei. The values of the (Z/Y) gaucha interactions have been estimated in different solvents from G 0 values measured in low temperature 13C-nmr spectra.

ChemInform Abstract: Rotational Barriers. Part 2. Energies of Alkane Rotamers. An Examination of Gauche Interactions.

AbstractThe barrier of rotation around C(2)‐C(3) and the trans/gauche energy difference of butane (Ia) is calculated to be 6.34 and 0.86 kcal/mol, resp., using several basis sets.

Conformational analysis of 3-aminothiacyclohexane and derivatives by low-temperature 13C NMR

Several gauche interactions between sulfur and nitrogen functions are determined from measurement of conformational equilibria of 3-(X)-thiacyclohexanes (X = NH 2, NMe 2, NHPh and NHCO 2Bu t), their epimeric sulfoxides, and the corresponding sulfones, by low-temperature carbon-13 and proton NHR spectroscopy. The (RNH/S) gauche interaction is 0.18 (R=H), -0.04 (R=Ph) and -0.31 (R=CO 2Bu t) kcal/mol. The (Me 2N/S) gauche interaction is 0.70 kcal/mol, of which 0.26 kcal/mol is estimated to arise from the gauche repulsive effect between the electron lone pairs. The (RNH/SO x) gauche interactions in the trans-sulfoxides (x=1) are approximately as destabilizing as expected on simple steric grounds, whereas in their cis epimeres and in the sulfones they are 0.65 (R=H, x=1), 0.28 (R=H, x=2), -0.78 (R=Ph, x=1), -0.22 (R=Ph, x=2), < -1.94 (R=Co 2Bu t, x=1) and <-1.41 (R=CO 2Bu t, x=2) kcal/mol. Concentration and solvent effects in the RNH- series are small, intermediate and large, respectively, when R is H, Ph or CO 2Bu t. The effect of protonation upon conformational equilibria is also discussed.

The temperature dependence of the Raman spectrum and gauche interactions of tri-N-butylamine: a conformational study

Raman spectra of tri-n-butylamine show pairs of bands whose temperature-dependent intensities clearly suggest their assignment to different conformers in simultaneous equilibria. These spectroscopic data are interpreted and correlated with structural information obtained from statistical analysis of gauche skeletal arrangements in tri-n-butylamine. The average numbers of gauche interactions in various tri-n-alkylamines are used to evaluate partial molal volumes which show excellent agreement with experimental data, thus imparting statistical meaning and usefulness to the concept of "average conformation".As the temperature decreases, the band at 904 cm−1 in pure liquid tri-n-butylamine increases in intensity at the expense of the band at 880 cm−1. Both of these bands are ascribed to CH2 and CH3 rocking vibrations. In solution, the conformer represented by the band at 904 cm−1 is favoured by polar solvents, whereas the conformer represented by the 860 cm−1 band is favoured by non-polar solvents.The relative intensity changes with increasing temperature of the bands at 1456 and 1440 cm−1 is explained by an increase in the number of CH2 groups adjoining two gauche bonds and a decrease in the number of CH2 groups adjoining a trans and gauche bond.Temperature dependence of the relative intensities of bands in the CH stretching region suggest, by comparison with mono- and di-n-butylamine, that the increase in the number of alkyl chains around the nitrogen atom makes molecular packing less restrictive and unique, giving rise to mesophases, as the overall shapes of the molecules become more spherical.

High-field proton and carbon-13 nuclear magnetic resonance studies of the conformational dynamic properties of seven-membered rings. 1,5-Benzodithiepin and 3-substituted derivatives

The conformational and dynamic properties of 1,5-benzodithiepin (1), its 3,3-dimethyl (2), 3-methyl (3), and 3-methoxy (4) derivatives have been investigated by high-field 1H and 13C dynamic nuclear magnetic resonance methods. Analyses of the spectra at low temperatures indicate that, in CS2, both 1 and 2 exist as a mixture of C and TB forms (97:3 for 1; 63:37 for 2). In contrast, both 3 and 4 exist as a mixture of three equilibrating conformations Ce, Ca, and TB in ratios of 55:25:20 and 88:8:4 respectively. Comparison with analogues derived from 1,5-benzodioxepins (1a–4a) indicates that the replacement of O by S decreases the amount of the TB form for all four compounds studied. The observation that Ce is the most abundant form for 4 while it is not observed for 4a can be explained by a repulsive S/O gauche interaction in 4 compared to an attractive O/O interaction in 4a.

Conformational studies by Raman spectroscopy and statistical analysis of gauche interactions in n-butylamine

Raman spectra of n-butylamine recorded at different temperatures show pairs of bands whose temperature-dependent intensities clearly suggest their assignment to different conformers in simultaneous equilibria. Normal coordinate analysis and i.r. spectra of n-butylamine are also used to assign the spectra. These vibrational data are interpreted and correlated with structural information obtained from a statistical analysis of gauche skeletal arrangements in n-butylamine at different temperatures.

Dependence of the γ carbon‐13 shielding effect on electronegativity

AbstractThree γ effects on 13C shielding in 3,3‐dimethylheteracyclohexanes as a function of the hetero‐atom X have been examined. The γ‐anti effect on the equatorial 3‐methyl group is small in absolute magnitude but strongly dependent on the polar properties of X. The plot of the 13C shielding of this carbon vs the electronegativity of X is linear, with a slope of −5.8 ppm/electronegativity unit. The γ‐gauche effects on the axial 3‐methyl group and on the 4‐carbon are large in absolute magnitude but have quite different dependences on the polar properties of X. Whereas the shielding of the 4‐carbon exhibits a linear dependence on electronegativity (slope −3.5), the axial 3‐methyl group shows little dependence (slope crudely −0.7), even though the geometric relationship between X and either carbon is almost the same. Neither gauche carbon shielding appears to be related to the steric properties of X. The polar component of both the γ‐anti effect and the γ‐gauche effect is interpreted as arising from overlap of appropriately positioned parallel orbitals. For the anti case, the pathway is the familiar zigzag arrangement of bonds. For the gauche case, the pathway may be either through space (the orbitals would be only on X and C‐α; for the 4‐carbon, this interaction would be through the center of the ring) or through bonds (there are parallel axial orbitals on all four atoms). The absence of a significant polar effect for the axial 3‐methyl group suggests that the gauche interaction requires a rigid pathway. The polar component of the general γ‐gauche effect is superimposed upon a larger contribution that is essentially independent of the nature of X and may be associated with the removal of the hydrogen on the β‐carbon and replacement with the γ‐X group.

Conformational effects on the enthalpy of formation of straight and branched-chain alkanes

Benson's scheme for calculating the enthalpy of formation of straight and branched-chain alkanes by addition of increments for methyl, methylene, methine, and quaternary carbon groups, and by correction (where necessary) for steric effects, has been modified by a more detailed consideration of the effect of gauche interactions.

Charge distributions and chemical effects. XXIV. On the role of vibrational energies in determining molecular stabilities

A simple equation has been derived for calculating accurate ZPE + HT − H0 (zero-point and heat content) energies of saturated hydrocarbons from their enthalpies of formation and carbon-13 nuclear magnetic resonance spectra. Applications to conformational analysis indicate a near invariance of vibrational energies with respect to chair–boat conformational changes of the cyclohexane ring, the loss in molecular stability arising then from a weakening of the chemical binding due to a reorganization of the electronic charges. The origin of the destabilizing effect of butane gauche interactions is found, in the cyclohexane series, in a weakening of the chemical binding (∼1.85 kcal/mol) which is partially compensated by a lowering (∼0.85 kcal/mol) vibrational energy, thus offering an explanation for the loss in molecular stability of ∼1.00 kcal/mol for one gauche interaction without invoking Coulomb-type repulsions between non-bonded atoms. Calculated enthalpies of formation are presentd for a number of cycloalkanes.

Effect of solvent (benzene, ethanol, cyclohexane) on the partial molal volumes of organic compounds

The partial molal volumes of n-alkanes and n-alkanols dissolved in benzene, ethanol, or cyclohexane are given with satisfactory accuracy by the equation previously developed for solutions in carbon tetrachloride, if certain parameters (the covolume, the volume increment for the hydroxyl group, and the volume decrement for some gauche interactions) are changed. Additionally, it is necessary to postulate a greater coiling of the alkyl chains when dissolved in cyclohexane.