Diaxial Conformation Research Articles

Synthetic studies on anthracyclinones. XIV. On the conformational aspects of ring A of daunomycinone: A model study.

A pair of stereoisomers of the ring A model for daunomycinone was synthesized. The stereochemistries of isomeric α-tetralol-type intermediates and of the target compounds were discussed on the basis of spectral evidences. For all of the synthetic cis-1, 3-glycol systems related to ring A of daunomycinone were demonstrated a favorable di-axial conformation of the hydroxyls and the outside orientation of the O-H bond in the quasi-axial benzylic hydroxyl, while a quasi-equatorial conformation of the benzylic hydroxyl was found favorable for trans-1, 3-glycol system of the stereoisomers epimeric at C1.

ChemInform Abstract: ANOMERIC EFFECT IN SULFUR HETEROCYCLES CARRYING SULFUR SUBSTITUENTS

AbstractEs werden mit 1H‐NMR‐spektroskopischen Methoden die Konformation von 1,3,5‐ Trithianen wie z.B. 2‐Phenylthio‐ und 2,4‐Bis(phenylthio)‐l ,3,5‐trithian sowie im letzteren Falle auch das cis‐trans‐Gleichgewicht untersucht.

Anomeric Effect in Sulfur Heterocycles Carrying Sulfur Substituents

Abstract Conformational analysis of 1,3,5-trithiane derivatives with sulfur-substituents was carried out with the aid of PMR spectra at various temperatures. 2-Phenylthio-1,3,5-trithiane exhibited the strong anomeric effect whereas 2-phenylthiothiane the moderate. This enhanced anomeric effect in trithiane derivatives was attributed to both the stabilization of the axial form and the destabilization of the equatorial form. cis-2,4-Bis(phenylthio)-1,3,5-trithiane was found to possess a diaxial conformation to a fair extent in support of the presence of the strong anomeric effect. Equilibration between cis and trans forms of 2,4-bis(phenylthio)-1,3,5-trithiane was carried out to show that the trans form was more stable than the cis. The barrier to inversion of trans-2,4-bis(phenylthio)-1,3,5-trithiane was obtained as ca. 11 kcal/mol.

Stereochemical studies: XVII—the proton coupling constants and conformational equilibria of trans‐1,2‐disubstituted cyclohexenes

AbstractThe vicinal 3Jaa and 3Jee spin‐spin coupling constants of a number of deuterated trans‐1,2‐disubstituted cyclohexenes and the ΔH and ΔS values of the conformational equilibria of these compounds have been determined by computer optimisation of the 3J(HH) = f(T) function. Compounds with —CF3 and CCl3 substituents were shown to have an enhanced proportion of the diaxial conformer.

Anisotropy of polarizability of trans-1,2-dibromocyclohexanes

On the basis of the dipole moments and Kerr constants of three trans-1,2-dibromocyclohexanes it was established that the diaxial conformers are nonpolar.

Rotational isomerism. Part XV. The solvent dependence of the conformational equilibria in trans-1,2- and trans-1,4-dihalogenocyclohexanes

The free energy difference between the two chair conformations of trans-1,2-dichloro- and -1,2-dibromo-cyclohexane (II) and trans-1,4-dichloro- and -1,4-dibromo-cyclohexane (III) has been determined by peak area n.m.r. measurements in a number of solvents at low temperature. Both equilibria show a strong solvent dependence [despite the absence of a dipole moment for either of the interconverting species in (III)] and this is given a quantitative explanation in terms of a known theory of solvation. From this the vapour phase free energy differences [ΔG(aa→ee)] have been estimated as 0·9 and 1·5 kcal mol–1(II; X = Cl and Br) and 0·8 and 0·9 kcal mol–1(III; X = Cl and Br), i.e. in all cases the diaxial conformer is preferred in the vapour phase. In the trans-1,2-dihalogenocyclohexanes this is interpreted on the basis of steric (repulsive) X ⋯ X interactions in the diequatorial conformer. The extra stability of the diaxial conformer of (III), over that of the corresponding cyclohexyl halides is shown by calculations of both dipole–dipole and charge–charge interactions between the C–X bonds not to arise from this mechanism. Attractive 1,3-polar interactions between the positively charged axial hydrogen atoms and the axial halogens are shown to account for the stabilisation of the axial conformers in the 1,4-compounds.

Rotational isomerism. Part XIV. Medium effects on the conformational equilibria of halogenocyclohexanes

The calculation of the solvent dependence of the conformational equilibrium in mono- and di-chloro- and -bromo-cyclohexanes is given and compared with experiment. The calculations are based on an electrostatic theory of solvation and the model uses a fixed cyclohexane geometry and constant C–X bond dipole moment. The model gives generally good agreement with the observed dipole moments of all the chloro- and bromo-cyclohexanes. There is no solvent dependence in cyclohexyl halides but a large solvent dependence in trans-1,2-, cis-1,3-, and trans-1,4-dichloro- and -dibromo-cyclohexanes. The model provides a quantitative explanation of all the observed effects. This agreement allows the prediction of the vapour state energy differences in these systems. The diaxial conformer of trans-1,2-dichloro-(and dibromo-) cyclohexane is the preferred conformer in the vapour phase (ΔEv= 0·7 and 1·3 kcal mol–1 respectively) and this can be rationalised in terms of halogen–halogen repulsions. However, the diaxial conformer of trans-1,4-dichloro-(or dibromo-) cyclohexane is also the preferred conformer in the vapour phase (ΔEv 0·8 and 0·7 kcal mol–1 respectively), and this has no simple rationalisation. The energy differences for benzene as solvent are anomalous in these, as in all other related equilibria, and a method of allowing for this anomaly is given.

Dipole moments and molar Kerr constants of adducts of diene synthesis of fumaronitrile and maleonitrile with acyclic dienes

1. Adducts of maleonitrile with divinyl, 2,3-dimethylbutadiene, and isoprene were synthesized. 2. The dipole moments and molar Kerr constants of a number of dieyanocyclohexenes were measured. 3. Trans-4,5-dicyanocyclohexene-1 and its methyl derivatives exist in solutions in the form of mixtures of diaxial and diequatorial conformers with a predominance of the former.

Conformation of non‐aromatic ring compounds: Part 63. Conformational equilibrium in trans‐1, 2 dihalogenotetralins

AbstractThe conformational equilibrium in trans‐1,2‐dichloro‐ (I), trans‐2‐bromo‐1‐chloro‐ (II) and trans‐l,2‐dibromotetralin (III) is studied with the aid of dipole moments, NMR, infrared and Raman spectroscopy. It appears that the diaxial conformer strongly predominates in solution. The trend in ΔG° on replacing bromine by chlorine as the substituent or carbon tetrachloride by benzene as the solvent is the same as previously found in other vicinal dihalogeno‐substituted compounds. From the IR and Raman spectra it appears that the three compounds crystallize in the diaxial conformation.

Mechanism of cyclopolymerization. Conformational analysis of cis‐1,3‐diisocyanatocyclohexane

AbstractIn 1,3‐disubstitued cyclohexanes, in general, the diaxial conformation of the cis isomer is, energetically, the least favored conformation. An interspacial electronic interaction in the ground state of a cis‐1,3‐disubstituted cyclohexane would be expected to increase the proportion of this conformer in the equilibrium mixture. Such an interaction would provide an energetically favorable pathway for cyclopolymerization. From nuclear magnetic resonance studies on cis‐and trans‐1,3‐diisocyanatocyclohexane the conformational equilibrium in the cis isomer was determined. It is shown that cis‐1,3‐diisocyanatocyclohexane exists in the diequatorial conformation; this is taken as evidence that a ground‐state interaction between isocyanato groups in this monomer, which readily cyclopolymerizes, is not a significant factor in the cyclopolymerization mechanism. The value of the free energy barrier, ΔG‡, for trans‐1,3‐diisocyanatocyclohexane was calculated as 11.1 kcal/mole.

The conformation of non‐aromatic ring compounds. Part 39. Dipole Moments and Conformational Properties of some trans‐1, 2‐Dihalogenocyclohexanes and their alkyl derivatives

AbstractA number of trans‐1,2‐dihalogenocyclohexanes and their alkyl homologues have been synthesized and their dipole moments determined in carbon tetrachloride and in benzene. The diaxial conformation is found to be favoured except in cases of considerable syn‐diaxial crowding. From the dipole data of some 4‐methyl derivatives a “ΔG°e‐a” of 1.8 kcal/mole for the methylgroup has been calculated. Similar calulations have led to much lower ΔG°e‐a values in the case of 1‐alkyl derivatives: 0.6 kcal/mole for the methyl group and 1.1 kcal/mole for the ethyl group. Values of ∼ 3.5 kcal/mole have been calculated for the syn‐diaxial methyl ‐ bromine interaction in some 4,4‐dimethyl derivatives. Values of 2‐3 kcal/mole have been obtained for the corresponding methyl ‐ chlorine interaction.The magnitude of the aa ± ee equilibrium shift towards the ee form going from carbon tetrachloride to benzene as a solvent, seems to be characteristically constant (0.5 kcal/mole) in the case of the trans‐1,2‐dibromo(chloro)‐ cyclohexanes and ‐alkylcyclohexanes.

Conformation of non‐aromatic ring compounds: Part 55. Dipole moments, NMR spectra and conformation of trans‐2,3‐dihalogenotetralins

AbstractThe conformational equilibria in trans‐2,3‐dihalogenotetralins are studied with the aid of dipole moments and NMR spectroscopy. It is concluded that the diaxial conformer strongly predominates in solution. From the combination of dipole moment and NMR data the thermodynamic quantities ΔH0 and ΔS0 are calculated for the dichloro compound. A comparison is made with the results obtained earlier for other vicinal dihalogeno compounds.

Conformation of non-aromatic ring compounds—XLVII : The conformation of trans-1,2-dihalogenoindans

Dipole moments, NMR, IR and Raman spectra of trans-1,2-dihalogenoindans were determined. Linear relations were found to exist between the squares of the dipole moments and the vicinal proton spin coupling constants. It is concluded that the diaxial conformer predominates in solution.

Corticosteroid analogs Communication 15. Reactions of 1-acetyl-1-bromo-2-cyclohexanol and its acetate with carbazic ester

1. The reaction of the bromohydrin acetate (I) with carbazic ester goes stereospecifically, like its acetolysis, and leads to the cis acetate hydrazone (III) with inversion of configuration. 2. About 30% of the products of the analogous reaction of the bromohydrin (II) have the configuration of the starting compound. It is considered that these products arise as a result of the reaction of the bromohydrin (II) in the diequatorial conformation, whereas under these conditions the diaxial conformer gives products of inverted configuration. 3. The isolation of the monoacetates (III), (V), (VII), and (IX) from the reaction products indicates the high stability of the secondary acetoxy group, as compared with the tertiary, and therefore the occurrence of acyl migration in the 1-acetyl-1,2-cyclohexanediol series. 4. The probable mechanism of the transformations observed is discussed.

The conformation of non-aromatic ring-compounds—XXVII : The dipole moments of trans-aa-dihalogeno-4-t-butylcyclohexanes

Some trans-diaxial-1,2-dihalogeno-4-t-butylcyclohexanes have been synthesized and the dipole moments determined in carbon tetrachloride and in benzene at 25°. It is concluded that the diaxial conformer of trans-1,2-dibromo(chloro)cyclohexane probably has a dipole moment of 1·20 D.

Conformation of non‐aromatic ring compounds XXXI: Infrared and Raman Spectra of some trans‐1,2‐dihalogenocyclopentanes

AbstractThe infrared and Raman spectra of trans‐1,2‐dichloro‐(I), trans‐1‐bromo‐2‐chloro(II), trans‐1,2‐dibromo‐(III) and trans‐1,2‐dibromo‐1‐methylcyclo‐pentane(IV) were measured in carbon disulfide and in the neat liquid. From the properties of the bands assigned to the carbon‐halogen stretching frequencies it is concluded that the diaxial conformations predominate in solution, the halogen atoms occupying the most buckled part of the ring. The absorption bands of I are broader than those of III and IV. This seems to indicate that the ring geometry of I is less defined and that in compound I twisting of the ring in a pseudolibration movement occurs to a larger extent. From a comparison with the carbon‐halogen stretching frequencies in the analogous cyclohexanes several common features emerge.

Conformation of non‐aromatic ring compounds XXX: Dipole moments, NMR spectra and conformations of some trans‐1,2‐dihalogenocyclopentanes

AbstractThe dipole moments and NMR spectra of trans‐1,2‐dichloro‐ (I), trans‐1,2‐bromochloro‐ (II), trans‐1,2‐dibromo‐ (III) and trans‐1,2‐dibromo‐1‐methylcyclopentane (IV) in several solvents are reported. Special attention is given to the separation of the outer peaks in the low‐field part of the NMR spectra, due to the protons in the CHX‐moiety. This separation is equal to JAX + JBX and is shown to be correlated linearly with the square of the electric moment.It is proposed that the conformational properties of these molecules be described in terms of a solvent‐dependent dynamic equilibrium aa ⇌ ee, with the diaxial conformation predominating even in a highly polar solvent. Each of the two conformers may correspond to the half‐chair or the envelope model with the halogen atoms in the most puckered part of the ring. A limited pseudolibration about these forms is possible.

THE CONFORMATIONS IN SOLUTION OF trans-CYCLOHEXENE DIHALIDES AND cis- AND trans-1,2-CYCLOHEXANEDIOLS AND DERIVATIVES

trans-1,4,4-Trideuteriocyclohexene dichloride, dibromide, and diiodide and the 1,4,4-trideuterio-cis- and trans-1,2-cyclohexanediols together with their O-acetyl, O-tosyl, and O-isopropylidene derivatives were synthesized. Their nuclear magnetic resonance (NMR) spectral parameters were obtained with a spectrometer operating at 100 Mc.p.s. and employing double irradiation to establish the chemical shifts and the signs of the coupling constants. The interpretation of the data according to expectations based on the Karplus relationship, for dihedral angles and coupling constants, support the conformational equilibria assigned to the trans-dichloride and trans-dibromide of cyclohexene on the basis of dipole moment measurements (previously published results). The results indicate that trans-cyclohexene diiodide exists to about 84% in the diaxial conformation. In the case of the 1,2-cis-disubstituted cyclohexanes, the occurrence of the signal for the 3-hydrogen in trans relation to the 2-hydrogen at lower field than its geminal 3-hydrogen is assigned to the deshielding influence on the 3-hydrogen when in axial orientation by an opposing axial oxygen at the 1-position. Support for this contention was obtained by determination of the chemical shifts of the geminal hydrogens at the 3- and 5-positions of the cis- and trans-4-t-butyl-2,2,6,6-tetradeuterio-1-methylcyclohexanols. The conformational equilibria indicated for the 1,2-diol, 1,2-diacetoxy, and 1,2-ditosyloxy trans derivatives of 1,4,4-trideuteriocyclohexane by NMR parameters obtained from the spectrum of the O-isopropylidene derivatives of the trans-diol allowed conclusions regarding the non-bonded interaction energies involved. The Karplus relation had to be adjusted to the form, [Formula: see text] and [Formula: see text] to accommodate the results. Solvent effects on conformation are noted. Also, the investigation provided further evidence for the opposite signs of the coupling constants for geminal and vicinal hydrogens. A consideration of the chemical shifts observed for a variety of derivatives of cyclohexanol appears to indicate that intramolecular shielding effects are better accounted for on the basis of neighboring atomic groupings than on the basis of individual chemical bonds.

Stereochemical Studies of Monoterpene Compounds. I. The Conformation of (+)-p-Menthane-3,4-diol Obtained by the Performic Acid Oxidation of (+)-p-Menth-3-ene

Abstract The conformational analysis of (+)-p-menthane-3,4-diol, which had been obtained by the hydroxylation of (+)-p-menth-3-ene with performic acid in the presence of water, has been performed mainly by means of infrared spectra. It has been shown that the two hydroxyl groups at the C3- and C4-positions take a diaxial conformation, that they are, accordingly, trans to each other, and that the methyl group presumably holds an equatorial orientation. It has also been found that p-menthane-trans (diaxial)-2,3-diol results from the p-menth-2-ene coexisting in the sample of p-menth-3-ene. A stereochemical course of the hydroxylation reaction has been discussed.