Conformational Studies of a Six-Membered Phostone

Abstract

Although 1,3,2-dioxaphosphorinanes generally assume chair conformations,¹ there are examples in which the ring adopts the boat or twist-boat form.¹ Recent studies on the synthesis, stereochemistry, and reactivity of 2-alkoxy-2-oxo-1,2-oxaphosphorinanes (phostones) have revealed both cis and trans isomers of 3-(diphenylhydroxymethyl)-2-ethoxy-2-oxo-1,2-axaphosphorinane² to assume a chair conformation in the solid state. In the present work, the conformational properties of cis and trans-3-methoxycarbonyl-2-methoxy-2-oxo-1,2-oxaphosphorinanes were investigated by X-ray analysis, variable temperature ³¹P, ¹H and ¹H{³¹P} NMR spectroscopy, molecular mechanics, and semiempirical calculations. The X-ray crystal structure of the trans isomer revealed a chair dormation with equatorial phosphoryl and carbomethoxy groups. No changes were observed in the ³¹P NMR spectra of either isomer in the temperature range of 183–333 K. A complete set of vicinal J_HH coupling constants was extracted from the ¹H{³¹P} spectra of each isomer taken at five temperatures over the range of 213–293 K and refined by simulation of the spectra. The best-fit analysis of this data using a generalized Karplus equation³ revealed that the conformation of the trans isomer in solution was close to that found in the solid state. This conformation corresponded to the global energy minimum calculated by both molecular mechanics and PM3 semiempirical method. A substantial contribution from an inverted chair conformation of the cis isomer had to be assumed to achieve a reasonable fit of the coupling constants calculated from the generalized Karplus equation.     

Conformational analysis of <Emphasis Type="Italic">cis-</Emphasis> and <Emphasis Type="Italic">trans</Emphasis>-isomers of 2,5-dimethyl-1,3-dioxane

The conformational isomerization of cis- and trans-isomers of 2,5-dimethyl-1,3-dioxane was investigated by means of ab initio RHF//6-31G(d) and PBE//ccpVDZ quantum-chemical methods. It has been shown that in comparison with cis-form the potential energy surface of trans-isomer has a less number of stationary points and includes the main minimum belonging to the diequatorial chair form. In the case of cisisomer the main minimum corresponds to the C 2e5a chair form. The values of potentional barriers of conformational isomerization were also determined. On the basis of experimental (NMR ¹H) and theoretical vicinal coupling constants we determine the value ΔG ⁰ of chair-chair inversion for the trans-isomer molecule.     

Déplacements chimiques induits en RMN par un réactif lanthanidique: I—Application á l'analyse conformationnelle de sulfites cycliques

The chemical shifts induced by Eu(fod)₃ in several series of 6-membered cyclic sulfites give the parameters K_c and Δ_SR of the complexation equilibrium for an assumed 1:1 stoicheiometry. The equilibrium constant K_c decreases with increasing bulk of the C-4 and C-6 substituents and polarity of the C-5 substituent, which corresponds to the increase of the i.r. stretching frequency vS?O. Thus axial S?O will be more tightly complexed than equatorial S?O. It can be predicted that when a conformational equilibrium exists without shift reagent, displacement towards an axial S?O form will occur with the reagent. Use of the Δ_SR pseudocontact equation confirms the following: (i) ax S?O chair forms are stabilized; (ii) eq S?O chairs with two eq C-4 and C-6 substituents show an equilibrium with a few percent of the ax S?O flexible conformation, particularly in the absence of an ax C-5 substituent; (iii) twist forms with a 2–5 axis, intermediate S?O and trans-4, 6-di-tert-Bu substituents give a boat form with O at the prow and ax S?O; (iv) the conformational equilibrium of trans-5-tert-butyl-2-oxo-1, 3, 2-dioxathiane (chair with ax tert-Bu and S?O ? 70%) is completely displaced towards that form; (v) cis-4,4,6-trimethyl-2-oxo-1,3,2-dioxathiane, which exists as an equilibrium in which the three types of S?O occur, is complexed essentially in the twist form with a 1–4 axis and ax S?O. Most of these results are supported by the coupling constants analysis for the ratio R₀/S₀ = 1.     

Stereochemistry of organophosphorus cyclic compounds—II : Stereospecific synthesis of cis- and trans 2-halogeno-2-oxo-4-methyl-1,3,2-dioxaphosphorinans and their chemical transformations

cis- and trans-2-Chloro-2-oxo-4-methyl-1,3,2-dioxaphosphorinans have been obtained by stereospecific reactions of diastereomerically pure 2-methoxy-4-methyl-1,3,2-dioxaphosphorinans or 2-hydrogen-2-oxo-4-methyl-1,3,2-dioxaphosphorinans with chlorine and sulphuryl chloride, respectively. Similarly, the action of the corresponding brominating agents on isomeric phosphites and phosphonates afforded pure cis- and trans-2-bromo-2-oxo-4-methyl-1,3,2-dioxaphosphorinans. It has been shown that halogenolysis proceeds with retention of configuration at the P atom. On the basis of the ¹H- and ³¹P-NMR spectra conformation of the halogenoanhydrides obtained has been discussed briefly.It has been also found that model nucleophilic substitution reactions occur with inversion of configuration at the P atom in the cyclic halogenoanhydrides.     

Ring conformations of 2-substituted 2-oxo-4-methyl-1,3,2-dioxaphosphorinanes. Evidence for a boat conformation in equilibrium with two interconverting chairs

The 220 MHz proton NMR spectra of three isomeric pairs of 2-R-2-oxo-4-methyl-1,3,2-dioxaphosphorinanes, where R = methoxy (1a, b), methyl (2a, b) and dimethylamino (3a, b) (a represents the trans and b the cis arrangement of R and the 4-methyl group) were analyzed by iterative computer techniques. Ten ring conformations, two chairs, two half-chairs and six boats were initially considered as being possible contributors to the overall solution conformations. Compounds 1a, 2a, 2b and 3b were all concluded to exist as single chair conformations with the 4-methyl group equatorially oriented (eqch). In addition to 68% of compound 3a being in that eqch conformation, however, significant concentrations of the chair form containing an axially oriented 4-methyl group (axch, 16%) and a boat conformation containing an equatorially oriented 4-methyl group with phosphorus and C-5 serving as the bow and stern (eq25, 16%) were also postulated. Similarly, it was suggested that 1b contained 60% eqch, 20% axch and 20% of the boat eq25. From the data for compounds 2a and b it was concluded that in the chair conformations of 2-oxo species the phosphorus substituent orientation has little effect upon the ³J(POCH) coupling constants.     

Spectral analysis of the high-resolution proton-coupled carbon-13 NMR spectra of 1,3,2-dithiarsolanes

The high-resolution proton-coupled ¹³C NMR spectra of 2-chloro- and 2-phenyl-4-methyl-1,3,2-dithiarsolane and 2-chloro- and 2-phenyl-1,3,2-dithiarsolane have been obtained and completely analysed. The spectral analysis has provided all the ¹³C chemical shifts and ¹³C? ¹H coupling constants, including their relative signs. The results of this work are adequately interpreted in terms of two rapidly equilibrating half-chair conformers with the 4-methyl pseudo-axial or pseudo-equatorial. The cis isomers appear to be conformationally biased towards the form with the 4-methyl pseudo-equatorial. The two one-bond ¹³C? ¹H coupling constants of the methylene group are distinctly different. For both the cis and trans isomers, the largest one-bond coupling always involves the methylene proton situated syn to the substituent at arsenic. The observed variation in the geminal and vicinal ¹³C? ¹H coupling constants are discussed in terms of a stereospecific inductive effect of the sulphur hetero-atoms and conformational factors.     

Conformational analysis of stereoisomers of 2,4-dimethyl-5-isopropyl-1,3,2-dioxaborinane

The investigation of conformation conversions of cis- and trans-isomers of 2,4-dimethyl-5-isopropyl-1,3,2-dioxaborinane using ab initio quantum-chemical approximation HF/6-31G(d) and the hybrid DFT-method PBE/3z showed that the routes of the transformations presuppose an equilibrium between sofa conformers with the different orientation of substituents at the atoms C⁴ and C⁵ of the ring that convert into each other through transition states corresponding to the equatorial and axial conformations of the 2,5-twist form. Based on experimental data of ¹H NMR spectra and calculated vicinal spin-spin coupling constants the quantitative conformational composition of cis- and trans-isomers was established and also the ΔG^o value of the conformation equilibrium was determined.     

1H-NMR-Spektroskopische Untersuchungen zur Konformation von Cyclohexandicarbonsäure-(1,2)-anhydriden

¹H NMR chemical shifts of 18 methyl substituted cyclohexane-1,2-dicarboxylic anhydrides were determined. In compounds with asymmetric substitution vicinal coupling constants were measured. In the series of trans-anhydrides it can be deduced from the NMR data, that the 6-membered ring has a chair-like conformation. Additionally, in the series of the cis-anhydrides a twisted chair conformation is favoured for the most part.     

Application of the temperature dependence of vicinal spin-spin coupling constants to the investigation of the configuration of substituents in saturated 5-membered rings

Temperature dependence of cis- and trans-vicinal spin-spin coupling constants of substituted cyclic 5-membered compounds is discussed. The temperature dependence of trans-vicinal coupling constants is shown to be essentially stronger than that of cis-vicinal coupling constants if the energies of the conformers corresponding to potential energy curve minima are different. The temperature dependence of 33 vicinal spin-spin coupling constants has been studied for di- and trisubstituted thiophanes with a known configuration of substituents. Experimentally determined changes of trans-vicinal coupling constants with temperature are markedly larger than those for cis-vicinal coupling constants, whose values, in most cases, are practically temperature independent. Differences in the temperature dependence of cis and trans-vicinal spin-spin coupling constants can be applied for the determination of the configuration of substituents in saturated 5-membered rings.     

Stereochemistry of alkyl 3-substituted 4-halotetrahydro-2-oxo-3-furancarboxylates: 2—1H and 13C NMR spectra

The ¹H NMR parameters of methyl 3-substituted cis-4-halotetrahydro-2-oxo-3-furancarboxylates are reported, with assignments of the ring protons based on solvent-induced changes in the vicinal trans coupling constants, ³J(H-4, H-5). Preferred conformations, ce with a pseudo-equatorial halogen for the cis isomers and ta with a pseudo-axial halogen for the trans isomers, have been suggested on comparison of the magnitudes of J(trans) and J(gem) in both series. The ³J(¹³CH₃, H-4) values measured for methyl cis-4-bromotetrahydro-3-methyl-3-furancarboxylate, methyl trans-4-bromotetrahydro-3-methyl-3-furancarboxylate and trans-3,4-dibromodihydro-3-methyl-2(3H)-furanone have confirmed the stereochemical assignments.     

Analyse Conformationnelle par RMN du Proton des Oxo-2 Oxathiazannes-1,2,3 (Sulfinamates Cycliques) Diversement Substitués en 3, 4 et 6

In this study, carried out with 16 compounds, the chair form with an axial S?O group (CA) is found, in the absence of C-4, C-5 and C-6 substituents, to be the most stable (ΔG>8,4 kJ mole^?1), as previously reported for analogous cyclic sulfites. When methyl or tert-butyl substituents are present on the 4 and 6 carbon atoms, the conformation of the ring depends on their respective orientation towards the S?O group, and on the nature of the substituent of the nitrogen atom. For the trans isomers, the conformation remains anancomeric chair (CA) except when important gauche interactions exist: thus the strong Me/tBu gauche interaction in the 3-tert-butyl-4-t-methyl-2-r-oxo-1,2,3-oxathiazan induces a twist form with a 3,6-axis and an axial S?O group (CNA). When the 4- or 6-substituent is cis, the conformation of the sulfinamate may be either a chair form with an axial S?O group (CA), if the 4-substituent is a methyl, (even with a tert-butyl group in the 3-position which would be in the axial orientation) or a twist form with a 1,4-axis and an axial S?O group (COA) if the 4-substituent is a tert-butyl. Unlike cyclic sulfites, the equatorial SO chair form (CE) and the twist forms with a 2,3-axis and an isoclinal S?O group (CS, CS′) are rarely involved.     

Interactions intramoléculaires: XXIII—Constantes de couplage et interactions gauches avec un groupement t-butyle (cyclohexanones disubstituées 3, 4)

The ¹H NMR spectra of a series of cis and trans-3R,4 X-cyclohexanones (-2,2,6,6-d₄) are analysed. By comparison of their ³J coupling constants with those of cyclohexane homologues we obtain information about the chair–chair equilibrium constants for R = CH₃, X = CN, the chair structure of cis isomers with an equatorial t-butyl group, and a conformational heterogeneity with trans (CH₃)₃C and CN groups. This latter situation is analysed by means of a simplified but controlled Karplus relationship, on the basis of a mixture of two conformers; this involves a diequatorial chair and a boat form with a dihedral angle Φ₃₄ of about ?6°.     

Conformational analysis—XXI : H NMR Conformational Study of Alkyl-Substituted 2-Oxo-1,3,2-Dioxathianes

2-Oxo-1,3,2-dioxathiane and all methyl- and several alkyl-substituted 2-oxo-1,3,2-dioxathianes were prepared for a ¹H NMR conformational study. The conformational energy of the axial SO group in CCl₄, - ΔG^θ_SO = 14.8±0.3kJ mol^?1, was determined by chemical equilibration of the epimeric cis-4,6-dimethyl derivatives and it was found to decrease with the increasing solvent polarity. The conformational equilibria of alkyl-substituted derivatives were solved and the proportions of the conformers estimated using ¹H NMR chemical shifts, vicinal coupling constants and in three cases also dipole moments. The configurational interactions in the C₄C₅C₆ moiety are close to the corresponding values of 1,3-dioxanes.     

A study of 5-membered ring conformations by the temperature dependence of the vicinal spin–spin coupling constants. Conformations of cis- and trans-isomers of 4-benzoylamino-3-acetoxythiophane

Conformational equilibrium in cis- and trans-4-benzoylamino-3-acetoxythiophanes has been analysed on the basis of the temperature dependence of the vicinal spin–spin coupling constants. The conformations of the compounds have been established. It has been shown that in problems of this kind the real accuracy of the experiments corresponds to a wide range of spin-spin coupling constant values and differences between the conformer energies. To narrow the range, additional data have been used, such as the temperature dependence of other vicinal coupling constants in the same molecule, angular dependence of the vicinal constants, etc.     

Interactions intramoléculaires. XXVII—Etudes structurales en série bicyclo[4.1.0]heptanique (effets d'anisotropie sur les déplacements chimiques du proton; constantes de couplage et équilibres conformationnels)

All the ¹H n.m.r. parameters of the following derivatives of 1,6-dimethylbicyclo[4.1.0]heptane are determined: 3,4-dimethoxycarbonyl (3 diastereoisomers), cis- and trans-3-methoxycarbonyl-2,2,5,5-d₄, cis- and trans-3-methyl-3-methoxycarbonyl; the cis- and trans-1,5,5-trimethylbicyclo[4.1.0]-3-heptanols are studied in the same way. The different chemical shifts are correlated with the aid of a collection of empiral increments. The conformational equilibria are determined from the vicinal coupling constants; the conformational free energies of the COOCH₃ group are evaluated; the part played by gauche interactions is considered.     

Conformational analysis of 7-membered dimethyl cyclic sulphites: 2-Oxo-1,3,2-dioxathiepanes and 3-oxo-2,4,3-dioxathiepins

2-Oxo-1,3,2-dioxathiepanes and 3-oxo-2,4,3-dioxathiepins, including two series of three diastereoisomers, were synthesized, isolated by HPLC and characterized by ¹H and ¹³C NMR spectroscopy. Their conformational behaviour was studied using a computer-assisted LIS technique and, for c-4, t-7-dimethyl-2-oxo-1,3,2-dioxathiepane, a 400 MHz spectral analysis. Single twist-chair conformations or an equilibrium between them are the most stable in the dioxathiepane series while chair or twist-boat forms, or both in equilibrium, are favoured in the dioxathiepin series. Conformations and equilibria are detailed, with and without LSR, taking into account ¹H coupling constants and IR S?O stretching frequencies as conformational probes.     

1H and 13C NMR studies on 1,3,2-dioxarsolanes

The ¹H and ¹³C NMR spectra of a series of 1,3,2-dioxarsolanes have been obtained at 2.1 T and some at 9.4 T. The chemical shifts and spin-spin coupling constants have been obtained from complete spectral analyses of the ¹H and proton-coupled ¹³C spectra. The spectral data are interpreted on the basis of two rapidly interconverting half-chair conformers with a pseudoaxial substituent at arsenic. Unique assignment of syn/anti or cis/trans geometries have been made from ¹H or ¹³C NMR spectroscopy alone. The syn and trans isomers of the 4-methyl- and 4,5-dimethyl-1,3,2-dioxarsolanes, respectively, appear to be conformationally biased towards the forms with pseudoequatorial methyl groups. The general trends in the geminal and vicinal ¹H? ¹H and ¹³C? ¹H coupling constants are interpreted in terms of stereospecific, electronegativity and lone-pair effects of the oxygen heteroatoms and conformational factors. The NMR data on the 1,3,2-dioxarsolanes are discussed with reference to related 1,3-dithoxa- and 1,3-dithia- five-membered rings with As, P, S or C at the 2-position.     

Conformational Analysis. XIX properties and reactions of 1,3-oxathianes VIII A 1H NMR conformational study of methyl-substituted derivatives

The addition of thioacetic acid to unsaturated alcohols or acids was utilized to obtain mercaptoalkanols which were condensed with suitable carybonyl compounds to prepare 24 methyl-substituted 1,3-oxathianes. The ¹H NMR spectra of the 1,3-oxathiane products were recorded at 60, 100 and/or 300 MHz and fully analysed. The results are best explained by a chair form which is completely staggered in the C-4? C-5? C-6 moiety ψ₄₅ or (ψ₅₆=60±1°). 1,3-Oxathianes having syn-axial 2,4- (and/or 2,6-) methyl-methyl interactions exist appreciably, if not exclusively, in twist forms. The vicinal coupling constants lead to the conformational free energies of axial methyl groups at C-4, ΔG°=7.4±0.4 kJ mol^?1, and at C-5, ΔG°=3.7±0.3 kJ mol^?1, in good agreement with previous estimates. They also show that both r-4,cis-5,trans-6- and r-4,trans-5,trans-6- trimethyl-1,3-oxathianes greatly favour the chiar form where the methyl group at C-4 is axial. The chair-twist energy parameters are reestimated at ΔH°_CT 27.0 kJ mol^?1, ΔS°_CT 11.6J mol^?1K^?1, and ΔG°_CT(298) 23.5 kJ mol^?1 for a 2,5-twist form.     

Interactions intramoleculaires. XXI—Constantes de couplage et interactions gauches avec un groupement t-butyle (molécules cyclohexaniques deutériées)

Different isotopic modifications of deuterated products of 1-t-butlyl-4-methoxycarbonyl cyclohexene (d₄-3,3,6,6), cis- and trans-3-methyl-4-cyanocyclohexene (d₃-3,6,6), cis- and trans-3-methyl-4-cyanocyclohexene (d₃,6,6), cis- and trans-3-t-butyl-4-methoxycarbonylcyclohexene (d₃,-3,6,6) are shown by nuclear magnetic resonance spectral analysis. By comparison of ³J and ⁴J coupling constants of model molecules and molecules with large gauche interactions, we obtain proof that the latter are in a chair conformation with moderate cycle deformations.     

Spectroscopic studies on olefins—III: NMR of cis- and trans- disubstituted olefins

The proton NMR spectra of four cis/trans pairs of 1,2-disubstituted olefins have been analysed. The observed trends of the olefinic, vicinal and allylic proton-proton coupling constants are discussed in terms of rehybridization at the sp² carbon atoms. It is found that in these substances the trans-allylic couplings are generally more negative than the cis-allylic couplings contrary to Barfield's¹ theoretical prediction but in agreement with some earlier experimental data. Steric hindrance between cisoid substituents is cited as the probable origin of this end related trends.