Stereochemical applications of potential energy calculations

Journal of Molecular Structure (Theochem), 124 (1985) 325-333 Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands

STEREOCHEMICAL APPLICATIONS OF POTENTIAL ENERGY CALCULATIONS Part V. Conformational studies of some 1,1,24risubstituted molecular mechanics method (MM2)*

PETKO M. IVANOV**

ethanes by the

and STEFAN L. SPASSOV

Institute of Organic Chemistry with the Centre of Phytochemistry, Sciences, 1040 Sofia (Bulgaria)

Bulgarian Academy

of

EIJI ~SSAWA Department

of Chemistry,

Faculty

of Science, Hokkaido

University,

Sapporo

060 (Japan)

(Received 15 March 1985)

ABSTRACT The conformational distribution of some 1,1,2trisubstituted ethanes was studied by the molecular mechanics method. An overall satisfactory correlation with ex-perimental data is obtained, especially when these refer to experimental conditions excluding possible dimerization. INTRODUCTION

Substituted ethanes have been one of the central concerns of molecular mechanics since they represent one of the cornerstones of conformational analysis. Systematic studies have been made by several groups [2-51. We have also utilized empirical energy procedures mainly for the estimation of conformational preferences in a variety of 1,2-disubstituted-1,2-diphenylethanes [6]. In order to gain deeper insight into the important contributions of interactions establishing the preferred conformation, of particular significance the analysis of conformations of simpler systems, e.g., substituted phenylethanes and monosubstituted 1,2-diphenylethanes is important. This work presents a full relaxation molecular mechanics treatment of 1,1,2trisubstituted ethanes containing methyl and phenyl groups as well as polar substituents, and provides some information for the statiomer’s (stationary point conformations [7] (minima only in this case)) preferences of these systems in addition to previous conformational studies mainly by ‘H NMR [8-111. The molecules considered here contain the ABC proton system *For previous communications, see ref. 1. **To whom correspondence should be addressed. 0166-1280/85/$03.30

o 1985 Elsevier Science Publishers B.V.

326

with JAc, Jnc vicinal coupling constants of similar magnitude. In that case computed statiomer’s populations are not so reliable and treatment with empirical energy functions could provide useful information. The Allinger’s (1977) force field [ 121 was used in the calculations. RESULTS

AND DISCUSSION

Computed conformational data (main torsional angles and relative steric energies) are presented in Table 1. 2,3-Diphenylpropanoic

acid (1)

Compound 1 has been extensively studied by NMR [8, 131. Spectra in CDC13 at 100 MHz [8] gave 7.06 and 8.23 Hz for the vicinal proton-proton coupling constants (JAc and JBc, respectively), and this obviously points to significant participation in the equilibrium of at least two statiomers (I and II). Taking the values 12.0 and 4.0 Hz for the anti and gauche couplings Spassov et al. [8] estimated a 53% population of the statiomer with anti phenyls (I) and 38% for statiomer II. Following the assumption for an additivity of conformational effects and correlating with data for simpler

molecules the authors [8] arrived at values 3.35 kJ mol-’ for the gauche Ph/Ph, and 2.51 kJ mol-’ for the gauche Ph/COOH interactions. Our computational results are in a general agreement with the experimental data. The lowest energy is calculated for a local minimum of the anti statiomer (I) favoured mainly by a torsional energy contribution. Another local minimum with anti phenyls is 4.85 kJ mol” higher in energy above the global minimum and these two statiomers comprise a total of 73% population for this form. This value is slightly above the experimental estimate and it is not surprising in view of the general tendency of the MM2 force field to favour anti phenyl disposition [6]. A local minimum with anti Ph and COOH groups (II) is only 2.89 kJ mol-’ above the lowest energy form, I. This statiomer has the most advantageous nonbonded interactions, and together with other two local minima of II gave a total of 24% population for this form. III is represented by three local minima with conformational energies higher than 8.37 kJ mol-‘. Only a 3% population is computed for this statiomer.

327 TABLE 1 Computed data for statiomers of 1,1,2trisubstituted Statiomer

Torsional angles (degrees)b WI

2,3-Diphenylpropanoic acid (1) I.1 -175.5 I.2 -176.5 11.1 -59.7 II.2 -60.4 II.3 -52.5 III.1 51.8 3-Phenylbutyric IV.1 v.l VI.1 VI.2

acid (2) -17 1.4 -55.8 61.2 61.8

2-Methyl-3-phenylpropionic VII.1 -175.7 VIII.1 -54.8 IX.1 65.1 Ix.2 68.4 Ix.3 74.2 2-Phenylbutyric x.1 x1.1 x1.2 x11.1

ethanesa

acid (4) 59.8 169.6 172.4 -57.6

2-Phenylpropanol(5) x111.1 -174.7 XIV.1 -58.0 xv.1 64.2 xv.2 63.0 xv.3 74.2

WI

W3

70.5 72.2 98.7 97.3 102.9 92.5

110.9 119.0 106.5 107.2 113.9 91.0

-70.5 -68.4 -107.9 -103.9 acid (3) -90.4 -78.1 -87.8 -96.5 155.9

-107.9 -108.0 -118.1 -93.4

a.4

-114.2 95.9 -118.9 75.5 13.0 -126.2

Relative steric energy (kJ mol-I)

0.00 4.85 2.89 8.66 9.83 8.37

50.3 117.3 -2.9 98.3

4.64 0.00 3.98 5.52

90.5 114.3 82.5 -5.4 11.9

5.19 0.00 4.10 6.82 10.08

-4.3 -9.8 139.7 -2.1

0.00 2.30 6.90 6.03

-72.7 -67.0 -81.5 -83.0 166.8

2.01 0.00 2.85 6.19 8.07

2-Phenylpropyl methyl ether (6) x111.1 -173.8 -72.1 XIV.1 -57.9 -68.1 xv.1 64.7 -78.7 xv.2 73.4 168.8

2.30 0.00 2.80 7.91

2-Phenylpropylamine (7) XIII.1 -175.8 XIV.1 -59.5 xv.1 61.3 xv.2 62.8

3.31 0.00 5.53 6.74

-73.0 -66.6 -84.7 -89.3

328 TABLE 1 (continued) Statiomer

Torsional angles ( deg)b WI

2-Phenylpropyl chloride (8) -172.1 XIII.1 XIV.1 -59.8 xv.1 62.4

w1

W3

-88.8 -62.0 -99.1

W4

Relative steric energy (kJ mol-‘)

4.31 0.00 3.47

aThe results for the methyl esters almost parallel those for the acids and are not presented in the Table. Local minima with relative steric energies higher than 10.5 kJ mol-’ are also not included. bDefinition of main torsional angles: 1 - w1 = Car-C”--C”-Car, w2 = Ca’Ca’ (at CH,)w, = c”-Calc==o, 2 - W, = car-@-@ca’-cm, w, = C” (at CH,)-CB’-Car-C~, COOH, w2 = Car-Car-Ca’-@ (at CH ), wg = C”-CB’-C=O, 3 - w1 = Car--@-C”-wj = &(at CH,)-@-C=O, 4 - W, = C~-ca’-ca’-c”, COOH, w2 = Car-Car-C~-Cel, = p-p-_c~--@, wp = Ca’--cB’-C=O. For 5-8: w, = Car-@--@-X (X = OH, w2 (at CH,). OCR,, NH,, Cl), ~2 = Car-Car-@-@

The molecular mechanics calculations provide detailed information for the intramolecular interactions and it seems worth checking on this example the validity of the assumption for an additivity of conformational effects [8] . All vicinal group interactions of the lowest energy I and II statiomers are presented in Table 2. Besides the nonbonded energy contribution these also contain the torsional term for the bonds connecting interacting vicinal groups. The computed value for the gauche Ph/Ph interaction (estimated as a difference for the Ph/Ph interaction in II (gauche Ph/Ph) and I (anti Ph/Ph)) is 4.39 kJ mol-‘, and this value is close to the one obtained from the additivity scheme (3.35 kJ mol-’ [8] ). The H/H, COOH/H, and Ph/H gauche interactions, which are usually neglected, amount to ca. 1.3 kJ mol-’ for each pair. In our scheme they are comparable with the gauche Ph/COOH which only change slightly with rotationa round C(2)+!(3). This shows that an important assumption in the additivity schemes (neglecting gauche interactions involving H) is obviously not justified. Thus, additivity of intramolecular group interactions cannot generally be expected (see also ref. 14). On the other hand, it may also be noted that in the particular case of such 1,1,2trisubstituted ethanes the use of a revised set of additive parameters [15] leads to conformational predictions which are in good qualitative agreement with the results from the present calculations. 3-Phenylbutyric

acid (2) and methyl ester (2a)

The rotational isomerism of 3-phenylbutyric acid been studied by NMR spectroscopy [ 91. The results nance of the statiomer with phenyl and carboxyl groups in anti-position to each other (statiomer IV).

and its methyl ester has indicate some predomi(or methoxycarbonyl) ORD and CD data for

329 TABLE 2 Energies of group interactions (in kJ mol-I) of the lowest energy statiomers I and II of 1 Interaction Ph. * lPh Ph. * *COOH Ph.**HA Ph. ..HB Ph. .H, COOH.. . HA COOH. - -H, H,.*.H, H,...Hc l

I -2.176 -1.075 0.330 0.941 1.205 -0.469 0.473 0.741 -0.226

II 2.213 -1.473 0.515 -0.657 0.485 0.632 0.916 -0.226 0.849

COOR

COOR

COOR

IV

V

VI

R=HQl R=CH3(2pl

the acid [ 161 has, however, been interpreted in favour of the statiomer with gauche Ph and COOH groups (V). The authors observed a strong Cotton effect at 220 nm probably due to n + n * transition in the carboxyl chromophore, enhanced by the interaction between the n-electron systems of the carboxgl and phenyl groups. Our results, which are relevant to an isolated molecule, are in very close agreement with the interpretation of the CD spectra [ 161. For the acid (2) and the methyl ester (2a) the computed lowest energy conformer has gauche phenyl and carboxyl chromophores (statiomer V). The form VI of 2 and 2a with two gauche-interactions which is usually excluded from consideration [9, 161 is represented by two local minima with relative energies 4-5 kJ mol-i above V. The form IV as depicted to be the preferred one by NMR [9] is almost of the same energy as VI for 2 and more than 9.0 kJ mol-1 higher than V for 2a. Form V has the most advantageous nonbonded and bond-angle deformation contributions while VI is mainly enhanced by torsional contribution. The small energy difference between statiomers of the acid could probably allow a shift of the conformational equilibrium to IV on dimerization which could take place at concentrations used for the NMR measurements [ 91.

330

2-MethyL3-phenylpropionic

acid (3) and methyl ester (3a)

Compounds 3 and 3a are structurally similar to 2 and 2a, respectively. Accordingly, the experimental data (NMR [lo] and CD [16] ) and our computational results parallel those for the 3-phenylbutyric acid/ester system. The NMR estimates slightly favoured statiomer VII [lo] while CD spectra were interpreted in the sense of through space interacting gauche carboxyl and phenyl chromophores [ 161. With the acid (3) and the methyl ester (3a) we computed the lowest energy for statiomer VIII, while form VII is more than 5.0 kJ mol-’ higher in energy. Statiomer IX which, from qualitative COOR

COOR

COOR

considerations, is the most sterically crowded one has relative energies 4-10 kJ mol-‘. Nonbonded interactions and bong-angle deformation contributions are, again, important factors to enhance population of statiomer VIII. This statiomer has the planes of the chromophores almost parallel to each other. As was the case with 3-phenylbutyric acid (2), a possible dimerization of form VII (i.e., phenylgroups far from the complexing sites) cannot be excluded under the conditions of the NMR experiment. 2-Phenylbutyric

acid (4) and methyl ester (4a)

The geminal disposition of a bulky phenyl group with respect to COOH in this case probably prevents dimerization and it is reasonable to expect better COOR

COOR

COOR

R=H(W

correlation of our calculational results with NMR data [lo] . Only a 2.30 kJ mole1 difference between the lowest energy statiomers X (global minimum) and XI is calculated both for the acid (4) and the methyl ester (4a) in agreement with an equal population of these forms estimated by NMR [lo] .

331

2-Phenylpropyl (7), Cl (6))

derivatives (CH,CHCfl,CH,X,

X = OH (5), OCH3 (6), NH2

The conformational distribution of these molecules has been studied by NMR [ll] and IR [ll, 171 spectroscopy. The results were interpreted in favour of the statiomer with methoxy- or chloro-groups anti to the phenyl group (XIII), but the amino group anti to the methyl group (XIV). For the alcohol both forms were estimated (by NMR and IR) to be equally populated, while LIS evidence is in favour of form XIV [ 111. The molecular mechanics analysis is in a general congruence with the experimental observations. For the alcohol (5) statiomer XIV is only 2.01 kJ mol-’ lower in energy than XIII. The sterically crowded form 5-XV also has comparatively low conformational energy (2.9 kJ mol-‘). Obviously, all three forms participate in the conformational equilibrium. Replacement of the hydroxyl proton by a methyl group (5 + 6) virtually does not change this picture. Here again statiomer XIV is computed to be the lowest energy form. In agreement with NMR and LIS data [ 111 and with results from empirical

energy calculations [ 181 the most populated form for the amine (7) has anti amino and methyl groups (XIV). Statiomer XIII in this case is 3.31 kJ mol-’ above the global minimum. For 2-phenylpropyl chloride (8) thegauche disposition of Cl to Ph (statiomer XIV) is calculated to be 4.3 kJ mol-’ more advantageous than anti XIII while NMR estimates [ 111 yielded 60% population for the latter form. This only significant deviation between experimental and computed data for the 1,1,2-trisubstituted ethanes considered here can partly be attributed to not completely satisfactory parametrization when halogens are considered. Torsional energy parameters for the unit Cl---C”‘Cal-Car which were missing in the original MM2 force field were assigned those for C1-Ca’-C”‘-Ca’. CONCLUSIONS

Detailed structural and energy information for 1,1,2-trisubstituted ethanes was obtained by the molecular mechanics method. The computational results are generally in satisfactory agreement with the experimental findings. Slight discrepancies observed in some cases could partly be attributed to not completely satisfactory parametrization (1 and 8), and possible dimerization at the conditions of the experimental measurements (2 and 3). The Ph/COOH

332

interaction in 1 is almost unaffected by the rotation around C(Z)-C(3). Face-to-face Ph/COOR disposition was found to be common for all of the lowest energy forms of compounds l-3. For 1 the reason is probably that Ph/Ph prefers to be anti; for 2 and 3, softer gauche Ph/COOR than gauche CH,/COOR (for 2) and gauche Ph/CHB (for 3) interactions. An analysis of the intramolecular group interactions of 1 demonstrated that the assumption of an additivity of conformational effects should not be expected to be fulfilled in all cases. ACKNOWLEDGEMENTS

The major part of this work was carried out during a visit of one of the authors (P. M. I.) to the Department of Chemistry, Hokkaido University (Japan) in 1983-1984. Computations were done at the Computing Centers of the Institute of Mathematics and Mechanics (Bulgaria) and of the Institute of Molecular Science (Japan). We acknowledge postdoctoral fellowship support from the Ministry of Education of Japan. REFERENCES 1 P. M. Ivanov, J. Chem. Res., 1985, (S)86; (M)1173. 2P. Finocchiaro, D. Gust, W. D. Hounshell, J. P. Hummel, P. Maravigna and K. Misiow, J. Am. Chem. Sot., 98 (1976) 4945; W. D. Hour&e& D. A. Dougherty, J. P. Hummei and K. Misiow, J. Am. Chem. Sot., 99 (1977) 1916; D. A. Dougherty, K. Misiow, J. F. Blount, J. B. Wooten and J. Jacobus, J. Am. Chem. Sot., 99 (1977) 6149; D. A. Dougherty, F. M. Llort, K. Mislow and J. F. Blount, Tetrahedron, 34 (1978) 1301; W. D. Hounshell, D. A. Dougherty and K. Mislow, J. Am. Chem. Sot., 100 (1978) 3149; S. G. Baxter, D. A. Dougherty, J. P. Hummel, J. F. Blount and K. Mislow, J. Am. Chem. Sot., 100 (1978) 7795; K. Mislow, D. A. Dougherty and W. D. Hounshell, Bull. Sot. Chim. Belg., 87 (1978) 555; D. A. Dougherty and K. Mislow, J. Am. Chem. Sot., 101 (1979) 1401; S. G. Baxter, H. Fritz, G. Hiiimann, B. Kitschke, H. J. Lindner, K. Mislow, C. Riichardt and S. Weiner, J. Am. Chem. Sot., 101 (1979) 4493; C. H. Bushweller, W. G. Anderson, M. J. Goldberg, M. W. Gabriel, L. R. Giiliom and K. Misiow, J. Org. Chem., 45 (1980) 3880. 3 G. Favini, M. Simonetta and R. Todeschini, J. Am. Chem. Sot., 103 (1981) 3679. 4C. Riichardt and H. D. Beckhaus, Angew. Chem., Int. Ed. Engl., 19 (1980) 429; G. Hellmann, S. Hellmann, H. D. Beckhaus and C. Riichardt, Chem. Ber., 115 (1982) 3364; H. D. Beckhaus, Chem. Ber., 116 (1983) 86; W. Barbe, H. D. Beckhaus, H. J. Lindner and C. Riichardt, Chem. Ber., 116 (1983) 1017; W. Barbe, H. D. Beckhaus and C. Riichardt, Chem. Ber., 116 (1983) 1042; 116 (1983) 1058; K. H. Eichin, H. D. Beckhaus, S. Hellmann, H. Fritz, E. M. Peters, K. Peters, H. G. von Schnering and C. Riichardt, Chem. Ber., 116 (1983) 1787. 5 M. I. Watkins and G. A. Olah, J. Am. Chem. Sot., 103 (1981) 6566; G. Bernardinelli and R. Gerdii, Helv. Chim. Acta, 64 (1981) 1372. 6P. M. Ivanov and L. S. Trifonov, J. Mol. Struct. (Theochem), 124 (1985) 239, and reference cited therein. 7 0. Ermer, Aspekte von Kraftfeldrechnungen, Wolfgang Baur VerIag, Miinchen, 1981; 0. Ermer, Angew. Chem. Int. Ed., 22 (1983) 998; Suppl. 1983,1353; 0. Ermer, P. M. Ivanov and E. bsawa, J. Am. Chem. Sot., submitted. 8 S. L. Spassov, A. S. Orahovats, S. M. Mishev and J. Schraml, Tetrahedron, 30 (1974) 365.

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