Conformational studies of 2-methyl-3-phenylpropionic acid, 2-phenylbutyric acid and their methyl esters by NMR spectroscopy

Journal o f Molecular Structure, 53 (1979) 219--224 © Elsevier Scientific Publishing Company, Amsterdam -- Printed in The Netherlands

CONFORMATIONAL STUDIES OF 2-METHYL-3.PHENYLPROPIONIC ACID, 2-PHENYLBUTYRIC ACID AND THEIR METHYL ESTERS BY NMR SPECTROSCOPY

S. L. SPASSOV and R. STEFANOVA

Institute o f Organic Chemistry, Bulgarian Academy of Sciences, 1113 Sofia (Bulgaria) (Received 26 July 1978)

ABSTRACT The conformational distribution of P h C H 2 C H ( C H 3 ) C O O R and C H 3 C H 2 C H ( P h ) C O O R (R = H, CH3) has been studied by N M R spectroscopy. In the former case the conformer with the phenyl and carboxyl (or methoxycarbonyl) groups in the anti position relative to each other is favoured. For 2-phenylbutyric acid and its ester the forms with the methyl group gauche to phenyl or C O O R are almost equally represented. The validity of the additive gauche-interaction scheme for prediction of conformational distribution in substituted ethanes is also discussed. INTRODUCTION

In a series of papers [1--4] the conformational equilibria in some 1,1,2-trisubstituted ethanes containing, among others, phenyl, methyl and COOR (R = H, CH3) substituents, have been studied. The compounds investigated in the present work, PhCH2CH(CH3)COOH (1), PhCH2CH(CH3)COOCH3 (la), CH3CH2CH(Ph)COOH (2), CH3CH2CH(Ph)COOCH3 (2a), (see Fig. 2) contain the same groups, but in different structural relation to each other. In this way, we expected to obtain more detailed information concerning the effect of the substituents upon the conformational distribution, as well as to test the possible additivity of non-bonded interaction energies in such systems [ 1]. RE S UL TS AND DISCUSSION

The NMR spectra of 2-methyl-3-phenylpropionic acid (1) and its methyl ester (la) were measured at 220 MHz. The methine multiplet is interposed between the quartets of the methylene AB-subspectrum. The spectra of 2-phenylbutyric acid (2) and its methyl ester (2a) were taken at 100 MHz using the double resonance technique. Irradiation of the methyl protons led to considerable simplification of the spectrum (Fig. 1), permitting the treatment of the CH2CH fragment as an ABC system. The analysis of the spectra was performed by use of the program LAOCOON-3 adapted for an

220

2~o

35~-0 - -

Fig. 1. 100-MHz spectra of the CHf--CH protons in CH3CH:CH(Ph)COOH. Bottom: normal spectrum. Top: with CH3 irradiation.

ICL-1904 A computer. The aliphatic protons of compounds (1) and (la) were regarded as an ABCD3 system. The final parameters are shown in Table 1. The three staggered conformers of compounds (1), (la), (2), (2a) are presented in Fig. 2. The two dominating conformers are expected to be I and II, TABLE 1 NMR parameters of PhCH,CH(CH3)COOR (at 220 MHz) and CH3CH~CH(Ph)COOR (at 100 MHz) a

vA vB vc "D

JAB

JAC JBC JAD

(1)

(la)

(la)

(lb)

(2)

(2a)

(2a)

(2b)

Solvent CDCI~

Solvent CDC13

Solvent CD3OD

Solvent CDCI3

Solvent CDCI3

Solvent CDCI3

Solvent CD3OD

Solvent CDC13

676.08 -+0.04 585.08 -+0.07 606.32 ¢0.09 253.52 -+0.05 --13.53 -+0.08 6.51 -+0.11 8.05 +-0.14 0.02 +-0.06

665.27 +-0.03 584.79 +-0.06 607.91 +-0.14 250.71 +0.03 --13.36 -+0.10 6.76 -+0.07 7.94 -+0.10 --0.13 -+0.04

647.38 -+0.04 588.24 -+0.06 604.10 +-0.08 244.16 -+0.04 --12.70 +-0.08 6.96 +-0.08 7.19 +-0.08 ---0.06 -+0.04

673.20

201.96 •+0.05 173.39 +-0.05 335.85 -+0.04

207.72 -+0.04 177.99 -+0.05 341.05 -+0.05

242.18 -+0.05 212.02 -+0.05 384.05 -+0.08

200.00

--13.72 ±0.06 7.72 +-0.06 7.35 +-0.06

--13.53 -+0.05 7.98 -+0.06 7.58 +-0.06

--14.41 +-0.06 7.81 +-0.09 7.98 ±0.08

JBD

---0.18

--0.18

---0.18

JCD

+-0.07 6.77 +-0.08

+-0.04 6.47 +-0.06

-+0.04 6.93 +0.05

585.2

172.0

aConcentration 2 M. Abbreviations used are A, B: CH 2 protons; C :CH proton; D :CH 3 protons. Chemical shifts are in Hz relative to internal TMS.

221

COOR R=H(1) HA ~.t... HB R=CH3(Io) HC- "T CH3

P.

COOR Ph.~HA

. ~ HB

Ph

HC" T ~CH3

HC "l"

CH3

Ne

I

C00R

R:H(Z~ H A ~ %

HA

II

III

CH3~HA C00R

CH3

C00R

"B-.~CHs

HB

HA

Fig. 2. Staggeredconformations of PhCH2CI-I(CH,)COOR and CI-I~CH~CH(Ph)COOR.

since III would not be favoured on steric grounds (three substituents in the

gauche position relative to each other). The assignment of the methine C proton is straightforward. The method of stereospecific deuterium-labelling was used to assign the geminal CH2 protons. Thus, the dideuterio-analogue of compound (1), PhCHDCD(CHs)COOH (lb), was prepared as shown in Fig. 3. The acid CH3CHDCD(Ph)COOH (2b) was prepared similarly, starting from a-phenyltrans-crotonic acid. As in other cases [1, 3] it was assumed that catalytic deuteration results predominantly in cis-addition (diastereomer T). The assignment of the methylene protons shown in Fig. 2 was deduced by comparison of their chemical shifts with those of the diastereotopic protons in compounds (lb) and (2b) (mixtures T + E), see Table 1. The same conclusion can be reached by consideration of the combined shielding effects of the gauche substituents on the CH2 protons. The experimental relation ~A > VBcould be attributed to shielding by gauche-oriented CH3 or Ph and deshielding by gauche COOR in favoured conformers I and II of compounds (1) and (2). These observations are in agreement with earlier results [2, 3, 4]. It seems that this approach could be used for the independent assignment of diastereotopic protons in systems of the type XCH2CHYZ, where the gauche-shielding effects of the substituents Y and Z are at least qualitatively known and sufficiently different from each other. The results for the vicinal couplings (Table 1) could be used for a semiquantitative estimation of the conformer population. For this purpose we

C00N

0A "~ Ph

0C CH 3

COON

93

HA

%

CH3

0c "~

Ph

Ph

T BO°/.

E

"CH 3

20"/,

Fig. 3. Scheme of preparation of PhCHDCD(CH3)CO()H.

222

have assumed t w o sets o f values for the anti and gauche couplings in the individual rotamers. The first consisted of the values Jt = 12 Hz, Jg = 4 Hz as used before [1, 3]. For the second set, which is probably more reliable, the anti coupling, Jt = 13.4 Hz, was calculated according to Marchese et al. [ 5 ] , and the gauche couplings in forms I and II (Jg = 3.8 Hz) and in form III (J~ = 3.0 Hz) were obtained following the approach of Abraham et al. [6]. The calculated values for the conformer populations and the energy difference b e t w e e n the dominating forms I and II are shown in Table 2. As can be seen, for c o m p o u n d s (1) and (la) the conformer with the phenyl and carboxyl (or methoxycarbonyl) groups in the anti position relative to each other is favoured. For 2-phenylbutyric acid (2) and its ester (2a) the forms with the methyl group gauche to phenyl or COOR are almost equally represented, probably with slight predominance of the latter. In chloroform-d the rotamer populations for the acids and the corresponding esters are very similar. Considering the effect of the polar solvent methanol-d4, in the case of c o m p o u n d (la), one could attribute the increased population of forms II and III to their expected larger dipole m o m e n t in comparison to I. For the ester (2a) where all conformers seem to possess similar polarity, the increased amount o f I at the expense of II and III might be due to increased steric requirements of the COOCH3 group caused b y solvation. An a t t e m p t was made to rationalize the results for AE H _~ in terms of the additive gauche-interaction scheme [7 ] which might be applicable for systems where the steric interactions are dominant [ 1 ] . Assuming the gauche -- anti energy difference in n-propylbenzene (0.5 kcal mol -l [8] ) as a measure for TABLE 2 C o n f o r m a t i o n a l d i s t r i b u t i o n a n d e n e r g y d i f f e r e n c e sa for c o m p o u n d s (1), ( l a ) , (2), (2a) Compound

Solvent

(1)

CDCI3

(la)

CDCI3 CD3OD

(2)

CDCI 3

(2a)

CDC13 CD~OD

Conformational population N (mol fraction)

A EII - - I

I

II

III

(kcal m o l -I )

0.51 b 0.46 c 0.49 b 0.45 c 0.40 b 0.38 c 0.42 b 0.38 c 0.45 b 0.38 c 0,50 b 0.45 c

0.31 b 0.30 c 0.34 b 0.33 c 0.37 b 0.35 c 0.46 b 0.42 c 0.50 b 0.45 c 0.48 b 0.43 c

0.18 b 0.24 c 0.17 b 0.22 c 0.23 b 0.27 c 0.12 b 0.20 c 0.05 b 0.17 c 0.02 b 0.12 c

0,294 0,253 0.218 0.184 0.046 0.049 --0.054 --0,059 --0.077 --0.100 0.024 0.027

aCalculated from equations: JAC = NwJg ~-NIIJt + NIIIJ~; JBC = NiJt + NIIJg + NmJ'-; 1 = N I + N i l + N I I I ; AEII

Jg = 3.8 Hz, J'g = 3.0 Hz.

_

I = RTIn(NII/NI)

•

b J t = 12.0 Hz, Jg = J~ = 4.0 Hz. e J t ~ 3 . 4

Hz,

223

the Ph/CH3 gauche interaction, from the equation AEIz_ i = S -- 0.5 and the data in Table 2 we obtain the following values for the gauche-interaction energies S (kcal mol -~, in chloroform-d solution): Ph/COOH = 0.75; CH3/COOH = 0.45; Ph/COOCH3 = 0.70; CH3/COOCH3 = 0.40. The validity of the additive approach could be tested on the example o f 3-phenylbutyric acid and its ester. The energy difference b e t w e e n the conformers with gauche-Ph/COOR and gauche-CH3/COOR groups should be: b E = 0.75 -- 0.45 = 0.30 kcal mo1-1 for the acid (R = H), and 0.70 -- 0.40 = 0.30 kcal mo1-1 for the ester (R = CH3). These values are in good agreement with those obtained experimentally by NMR (0.2--0.3 kcal mol -~ in chloroform-d, calculated from the data in ref. 3). The values for Ph/COOH and Ph/COOCH3 can be compared to the experimental gauche -- anti energy differences in hydrocinnamic acid, PhCH2CH2COOH and its methyl ester, which were found to be 0.54 and 0.53 kcal mol -~, respectively [9]. These results support the applicability o f the additive approach for the approximate estimation o f conformational equilibria governed predominantly by steric effects. EXPERIMENTAL

Compounds 2-Methyl-3-phenylpropionic acid (1) was obtained by reduction o f a-methyl-

trans-cinnamic acid with hydrazine hydrate in the presence of a 10% Pd/C catalyst [10] ;b.p. 140°C/1 mm. 3-Phenylbutyric acid (2) was obtained commercially (Fluka). The methyl esters o f (1) and (2) were prepared by treatment of the corresponding acids with diazomethane. 2-Methyl-3-phenyl-2,3-d2-propionic acid ( l b ) was synthesized by addition o f deuterium to ~-methyl-trans-cinnamic acid (0.150 g in 20 ml of hexane) in the presence of a 1 0 ~ Pd/C catalyst (0.050 g). 2-Phenyl-2,3-d2-butyric acid (2b) was obtained in a similar manner starting from 2-phenyl-trans-crotonic acid [ 11 ].

Spectra The NMR spectra were measured on Varian HR-220 and JEOL PS-100 spectrometers at normal probe temperatures. REFERENCES 1 2 3 4 5

S. L. Spassov, A. S. Orahovats, S. M. Mishev and J. Schraml, Tetrahedron, 30 (1974) 365. V. S. Dimitrov, S.L. Spassov, T . Z h . Radeva and J. A. Ladd, J. Mol. Struct., 27 (1975) 167 S. L. Spassov, R. Stefanova and J. A. Ladd, J. Mol. Struct,, 36 (1977) 93. S. L. Spassov and R. Stefanova, J. Mol. Struct., 42 (1977) 109. G. Marchese, F. Naso, D. Santo and O. Sciacovelli, J. Chem. Soc., Perkin Trans. 2, (1975) 1100. 6 R. J. Abraham, P. Loftus and W. A. Thomas, Tetrahedron, 33 (1977) 1227.

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7 8 9 10 11

E. I. Snyder, J. Am. Chem. Soc., 88 (1966) 1165. E. I. Snyder, J. Am. Chem. Soc., 91 (1969) 2579. S. L. Spassov and S. D. Simova, J. Chem. Soc., Perkin Trans. 2, (1978) 1113. N. S. Hjelts,Acta Chem. Scand., 15 (1961) 1200. H. Rupe, Ann. Chem., 369 (1909) 332.