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Effect of Ortho Substitution on the Aminolysis of Active Esters In Notizen 1359 1 F . A. S c h r ö d e r , Z. Naturforsch. 32b, 361 [1977]; 5 W . H . B a u r , Acta Crystallogr. B28, 1456 [1972]. in this paper the positional parameters of H2II should read 0.1, 0.65, 0.6 and not 0.1, 0.65, 0.82 6 The 0(w)-H(w) distances assumed by Schröder (private communication from F. A. S c h r ö d e r ) . range from 1.3 to 1.9 A, the angles (Hw(-O(w)-H(w) vary from 57 to 93°. None of these values are real­ 2 F . A. S c h r ö d e r and A. N 0Rlund Christensen, Z. Anorg. Allg. Chem. 392, 107 [1972]. istic. 3 H . S c h u l z and F. A. S c h r ö d e r , Acta Crystallogr. 7 W . H . B a u r , Inorg. Chem. 4, 1840 [1965]. A 29, 322 [1973]. 4 W . H. B a u r , Acta Crystallogr. 19, 909 [1965]; pro­ 8 Z. M. E l S a f f a r and G. M. B r o w n , Acta Crystallo­ gram for calculating electrostatic energies, MANIOC. gr. B 27, 6 6 [1971]. Effect of Ortho Substitution on the Aminolysis of several active esters in two aprotic solvents. For of Active Esters in Aprotic Solvents this study active esters of acetic acid were used3 because a) aminolysis of carboxylic acid esters (including aminoacyl derivatives) proceeds through T. K Ö m iv es , A. F. MÁrton , F. D u t Ka a common mechanism4, and b) intramolecular Central Research Institute for Chemistry interactions between the leaving group and the acyl of the Hungarian Academy of Sciences, portion (as it may occur when using esters of amino- H-1525 Budapest, Hungary acids5) are absent. Under the pseudo first order conditions of excess M. LÖw, and L. K i s f a l u d y amine all the reactions followed the general rate Chemical Works of Gedeon Richter Ltd., equation for ester aminolyses in aprotic solvents6: H-1103 Budapest, Hungary d [ester] (Z. Naturforsch. 32b, 1359-1360 [1977]; received August 8, 1977) -------- ^ ----= (k2 [amine] + k 3 [amine]2) [ester]. Kinetics, Aminolysis, Active Ester, Our second and third order rate constants together Aprotic Solvent, Ortho Effect with literature pKa values for the leaving phenoxy groups are summarized in the Table. Kinetics of the piperidinolysis of active In accord with the early observation that esters of acetic acid in acetonitrile and chloro- aminolytic reactivity of active esters strongly benzene was investigated. The rate data show depends on the basicity of their leaving group8, with the exeption of 2,6-disubstituted compounds which intramolecular catalysis for the aminolysis of exhibit negative deviations, logarithms of k 2AN and 2 -nitro- and 2 -cyanophenyl esters, while k3CB values in the Table can be correlated linearly reactions of 2 ,6 -disubstituted compounds are with the p K a’s of the leaving groups (not shown). hindered by steric inhibition. Since the extent of the lag behind the expected rates for the aminolyses of 2,6-disubstituted re­ The active ester procedure of amide bond forma­ actants is related to the steric requirements for the tion plays an important role in peptide syntheses. o,o'-substituents (H < F <C1 <CH 3 «Br), steric in­ From the time of the introduction of this technique hibition is that hinders the aminolysis in these a number of leaving phenoxy groups have been cases. examined many of them containing ortho substi­ The facts that k 2AN and k 3CB for the reaction of tuent^)1. Though the activation observed when 2-nitro- and 2-cyanophenyl acetate fit the above introducing electron-withdrawing substituents into correlation, while k 2CB constants are considerably the meta and para position of the leaving group was higher than expected (leading to slight solvent supported by kinetic studies2, the effect of ortho dependences for k 2 and low k 3CB/k 2CB ratios), substitution on the kinetics of amide bond formation clearly indicate7 anchimeric assistance by the has not been investigated so far. o-nitro- and o-cyano functions. These results provide This paper presents kinetic data on the aminolysis the first example of intramolecular participation by an o-cyano group in ester aminolyses, and suggest Requests for reprints should be sent to D r . F. that aminolytic reactivities of 2-nitrophenyl esters D u t k a , Central Research Institute for Chemistry of of aminoacids exceeding those of the 4-nitro the Hungarian Academy of Sciences, H-1525 Budapest, analogues are, at least in part, due to the intra­ Hungary. molecular catalysis by the o-nitro group. 1360 N otizen Table. Second and third order rate constants for the reactions of esters with piperidine in acetonitrile (k 2AN and ks^N) and chlorobenzene (k 2CB and k 3CB) at 25 °C; pKa values for the leaving phenoxy groups in water at 25 °C. Ester pK a k 2AN k 3AN k 2CB k 3CB M -is-1 M -2s - 1 M -iS-i M-2 s-i PhOAc I 0 .0 0 a 3.9 10- 5 5.6 1 0 - 5 _ _ 4-Cl-PhOAc 9.42a 8.5 10 - 4 1.5 1 0 - 3 1.0 io-4 8.3 I0 - 4 4-CH3OCOPhOAc 8.47b 2.70 IO " 2 3.2 1 0 - 2 1 . 2 1 0 - 3 1.6 IO- 2 4-CH3COPhOAc 8.05b 4.37 IO - 2 c 1.05 10- 3 2.40 10- 2 4 -N 0 2P h 0A cd 7.15e 2.19 c 3.50 10- 2 8 .2 10-i 2-F-PhO Ac 8.70* 1.51 10- 2 2.52 10-2 1.0 10-3 1.26 1 0 - 2 2-Cl-PhOAc 8.53a 1.15 10 - 2 2.07 io-2 7.5 10 - 4 1.42 10- 2 2 -N 0 2-Ph0Ac 7.23e 2.26 c 5.30 10-1 1.53 2-CN-PhOAc 7.18f 2.67 c 6.08 1 0 - 1 2.07 2,6-Cl2-PhOAc 6.79f 2 .8 8 1 0 - 1 c 2.58 10 - 2 7.6 IO - 3 2,6-(CH 3)2 -4-N 0 2-Ph0Acd 7.078 2.44 10- 3 c 1 . 2 1 0 - 4 1.5 10- 4 2,6-Cl2-4-N 0 2-Ph0Ac 3.55e 64.2 c 1 1 . 0 c 2 ,6 -Br2-4 -N 0 2 -P h 0 Ac 3.38e 13.4 c 4.49 c F s P h O A c d 5.53h 73.0 c 4.70 c Cl5PhOAcd 4.821 15.7 c 2.29 c a A . I. Biggs and R. A. Robinson, J. Chem. Soc. 1961, 390; b P. M. G. Bavin and W. J. Canady, Can. J. C h e m . 35, 1555 [1957]; c undetectable third order rate constants; d rate data taken from ref. 7 ; e J. Juillard, C. R. Acad. Sei. Ser. C. 262, 241 [1966]; f J.-C. H alle, R. H arivel, and R. Gaboriaud, Can. J. Chem. 52, 1774 [1974]; s A. Fischer, G. J. L eary, R. D. Topsom, and J. V aughan, J. Chem. Soc. B,1966, 782; h J. M. B irchall and R. N. H aszeldine, J. Chem. Soc. 1959, 3653; 1 R. A. R obinson and R. G. B ates, J. Res. Nat. Bur. Stand. A 70, 553 [1966]. 1 M. Bodanszky, Y . S. K l a u s n e r , and M . A. K o n d o , C. Y . L i n , and A. Bodanszky, J. Am. O n d e t t i , Peptide Synthesis, Wiley, New York 1976. Chem. Soc. 96, 2234 [1974]. 2 H . R. K ircheldorf, E. S t e n g e l e , and W . R e g e l , 6 D . P. N. S a t c h e l l and 1.1. S e c e m s k i , J. Chem. Soc. Liebigs Ann. Chem. 1975, 1379. B 1969, 130. 7 L. K isfaludy, M. Low, Gy. Argay, M. Czugler, 3 Kinetic arrangements followed previous lines, T. T. K ö m i v e s ,P. S o h ä r , and F. D a r v a s , in “Peptides K ö m i v e s , A. F. M a r t o n , and F. D u t k a , Z. N atur - 1976”, p. 55, Proc. XIVth Peptide Symposium, forsch. 31b, 1714 [1976]. Wepion, Belgium 1976. 4 H . J . J o n e s ,Chem. Ind. (London) 1974, 723. 8 J.P l e s s and R . A. Boissonas, Helv. Chim. Acta 46, 5 M. Bodanszky, M. L. F i n k , K . W . F u n k , M . 1609 [1963]. Nachdruck — auch auszugsweise — nur mit schriftlicher Genehmigung des Verlages gestattet Satz und Druck: Allgäuer Zeitungsverlag GmbH, Kempten.
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