MICELLAR
EFFECTS
N-SUBSTITUTED
IN T H E
ACYLATION
IMIDAZOLES
ESTEI~S
OF
CA13BOXYLIC
A. A.
P. K.
Osipov, K. Yatsimirskii,
OF
BY p-NITROPHENYL
ACIDS
Martinek, a n d I.
UDC 541.124:542.951.1:547.781 V.
Berezin
The imidazole group is contained in the active sites of many e n z y m e s [1-3]; t h e r e f o r e , the investigation of m i c e l l a r [4, 5] and p o l y m e r i c [6] effects in imidazole c a t a l y s i s is of g r e a t i n t e r e s t . We studied the influence of m i c e l l e s of s u r f a c e - a c t i v e s u b s t a n c e s (surfactants) on the acylation of imidazole (IM) and its N - a l k y l d e r i v a t i v e s by p - n i t r o p h e n y l e s t e r s of aliphatic c a r b o x y l i c acids: ON
0
+R N [ R1
_c_o
;.
R2
'
-
app
+ """
(1)
t NO~
R1= H, CHs, (CH2)~CHs,(CH2)sCH3,CH~C~Hs; R2= CHs, (CH~)2CHa, (CH-~)sCH3 C e t y l t r i m e t h y l a m m o n i u m b r o m i d e (CTAB) and sodium dodecylsulfate (SDS) w e r e used as s u r f a c t a n t s . The b a s i c o b s e r v a t i o n s were the following: 1) CTAB and SDS change the rate of reaction (1) by no m o r e than 2 - 3 - f o l d (Figs. 1 and 2). 2) The nature and magnitude of the o b s e r v e d effects p r a c t i c a l l y do not depend on the sign of the charge of the micelle (see Figs. 1 and 2). 3) An i n c r e a s e in the hydrophobic c h a r a c t e r of the nueleophile (IM derivative) has a positive effect on the r e a c t i o n rate. F r o m Fig. i it is evident that the inhibiting influence of s u r f a c t a n t s on the acylation by p - n i t r o p h e n y l a c e t a t e d e c r e a s e s with i n c r e a s i n g length of the N-aliphatic chain R I in the N - a l k y l i m i d a z o l e , while in the case of N - h e p t y l i m i d a zole or N - b e n z y l i m i d a z o l e , an addition of s u r f a c t a n t p r o m o t e s r e a c t i o n (1). 4) On the c o n t r a r y , an inc r e a s e in the hydrophobic c h a r a c t e r of the acylating agent has a negative effect on the r e a c t i o n r a t e . F r o m Fig. 2 it is evident that the p r o m o t i n g influence of s u r f a c t a n t s on the r e a c t i o n in which N-heptylimidazote p a r t i c i p a t e s d e c r e a s e s with growth of the 132 chain in the e s t e r molecule. In a d i s c u s s i o n of the c a u s e s of the change in the rate of the second o r d e r r e a c t i o n in the p r e s e n c e of s u r f a c t a n t m i c e l l e s A + B ~app Products
(2)
we should s e p a r a t e l y consider: a) the contribution to the a c c e l e r a t i o n of the reaction on account of the concentration of the r e a g e n t s in the micelle and b) the change in the r e a c t i v i t y of the r e a g e n t s in the m i c e l l a r medium in c o m p a r i s o n with aqueous medium. The kinetic theory of m i c e l l a r c a t a l y s i s [7] gives the following e x p r e s s i o n for the apparent rate constant (kap p) kmKAKBC/F + kaq kapp = (1 + KAC)(I 7}- KBC)
(3)
where k m and kaq are the true rate constants of the reaction in the m i c e l l a r and aqueous " p h a s e s " , r e spectively; KA and KB a r e the constants of binding of the r e a g e n t s to the mieelles, equal to (P-1)V, where the distribution constant P is equal to the ratio of the r e a g e n t c o n c e n t r a t i o n s in the m i c e l l a r and aqueous " p h a s e s " ; C is the concentration of the surfactant, reduced by the value of the c r i t i c a l concentration M. V. L o m o n o s o v Moscow State U n i v e r s i t y . T r a n s l a t e d f r o m Izvestiya Akademii Nauk SSS13, Seriya Khimicheskaya, No. 9, pp. 1984-1988, September, 1974. Original a r t i c l e submitted J a n u a r y 4, 1974.
9 19 75 Plenum Publishing Corporation, 227 West 17th Street, New York, N. Y. 10011. No part o f this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, microfilming, reeording or otherwise, without written permission o f the publisher. A copy o f this article is available from the publisher for $15.00.
1905
[CTAB], mmol~s 0
12
q
[CTAB], mmoles 20
0
+t
7oo
80
80
60
5O
q
12.
2g
o
A
f
uo O
g
1gOr-
O
"t
"I20
~
o
+f
1
o'
r,
Z]
80
B
2
9 r
20
"P
o
1
J
60
[SDS], mrnoles Fig. 1
r
100
0
20
60
lO0
[SDSJ, mmoles Fig. 2
Fig. 1. Dependence of the a p p a r e n t r a t e Constantof the acylation by p - n i t r o phenylacetate on the concentration of the s u r f a c t a n t s for: 1) N - h e p t y l i m i d a zole; 2) N - p r o p y l i m i d a z o l e ; 3) N - m e t h y l i m i d a z o l e ; 4) N - b e n z y l i m i d a z o l e ; 5) imidazole. A) CTAB; B) SDS. 30 ~ 1 vol. % DMSO, 0.02 M b o r a t e buff e r : pH 8.5 (A), 9.6 (B). Fig. 2. Dependence on the s u r f a c t a n t concentration of the a p p a r e n t r a t e constant of acylation of N - h e p t y l i m i d a z o l e : 1) by p - n i t r o p h e n y l a c e t a t e ; 2) by p - n i t r o p h e n y l b u t y r a t e ; 3) by p - n i t r o p h e n y l heptanoate. A) CTAB; B) SDS. C u r v e s 2 and 3 in Fig. 2A w e r e c o n s t r u c t e d a c c o r d i n g to Eq. (4), using the values of the constants indicated in T a b l e 1. 30 ~ 1 vol. % DMSO, 0.02 M b o r a t e buffer: pH 8.5 (A), 9.6 (]3). of micelle f o r m a t i o n ; V is the m o l a r volume of the s u r f a c t a n t . Equation (3) is c o r r e c t u n d e r the condition that the r e a g e n t s a r e well bonded to the m i c e l l e s (P >> 1 and, consequently, K > 0) and the fraction of the m i c e l l a r "phase" is r e l a t i v e l y s m a l l (CV << 1). To r e s o l v e the questions posed, we should find the constants KA and KB and c o m p a r e the true r a t e constants (kaq and k m) in the aqueous and m i c e l l a r " p h a s e s . " We analyzed the e x p e r i m e n t a l r e s u l t s (see Figs. 1 and 2), using l i n e a r plot's of Eq. (3) [7]. As an e x a m p l e , T a b l e 1 cites the constants obtained in the t r e a t m e n t of the data of Fig. 2A, Since the r e a g e n t s exhibit s t r o n g bonding to the m i c e l l e s , it should have been expected that the concentration of the r e a g e n t s in the m i c e l l e s should have a significant influence on the r e a c t i o n r a t e . F r o m Eq. (7) (see E x p e r i m e n t a l Method) it follows that concentration of the r e a g e n t s in m i c e l l e s should lead to an a c c e l e r a t i o n of r e a c t i o n (1) by at l e a s t 10-100-fold (at k m = kaq and V" = 0.35 l i t e r / m o l e [8]). However, in the p r e s e n c e of s u r f a c t a n t s there is only a negligible change in kap p (see F i g s . 1 and 2). This is due to the f a c t that the t r a n s f e r of r e a c t i o n (1) f r o m w a t e r to the r n i e e l l a r m e d i u m leads to a substantial d e c r e a s e in the true s e c o n d - o r d e r r a t e constant (km << kaq, see Table 1). To explain the r e s u l t o b s e r v e d , let us indicate that an i n c r e a s e in the concentration of the organic c o m ponent in an aqueous ethanol m i x t u r e leads to a s u b s t a n t i a l inhibition of the r e a c t i o n of acylation of d e r i v a tives of IM by p , n i t r o p h e n y l c a r b o x y l a t e s [9]. The t r a n s i t i o n state of the r e a c t i o n is p r o b a b l y m o r e p o l a r than the initial compounds (possibly b e c a u s e the t r a n s i t i o n state is close to a t e t r a h e d r a l adduct with s e p a r a t e d c h a r g e s [1, 2]); in such a c a s e the r e a c t i o n r a t e should d e c r e a s e with d e c r e a s i n g d i e l e c t r i c p e r m e a bility and solvating ability of the m e d i u m [10, 11]. The value of the d i e l e c t r i c p e r m e a b i l i t y not only within the m i c e l l e s but also in t h e i r s u r f a c e l a y e r is substantially l o w e r than in w a t e r [7, 12], and the w a t e r content in the m i c e l l e d e c r e a s e s s h a r p l y with i n c r e a s i n g distance f r o m the s u r f a c e Layer to the hydrophobic
1906
T A B L E 1. A c y l a t i o n of N - H e p t y l i m i d a z o l e b o x y l a t e in the P r e s e n c e of C T A B M i c e l l e s
by p-Nitrophenylcar-
Binding constants, liters CnH2n+l COOC6H4= I/mole
NOd-p)
~-hepthy-
[ester*,
~midazole ~ n= 6 n: 3 n= t
tt0
I
3500
120
]
27
130
~m/V'min-1
km/kaq?
(kapp/kaq)max
0,6
0,0053
t,4
5--10
0,03--0,06
1,9
KB
]
530
0,9
0,0070
1,6
* For the values of KB, see [8]. ?The values of km/kaq were calculated from kaq and km/V at ? = 0,85 liters/mole [8]. n u c l e u s [7]. F r o m t h i s i t b e c o m e s u n d e r s t a n d a b l e why a t t e m p t s to c r e a t e e n z y m e - l i k e c a t a l y s t s on the b a s i s of s y n t h e t i c p o l y m e r s , i n c l u d i n g the IM g r o u p , in w h i c h the c a t a l y t i c a l l y a c t i v e n e u t r a l IM g r o u p i s i n s i d e (or c l o s e to) the h y d r o p h o b i c s o r p t i o n r e g i o n , w e r e u n s u c c e s s f u l (an a c c e l e r a t i o n of the r e a c t i o n b y o n l y 3 - 5 - f o l d ) [6, 1 3 - 1 5 ] . Such a s t r u c t u r e of the " e n z y m e m o d e l " c a n s c a r c e l y l e a d to e f f e c t i v e c a t a l y s i s , s i n c e the e f f e c t of c o n c e n t r a t i o n of the r e a g e n t s (due to a h y d r o p h o b i c i n t e r a c t i o n of the s u b s t r a t e w i t h the c a t a l y s t ) i s a l m o s t e n t i r e l y c o m p e n s a t e d f o r , a s a r u l e , b y the u n f a v o r a b l e i n f l u e n c e of the m e d i u m of the a c t i v e s i t e on the r e a c t i o n , i t s low d i e l e c t r i c p e r m e a b i l i t y , o r b y i t s w e a k s o l v a t i n g a b i l i t y . EXPERIMENTAL
METHOD
I m i d a z o l e f r o m R e a n a [ w a s u s e d w i t h o u t p u r i f i c a t i o n . N - S u b s t i t u t e d d e r i v a t i v e s of IM w e r e s y n t h e s i z e d a c c o r d i n g to [16-18] a n d p u r i f i e d b y v a c u u m r e d i s t i l l a t i o n no t e s s t h a n s i x t i m e s . SDS a n d C T A B w e r e p u r i f i e d b y r e c r y s t a l l i z a t i o n [19]. T h e c r i t i c a l c o n c e n t r a t i o n of m i c e l l e f o r m a t i o n of SDS, d e t e r m i n e d a c c o r d i n g to the a b s o r p t i o n of r h o d a m i n e 6G, i s e q u a l to 5 - 10 -3 M (25 ~ 1 v o l . % DMSO). T h e c r i t i c a l c o n c e n t r a t i o n of m i c e l l e f o r m a t i o n of C T A B (6 9 10 -4 M, 25 ~ w a s m e a s u r e d a c c o r d i n g to the e l e c t r i c c o n d u c t i v i t y of the s o l u t i o n o f the s u r f a c t a n t . F o r the c h a r a c t e r i s t i c s of p - n i t r o p h e n y l c a r b o x y l a t e s , s e e [8]. T h e r a t e of the a c y l a t i o n r e a c t i o n s w a s f o l l o w e d s p e c t r o p h o t o m e t r i c a t l y (400 n m , H i t a c h i - P e r k i n - E l m e r - 1 2 4 w i t h t h e r m o s t a t i c a l l y c o n t r o l l e d c e l l ) . T h e c o n c e n t r a t i o n of IM and i t s d e r i v a t i v e s ( f r o m 8 9 10 -4 to 5 9 10 -2 M) w a s t a k e n in e x c e s s in c o m p a r i s o n w i t h the c o n c e n t r a t i o n of the e s t e r s ( 4 . 1 0 -5 M). T h e p s e u d o f i r s t - o r d e r r a t e c o n s t a n t w a s d e t e r m i n e d a c c o r d i n g to the G u g g e n h e i m m e t h o d . T h e s e c o n d o r d e r r a t e c o n s t a n t k a p p w a s found a s the s l o p e of the d e p e n d e n c e of the p s e u d o f i r s t - o r d e r r a t e c o n s t a n t on the t o t a l c o n c e n t r a t i o n of IM. T h e d d p e n d e n c e of k a p p on the s u r f a c t a n t c o n c e n t r a t i o n w a s a n a l y z e d w i t h i n the f r a m e w o r k of Eq. (3), in o r d e r to find the b i n d i n g c o n s t a n t s of IM w i t h the m i c e l l e s , a s w e l l a s the v a l u e s of the t r u e r a t e c o n s t a n t s of the r e a c t i o n s in the m i c e l l a r " p h a s e . " In t h i s c a s e we u s e d l i n e a r p l o t s of E q . (3) [7]. T h e t h e o r e t i c a l c u r v e s k a p p v s C, c o n s t r u c t e d u s i n g the v a l u e s found f o r the " e l e m e n t a r y " c o n s t a n t s ( s e e T a b l e 1) a r e in g o o d a g r e e m e n t w i t h the e x p e r i m e n t a l d a t a (see F i g . 2A). M a t h e m a t i c a l A n a l y s i s of the T h e o r e t i c a l E q u a t i o n (3). T h e c u r v e s of the d e p e n d e n c e of k a p p on the surfactant concentration may take various forms - they may be curves with a maximum, decreasing c u r v e s with a p o i n t of i n f l e c t i o n o r w i t h o u t it, e t c . [20]. Such a v a r i e t y of the k i n e t i c m i c e l l a r e f f e c t m a y b e e x p l a i n e d on the b a s i s of the r e c e n t l y p r o p o s e d t h e o r y [7]. L e t u s c o n s i d e r the b i m o l e c u l a r r e a c t i o n (2), w h e r e the e x p r e s s i o n f o r k a p p in the p r e s e n c e of s u r f a c t a n t m i c e l l e s c a n b e w r i t t e n in the f o r m of (3) f r o m w h i c h it f o l l o w s t h a t 3 k a p p / S C = 0 when C = (--1 __ V (xK~ - - f)(• where ~ = km/kBV. when
- - I)/•
E v i d e n t l y , (4) h a s p h y s i c a l m e a n i n g o n l y when C -> 0. • > I/K.~ + I/KB
(4) This requirement
is fulfilled
(5)
In t h i s c a s e the d e p e n d e n c e of k a p p on the s u r f a c t a n t c o n c e n t r a t i o n h a s a m a x i m u m , s i n c e the f i r s t d e r i v a t i v e c h a n g e s s i g n f r o m p l u s to m i n u s with i n c r e a s i n g C. T h e c o n v e r s e i s a l s o c o r r e c t - if the e x p e r i m e n t a l c u r v e h a s a m a x i m u m , then c o n d i t i o n (5) i s f u l f i l l e d .
1907
At the s a m e time, if
U < I/KA -4- 1~Ks
(6)
then the d e r i v a t i v e 3kapp/0C at all C - 0 takes negative values, and, consequently, with i n c r e a s i n g s u r factant concentration the value of kap p d e c r e a s e s . The nature of the dependence of kap p on C is d e t e r m i n e d by the functions (5) and (6), f r o m which it is p o s s i b l e to e s t i m a t e the rate constant of the r e a c t i o n in the m i c e l l a r "phase" if only the constants of binding of the r e a g e n t to the m i c e l l e s a r e known f r o m an independent e x p e r i m e n t . Evidently the c a s e kap p < kaq, when the c u r v e of kap p vs C n e c e s s a r i l y p a s s e s through a m a x i m u m , is the m o s t i n t e r e s t i n g . F o r the value of the m a x i m u m a c c e l e r a t i o n we have the e x p r e s s i o n ( ka_~p2_~ kaq /max
-:
V (•
-- t)(•
(I + V(•215 •
-- l)
l-~ v(•215
nKB
)
(7)
The optimum conditions f o r m i c e l l a r c a t a l y s i s o c c u r at the s u r f a c t a n t concentration Copt = (V (UKA -- i)(•KB -- i) --
t)/•
(8)
When ~ >> 1/KA and ~ >> 1/KB, the position of the m a x i m u m does not depend on the r a t i o between the true r a t e constants in the m i c e l l a r and aqueous " p h a s e s " and is d e t e r m i n e d only by the constants of the binding of the r e a g e n t s to the m i c e l l e s
Copt =
I/1/KAK~
(9)
In this case the m a x i m u m a c c e l e r a t i o n is d e t e r m i n e d f r o m kapp "/ km KAKB kaq /max ~ kaq" F (V ~ Z ~ - ]/KB) -''-2
(10)
T h i s p a r t i c u l a r case was also d i s c u s s e d t h e o r e t i c a l l y e a r l i e r [8]. CONCLUSIONS 1. The kinetics of r e a c t i o n s of acylation of i m i d a z o l e and its N-alkyl d e r i v a t i v e s by p - n i t r o p h e n y [ e s t e r s of n - a l i p h a t i c c a r b o x y l i c acids in the p r e s e n c e of m i c e [ l e s of s u r f a c e - a c t i v e s u b s t a n c e s (surfactants) was studied. Surfactants have a weak influence on the r e a c t i o n r a t e , and the magnitude of the effect is p r a c t i c a l l y independent of the sign of the charge of the m i c e l l e . 2. The positive effect of c o n c e n t r a t i o n of the r e a g e n t s by the m i c e l l e s is a l m o s t e n t i r e l y c o m p e n s a t e d f o r by the u n f a v o r a b l e influence of the m i c e l l a r m e d i u m , which explains the m e c h a n i s m s of the action of i m i d a z o l e - c o n t a i n i n g p o l y m e r i c e n z y m e - l i k e c a t a l y s t s . LITERATURE 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
1908
CITED
T. B r u c e and S. Benkovich, M e c h a n i s m s of B i o o r g a n i c R e a c t i o n s [Russian translation], Mir (1970). W. J e n k s , C a t a l y s i s in C h e m i s t r y and E n z y m o l o g y [Russian translation], Mir (1972). R.M.S. Smeliie (editor), C h e m i c a l R e a c t i v i t y and Biological Role of Functional Groups in E n z y m e s , A c a d e m i c P r e s s , L o n d o n - N e w Y o r k (1970). R . G . Shorenstein, C. S. P r a t t , C. J. Hsu, and T. E, Wagner, J. A m . Chem. Soe., 90, 6199 (1968). C. GitIer and A. Ochao-Solano, ibid., 90, 5004 (1968). C . G . O v e r b e r g e r and J. C. Salamone, Accounts Chem. R e s . , 2, 217 (1969). I . V . B e r e z i n , K. Martinek, and A. K. Y a t s i m i r s k i i , Usp. Khim., 4..~2, 1729 (1973). A . K . Y a t s i m i r s k i i , K. Martinek, and I. V. B e r e z i n , T e t r a h e d r o n , 2___77,2855 (1971). A . P . Osipov, K. Martinek, A. K. Y a t s i m i r s k i i , and I. V. B e r e z i n , Dokl. Akad. Nauk SSSI~, 215, 914 (1974). W. P. J e n c k s and M. G i l c h r i s t , J. A m . Chem. Soc., 8__88, 104 (1966). H. B e i c h a r d t , Solvents in Organic C h e m i s t r y [Russian translation], Khimiya (1973). P. Mukerjee and A. Ray, J. P h y s . Chem., 7.__0.0,2144 (1966). C . G . O v e r b e r g e r and M. Morimoto, J. A m . C h e m . Soc., 9__.33,3222 (1971). Y. Okamoto and C. G. O v e r b e r g e r , J. P o l y m e r Sci., 1._.00, 3387 (1972). T . Kunitake and S. Shiakai, J. A m . Chem. Soc., 93, 4256 (1971).
16. 17. 18. 19. 20.
T . F . Dankova, E. I, Genkin, and N. A. Preobrazhenskii, Zh. Obsheh. Khim., 1_~5, 189 (1945). O. Wallach, Bet., 1_..66, 534 (1883). M. Hating, Helv. Chim. Acta, 4__22, 1845 (1959). E . F . Dunynsteen and E. Grunwald, J. Am. Chem. Soc., 8__!1,4540 (1959). E. Fendler a n d J . Fendler, in: Methods and Achievements in Physicoorganic Chemistry [Russian translation], Mir (1973).
1909