59s
R . L. GUSTAFSON, S. CHABEREK, JK., [ COATRIBUTION
O F THE
DEPARTMEXT O F CHEMISTRY
OF
AND
A. E . RIARTELL
Vol. 85
CLARK LTNIVERSITY, WORCESTER, MASS.j
A Kinetic Study of the Copper(I1) Chelate Catalyzed Hydrolysis of Diisopropyl Phosphorofluoridate BY RICHARD L. GUSTAFSON, STANLEY CHABEREK, JR.,
AND
4E. MARTELL? ~ ~
A
~
~
RECEIVEDJULY 24, 1962 The catalytic effects of 1 : 1 Cu( 11)chelates of S,N'-dimethylethylenediamine( D M E S ) , N , S , ~ ' , S ' - t e t r a m e t l i y l e t h ~ l ~ r i e diamine ( T M E S ) , S-hydroxyethylethylenediamine ( H E N ) , S,N'-dihydroxyethylethylenediarnine (2-HEN), a,a -diyyridyl (DIPY), 1,lO-phenanthroline ( P H E S ) , glycylglycine (GG) and diglycylglycine (GGG) on the hydrolysis of diisopropyl phosphorofluoridate ( D F P ) h a r e been studied over a range of p H and metal chelate corxentration. Detailed studies of the aqueous metal complex equilibria were correlated with rate measurements in order to calculate specific rate constants or monohydroxo (Cu[OH]L(H?O))chelates. The specific rate constants for for catalysis by the 1 :1 diaquo CUL(H~O)J catalysis by chelates of the various ligands decreased in the order D I P Y > T M E N > P H E S > D M E K > H E N > 2 - H E S . Tlic specific rate constant for the interaction of D F P with hydrosyl ion vms foulid to be 0.31 + 0.03 liter mole-' set.-'. The protonated cupric chelate of glycylglycine was shown t o have slight catalytic activity whereas the observed rates for the Cu:IIFGGG system were the result of catalysis by the aquo cupric ion which was present in equilibrium with the clielate. The heat and entropy of activation of the Cu( II)-dipyrid>-l catalJ-stare reported.
Introduction Following the preliminary report of Wagner- Jauregg, et aLJ3the role of metal ions and metal chelates as catalysts in the hydrolysis of cholinesterase inhibitors such as isopropyl methyl phosphonofluoridate (Sarin) and diisopropyl phosphorofluoridate (DFP) has been dt scribed by several workers. Wagner- Jauregg, ?t rcported the use of copper(I1) complexes of a,cr'-dipyridyl, imidazole, histidine and other ligands as catalysts for the hydrolysis of D F P and have outlined some possible mechanisms. Courtney, et aLJ4showed that chelates of Cu(II), La(III), Fe(III), Cr(III), Ti(IV), Sn(IV), U02(VI), VO(IV), Mo02(VI) and ZrO(1V) have considerable catalytic activity in the hydrolysis of Sarin, and also studied the effect of various copper(I1) chelates on the hydrolysis of DFP. Fowkes, et u L . , ~ carried out a detailed study on the interaction of Cu(1I)-dipyridyl with D F P , while Epstein, et aZ.,5investigated the catalytic hydrolysis of Sarin in the presence of cerous, cupric and manganous ions. Gustalson and RIartel17reported in detail the catalytic effects of six copper(I1) chelates upon the hydrolysis of Sarin and proposed a mechanism for the catalytic hydrolysis reaction. It is the purpose of this investigation to extend the scope of the Sarin studies to include the reactions of the analogous compound, DFP. As in the previous case,' the ligands chosen were N,N'-dimethylethylenediamine (DRIEN) , N,N,N ',N '-tetramethylethylenediamine (TRIEN), N-hydroxyethylthylenediamine (HEN), N, N '-dihydroxyethylthylenediamine (2 - HEN), a,a' - dipyridyl (DIPY) and 1 , l O - phenanthroline (PHEN). Also, the catalytic effects of two copper(I1) chelates containing peptide ligands, Cu(I1)-glycylglycine and Cu(I1)-diglycylglycine, are investigated. Experimental Reagents.-The D F P was obtained from the Colgate-Palm; olive Co. and had the following physical properties: b.p. 60-61 ~ A stock solution of 0.06 molar (8.2 mm.), d25 1.055, n Z 51.3792. concentration was prepared in spectrograde anhydrous isopropyl alcohol. Standardization was carried out by titration of the acid produced during catalytic hydrolysis by the cupric chelate of T M E N at -log [H+]values of 6.9 and 8.9 with a Beckman automatic titrator. Cupric nitrate and the various ligand solutions were prepared and standardized as described in previous publica(1) This paper reports work done under contract with the Chemical Corps, U. S. Army, Washington 25,D. C. (2) Department of Chemistry, Illinois Institute of Technology, Chicago 16,Ill. To whom inquiries should be addressed. (3) T. Wagner-Jauregg, B. E . Hackley, Jr., J. A. Lies, 0. 0. Owens and R. Proper, J . A m . Chem. SOL.,77,922 (1955). (4) R. C. Courtney, R. L. Gustafson, S. Westerback, H. Hyytiainen, S. Chaberek, Jr., and A. E. Martell, ibid., 79,3030 (1957). ( 5 ) F. M. Fowkes. G. S. Ronay and L. B. Ryland, J . Pkys. Chem., 68, 867 (1958). (6) J . Epstein and D. H. Rosenblatt, J. A m . Chem. 306.. 80, 3596 (1958). (7) R . L. Gustafson and A. E . Martell, ibid., 84,2309 (1962).
t i ~ n s , ~Standard J potassium hydroxide was prepared by the method of Schwarzenbach and Biedermann .lo Samples of glycylglycine and diglycylglycine were obtained from F. Iloffman LaRoche and Co., and aqueous solutions of these compounds were standardized by potentiometric titration with standard potassium hydroxide. Kinetic Measurements.-The formation of acid during the course of D F P hydrolysis was measured as a function of time with a Beckman automatic titrator, which maintained the experimental solution at constant pH by automatic addition of standard potassium hydroxide from a microburet. The reaction was ~' carried out in a multinecked flask, described p r e v i o ~ s l y , ~which accommodated a mercury seal stirrer, gas inlet and outlet tubes, glass and calomel electrodes and microburet delivery tubes for D F P and potassium hydroxide solutions. In a typical run an aliquot of copper chelate solution was introduced into the titration cell and the volume was adjusted t o 100ml. with potassium nitrate solution and distilled water such that the final ionic strength was 0.10. Presaturated nitrogen was passed through the solution to exclude carbon dioxide and the hydrogen ion concentration was adjusted by means of the automatic unit. An anticipation setting of 9 was used in all experiments. An aliquot of D F P was added by means of an automatic buret and time measurements were begun when half of the D F P had been added. Readings of time v s . corresponding standard base delivered were recorded over the course of the titration. I n nearly all cases, linear plots of time vx. log [u/'(a - F)] (where u is the amount of base required for complete hydrolysls of D F P and x is the amount of base added at time t ) were obtained indicating first order kinetics. Catalytic hydrolysis of D F P in the presence of the Cu(I1) chelates of DMEN, T M E N , H E N , 2-HEN, D I P Y and P H E N were carried out a t -loa IH+1 values of 6.90, 7.40, 7.90, 8.40 and 8.90 with several conc&'trat'ions of catalyst at 25.0". Several experiments were also performed at 0.3 and 42.5' with each of the chelates mentioned above. The catalytic effects of the copper( 11) chelates of glycylglycine (GG) and diglycylglycine (GGG) were also measured at -log [H+] values of 6.90 and 8.90 at 25.0°, and the reaction of D F P with hydroxyl ion was studied in the PH range 10.0- 11.5 a t 25.0"
Calculations A plot of time 11s. log [a/ (a-x)3 resulted in a straight line, indicating first-order kinetics, since copper chelate and hydroxyl ion concentrations were maintained a t constant values during the course of each hydrolysis experiment. First-order constants were calculated according to the relationship kubs
= 0.693/tl/t
(1)
where kobs is the first-order rate constant and t l / , is the experimental half -time. Since hydroxyl ion alone will react with the DFP, rate measurements were carried out in the absence of a metal chelate catalyst. The measured hydrolysis rate may be summarized by the expression kobs =
where
koH
koH [OH]
+
C
(2)
is the rate constant assigned to the hydroxyl
(8) R. L. Gustafson and A. E. Martell, ibid., 81,525 (1959). (9) R. C. Courtney, R. L. Gustafson. S. Chaberek, Jr., and 4 . E. Martell, ibid., 81, 519 (1959). (IO) G. Schwarzenbach and W. Biedermann, Helu. Chinz. A c f o , 51, 331 (1948).
~
HYDROLYSIS OF DIISOPROPYL PHOSPHOROFLUORIDATE
March 5, 1963
ion and c is a constant which allows for the spontaneous hydrolysis of D F P in the solvent system employed. A plot of [OH-] as abscissa LIS. kobs as ordinate should give a straight line of slope koH, while the intercept a t [OH-] equal t o zero should give a value of the constant c. The possible catalytic copper(I1) species are: 1, the diaquo chelate, CuLZ+;2, the monohydroxo chelate Cu[OH]L+; 3, dihydroxo chelate, Cu[OH]gL; 4, a dimer, ( C U [ O H ] L ) ~ ~and + ; 5, the unbound or aquo copper(I1) ion, Cu2+. The calculation of the distribution of the above species as a function of p H and total concentration has been described in detail in previous publication^.^^^ Correlation of the equilibrium data with kinetic data obtained upon catalytic hydrolysis of D F P permitted the calculation of rate constants in the manner described p r e v i ~ u s l y . ~The total observed rate, kobs, may be defined in terms of thev arious catalytic and reacting species as k,i,
=
k~ [CuI,2t]'OH-]
+ KB[CU[OH]~L] +
where kobs* = bobs - kon[OH-]. Thus a plot of kobs*/ [Cu?+][OH-] as ordinate L I S . [CuL2+]/[Cu2+]as abscissa will give a straight line of slope k L and intercept klr. Results and Discussion Interaction of Hydroxyl Ion with DFP.-The results of experiments in which the hydrolysis of D F P was carried out in the absence of a copper(I1) chelate catalyst in the -log [ H + ]range 9.9-11.4 are shown in Table I. A plot of ko, vs. [OH-] using these data resulted in a straight line with an intercept a t or near the origin indicating that the constant c in eq. 2 is small. The rate of spontaneous hydrolysis of D F P due to interaction with the solvent medium alone may therefore be said t o be negligible with respect to the effects observed when either copper(I1) chelates or high hydroxyl ion concentrations are present. TABLE I REACTION OF D F P WITH HYDROXYL ION D F P = 1800 Mmoles/liter, t = 25.0' kohr/
[Hi]
[OH-], moleslliter
hobs, sec. - 1
1 -1 ; n
U
\ m
m
*O
~M[CU'+] [OH] l'- k o ~ [ o ~ I - ](3) Here k L is a rate constant which represents catalysis by both the diaquo chelate and the monohydroxo compound or either one alone, and kB, k M and kOH are the rate constants assigned to the dihydroxo chelate species, unchelated copper(I1) species and hydroxyl ion, respectively. Equation 3 assumes that the dimer is catalytically inactive and that there is negligible spontaneous hydrolysis of D F P due t o interaction with the solvent water. i n p H regions where the concentration of dihydroxo chelate species is negligible, eq. 3 may be rearranged to give the slope intercept equation
-log
599
[OH-], I./mole sec. X 101
9.86 1.1; x 10-4 4 . 4 9 x 10-5 10.12 e . 12 x 10-4 6 . 0 8 x 10-5 10.22 2.67 X 9.0 x 10-5 10.23 2.73 x 10-4 9 . 6 x 10-5 10.26 2 . 9 3 x 10-4 9 . 0 x 10-6 10.40 4.04 x 10-4 1.14 x 10-4 10.60 6.41 x 10-4 1.93 x 10-4 10.63 6 . 8 7 X lo-' 2.14 x 10-4 10.80 1 . 0 2 x 10-3 2 . 7 5 x 10-4 11.08 1 . 9 4 x 10-3 5 . 9 x 10-4 11.40 4 . 0 4 x 10-3 7 . 1 x 10-4 Average: koa in -log [H+] range 9.86-11.08 = 0.3 X 10-1 liters/mole sec.
3.8
2.9 3.4 3.5 3.1 2.8 3.0 3.1 2.7 3.0 1.8 3.1 =k
I .
Po I .o
0.5
0
15
CCuLl/CCul x IO? Fig. 1.-Graphical evaluation of the third-order rate colistants for catalysis of D F P hydrolysis b3- the Cu(I1) ion and by the 1 : l Cu(I1)-DMES complex; k:bs = k,i., - k o w [OH-]; slope = k L and intercept = ksf.
Catalytic Effect of Cu(I1) Chelates.-The results obtained on the catalytic hydrolysis of D F P in the presence of copper(I1) chelates are shown in Tables I1 and 111, in which the experimental half-times are given as a function of -log [ H + ] and total metal concentration. On the basis of these data and the equilibrium data for the various copper(I1) chelate systems employed,s rate constants for the diaquo (and or monohydroxo) chelate, kL, and for the dihydroxo (and/'or nionohydroxo) chelate, kB, were calculated and are listed in Table IY. Similar constants calculated for the copper chelate catalyzed reaction of Sarin' are also tabulated for comparison, The results of typical calculations based on eq. 4 are shown in Fig. 1 for the Cu(I1)DMEN-DFP system. 4lthough the values of k L obtained for hydrolysis of Sarin in the presence of Cu(I1) chelates of T M E X , D M E K , H E N and ?-HEN are 13 to 15 times those obtained for D F P hydrolysis, the values of k L calculated for Cu(I1)-DIPI' and Cu(I1)-PHEN catalyzed hydrolysis of Sarin are only greater than those of the analogous D F P case by a factor of four. This is somewhat surprising since one might expect a larger difference in the relative reactivities of D I P Y and P H E S with Sarin and D F P due to possible steric effects which might be encountered in the latter compound because of the presence of an additional isopropyl substituent. Based on data for Cu(I1)-DIPY catalyzed D F P hydrolysis shown in Table V, in which i t was assumed that no unchelated copper(I1) species mere present, a heat 0.6 kcal.,'mole was obof activation, AH*, of 3.1 tained for the aquo or monohydroxo chelate catalyzed hydrolysis reaction, the rate constant of which is represented by kA'. For the purpose of comparative calculations at -log [ H + ] = 6.90 it was assumed that
*
ka'
=
kobs/'[C~L2+] [OH-]
since the concentration of the dihydroxo chelate was negligible. The value of AH* calculated previously for
R.L. GUSTAFSOK, S.C H A B E R E K , J R . ,
60lI
TABLE I1 CATALYTIC HIDROLVSIS OF D F P BI Cu(I1) CHELATES t = 25 ( I c , p = 0 10 (KSO:), results given as half-tinies 111 seconds C ~ ( I I ) - H E NDFP , = 4x0 CU(II)-%-HES, D r w = pirioles/liter 1750 prnoles/hter Si40
-log [H-I
1910 p11/1
plf/l
6 90
5700 3480 2520 2280 1080 2100
2341.1 1440 1260
7 40 7 90
8 41 S CiO
-log 5x0 [ H + ] fiM/l
271" p W I
18500 9120 5940 5280 4860
6 90 7 40 7 90 8 90
[II ]
ill plf/l
430 i.l-M/l
1090 740 ,520
1440
8 40 8 41)
330 3111
- I > ~ [IT j
1410 ~ I I 'I
90 40 RO 90
1930
0 7 7 8
410 plI I
--no
2880 1110
5x
s5i 1
39(l 360
OH1
I
888 pM/1
6 90 7.40 7 90 8 90
2700 2220 2100 2040
1981I 1860
-log
1140
[H'l
p-11/1.
345 pM/1
pM/l
6 90 7 40 7 90 8.90
1380 1110 1050 1000
3360 2220 1930 1810
8520 4800 3660 3300
137 p/JI1
330
p
=
115
3460 pmoles/liter
M/1
198
5280 3i20 3360 3 121I
p
100 p M/l
U/l
7920
13600 8280 6360 56411
5100 4380 40'0
TABLE I11 OF D F P WITH COPPER( 11) CATALITICHYDROLYSIS CHELATES AT 0 3 AID 42 5' Ligand
-.log [ K tI
t, o c
DIPl TMES 2-HES r)Ipy DIPT PHES TMES 2 -HEs
Catalyst concn , pmoles/liter
6.91) 7.90 8.90 6.90
0 3
.3 .3 42 5 42.5 42 5 42 5 -12 5
ll 2
sec
14,301i 13,90P 17,800 530 500 650 8 31 1, 0311
1150 74 4 2010 1140 1140 1000 74 4 2980
6.90 7.90
7.90 8.90
TABLEIV 11) CHELATE RATECOSSTASTSASSICSEDTO COPPER( SPECIES AT 25.0'
_--_
D F F - 7
kL,
a
.lsstiirics kll
=
~.
--Sarin---
ks.
kLs
kB,
inole-? i. mole-1 sec.-l sec. - 1 ' i . 0 x 1060 . . 2 . 3 X 106 7 . 4 X 106 . . . 4 . 9 x 10s . ... ~ . 4 ~ 1 0 ;,xin-lu 9 4 0 x 1W" 3 x 10." 1.2
Ligand TNES DMEN DIPY PHEX HES 2-IIES
T5r5 [CuL2+]
1.2
1. m u l e - '
mole-' sec.
x x
103 3.2 10; 3 . 1 0 X 10' 1 . w x 107 0 3 xi06 i 2 x 10' 1.0
sec _ ..
-1
1.0 X 10' liters? mole-? s w -
2 2
x
. ..
IO'
.
.x $1
0
x
'C. o.:? 25.0 42.5
koba, sec.-z
K 104
X 101 1.150 1.147 1 144
8.60 4.89
4.83
x
10-6
5 . 0 2 X 10-r 1 . 3 3 X 10-3
2.04
[OH-] 1 . 4 9 x 10-8 1 . 2 8 X 10-7 4 4 5 X 10-7
a Tl1 = total metal ion concentration; AH* kcal./mole, ASf = -9.8 cal./rnole deg. at 25".
Cu(I1)-DIP\', D F P = 1750 pmoles/hter
5160 14900 SSO 2250 6120 650 1290 2820 500 920 1690
[H '1
8340 4080 2820
580
=
Cu( 11)-PHES, D F P --log
5940 A240
72 i . l i l / l
21G pll,1
Vol. 85
TABLE2' DATA USED FOR CALCUL.4TIUS O F THE ESTHALPY OF ACTIVATION FOR THE Cu( 11)-DIPY CATALYZED OF D F P AT -LOG [H'] 6.90 HYDROLYSIS
14400 8220
6480 3720 2940 2940
3480 ptnoles/hter
=
0 90 7 4 1 7 911
C t 1 ( I I ) - D l I E l , L)FP 1750 pmoles liter
1280 pV'1
A. E. MARTELL
are not unreasonable. These results, therefore, are cotnpatible with the assumption t h a t metal chelate catalysis of Sarin and D F P solvolysis occur via the same mechanism. Experimentally, i t is found t h a t whereas there is an eighty-fold difference in the values of koH obtained for Sarin and D F P hydrolysis, only a four- to fifteen-fold change in KI, is observed re1:itive to the two substrates.
1.
Cu(I1)-TMES, 1)FP -log
3660 2100 1860 1800
3020 pll/l
AND
10 :
I.
the Cu(I1)-DIPT catalyzed hydro!ysis of Sarin was 2.4 kcal. /mole nnd t h a t for the hydroxyl ion reaction, 10.0 kcal. /mole. The entropy 2nd enthalpy of activation gi\wi in Table 1,-differ sonewhat from those reported for Sarin7 (AT{* 2.4 and AS* - 1 G ) catalysis by the same metal chelate. Remuse of the difference in the electronic interaction expected for Sarin and D F P , how~ T T ,thc (ibsen-eci differences in activation parameters
kA'
3 . 7 6 x 106 8 . 0 2 X 108 1.48 X 107
5.1 i.0.6
=
Catalysis by Cu(I1)-glycylglycine (GG) and Cu(I1)diglycylglycine (GGG).-The results of catalytic hydrolysis of D F P by Cu(I1)-GG and Cu(I1)-GGG are shown in Table VI. Two interesting results may be noticed. First the catalytic effect of the chelate of the quadridenbate ligand, GGG, is greater than t h a t of the terdentate ligand, GG, a t -log [H+] 6.90 and, second, the rate observed in the presence of Cu(1I)-GGG is greater at -log [H-] 6.90 than a t 8.99. Consideration of the distribution of chelate species under the conditions employed makes it possible to explain the effects noted above. From data published by Murphy and Martellll the equilibrium constants for the following reactions were interpolated to the following values a t 25" k, H.?G
