May 1969
CARBA4MATESIK THE
regression analyses. The hydrophobic bonding power of the S-phenyl substituent and not that of the molecule as a whole mas the major factor involved in correlating activity of substituted N-phenylamides. However, 3,5-disubstituted N-phenylamides failed to show the predicted activity. The present study represents an attempt to correlate the geometry of the carbamate group with the inhibition of the Hill reaction in a series of cyclic carbamates (la-c). Xn effort was made to keep the electronic and
Rqio
R'
la, R = H; R' = H b,R=C1;R1-H C, R=H: R'==C1
hydrophobic bonding effects constant so that the inhibition would be a function of the molecular geometry of the inhibitor. The corresponding linear carbamates (2-7) were also prepared so that a direct comparison could be made. R' R z d I \ H C 0 2 R
7-
R3 2, R = CH3; R', R2 = H ; R3 = C1 3, R CH3; R', R3 = H ; R' = C1 4, R = PhChn; R', R2 = H ; R3 = C1 5 , R = PhCHz; R', R 3 = H ; R2 = C1 6, R, R' = CHI; RZ = H ; R3 = C1 7, R, R' = CHI; RZ = C1; R 3 = H
Chemistry.-For the synthetic approach to the cyclic carbamates 1, the appropriate anthranilic acids were reduced to the corresponding aminobenzyl alcohols (8). Cyclization of 8 with COC12 gave the desired cyclic carbamates. The linear carbamates (2-5) were synthesized from the appropriate phenyl isocyanate and the corresponding alcohol. The ortho-substituted linear carbamates (6, 7) were prepared from the substituted anilines and methyl chloroformate. Biological Assays.-The molar concentration of the carbamate reducing the photolytic activity of the isolated chloroplasts to half its normal activity (Id was determined by previously described techniques,j except that ferricyanide reduction was followed by measuring the decrease in ferricyanide absorption at 420 mk using a Iilett colorimeter. 411 assays were performed in duplicate with chloroplasts obtained from spinach. Data are presented as the arithmetric averages of the individual determinations.
Results and Discussion The carbamate group, -O,CK=, is planar because of resonance and may exist in four possible conformations (A-D) depending on the position of the carbonyl group with respect to the imino hydrogen atom and the R group of the ester portion. Data concerning dipole mo( 5 ) U. E. 1Ioreliind and Ii. L. Hill, J. &r.
Pood Chcm., 7 , 832 (198'3).
HILLREACTIOS
427
I
A, cis,cis
R
B, cis,tram R'\
0
NC H/ \O/R C, trans,cis
R'\
H'
0
NC
'9 I
R
D,trans,trans ment measurements6 indicate that the cis conformation with regard to the ester portion of the carbamate is the preferred conformation. In the case of amides, the trans form predominates with respect to the carbonyl group and the imino hydrogen atom.' Thus one can predict that the linear carbamate group possesses predominantly the trans,cis conformation (C). The geometry of the cyclic carbamate group involving medium-sized rings is such that only the &,trans conformer B can exist. In an effort to assess the importance of conformational factors of the carbamate group during binding to the receptor, inhibitors containing a carbamate group with a fixed conformation were studied. These carbamates 1 exist solely in the cis,tl*ans conforniation. The electronic properties of the aromatic ring in the linear and cyclic carbamates appear to be similar based on the uv spectra. The linear carbamates were active inhibitors at 6 X lop4Ji (see Table I1 for the Isovalues). The cyclic carbamates were inactive at all concentrations. The maximum concentration attainable was 3 X X because of solubility limitations. The inactivity of the cyclic carbamates may be the result of several factors besides the conformation of the inhibitor. The need for a free and sterically unhindered imino H has been demon~trated.~b,5The cyclic carbamates possess a CH2 group ortho to n" which may result in reducing the accessibility of the imino group t o a binding site on the receptor site on the receptor. I n an effort to assess this effect, two linear carbamates 6 and 7 containing CH3 ortho to NH mere prepared. The Is, values for these CH3-substituted compounds are similar to the Is0 values of 2 and 3. Therefore, the steric factor of the CH, group appears to be negligible. A second factor which could conceivably play a role in the inactivity of the cyclic carbamates is that of metabolic inactivation. Oxidation of the CH2 group is a possibility, since it is benzylic and activated by the inductive effect of the oxygen atom of the ester portion of the carbamate.* In an attempt to evaluate this factor, two linear carbamates 4 and 5 containing a benzyl ester function were prepared and assayed. The Is,values (see Table 11) for the benzyl carbamate 4 and the methyl carbamate 2 are very similar. A comparison of the benzyl carbamate 5 with the methyl carbamate 3 is difficult since the solubility properties of 5 do not allow an 1.50 value to be determined. A qaturated test solution of 5 W. D. Kumler, J. Am. Clem. Soc., 83, 4596 (1961). (7) (a) S. hlizushima, T. Simanouti, S. Nagakura, K . Kuratani, hI. Tsuboi, H. Baba, and 0. Fujiopa, J. Am. Chem. Soc., 72, 3490 (1950); (b) L. LaPlanche and M.Rogers, ibid., 86, 337 (1964). (8) Professor C . Hansch, Department of Chemistry, Pomona College, Ciaremont, Calif., private communication, 1966. (6) C . 11. Lee and
produced :i :L;C;c iiihibitiorl Hon ever. coiielusioric drawn from data obtained from Yaturated te mi1.t bc vie\\ cd Jvith some uncertainty, iiilcc t io11or ;i ~siltinpout of the inhibitor may take place i i i the ~ ~ c a c t i o r ni ~ x t u r e . ~ "Therefore, t h r obitmwl inhibit io11 may h i t v ~rc-ulted from :I Ion cr corlcc>ntrntioliof R I I tih hi bit or 0 1 1 thc b:iiic of the .imilar activitiei of r;irl):iiiiat(~2 arid 4 the factoi, of nict:tbolic iii:-tcti\ : i t i o i i ,tppc:ir~t o lie negligible Thc geometry of the c:irh:lm:ite group :i-n cll ;ti tlic -hap(> of t hcl ov("111 molecule I - defined in tht. cyclic c * a i + w n a t t > - In thii c a ~ et ,h e pliciiyl ring, the S atom, t tic ('-tw oxygeii :itom, :ind thc CO utrbon atom :ire c~switi:ilIycoplariar 'l'hi- condition is not required iii t h c Iiiiear carbamate, :md the cirbainate group a- well :4i t phenyl ring may n.;sumc a conformation which illo on^ hiridiiig t o thc :ictive q t e oi t h e receptor. The p r t w i i t ~m~ of c.yciir r:irb:i~n:ite~examines only o w coriformitioii ot thcx four hich might be ~nvolved t l u r irig t h c billding o f the csrb:imate group Therefore, furthcr -t d i e . : m u i t he performed with other specifically e i i the role of the contl+igiictl inhibitor- 111 order t o fornint ioii:il factor 111 the inliihitioii oi the Hill reaction. h ( b
Experimental Section 4H-3,1-Benzoxazin-2-ones(Tables I and 11).--To a rold i;-IOo) of 1) 1 m d e of the appropiiate o-aminobeuzyl alrohiil :iii(I 0 2 mille of TI:.?, 111 300 nil of CsH, \va> added droprsise vJ1titiiiii
SO.
I :I Ill I I'
1
1111, " ( '
I'ielii, (;;
Inliili of photolytic act.
II
1 I h I 20"." 200--202' 16!) 171"
r,o
?;one
30 ii;
