I07 1
lmidazolylphosphinarnidothionates
I
R
comparing Ia with Ie, I b with If, and I d with I g indicated that the shape of the site of toxic action in fungi that cause late blight might be different from the shape of this site in fungi that produce powdery mildew. For maximum toxicity against both types of fungi the R substituent evidently had to be planar and weakly electron attracting, as in Ib. According to these findings the influence of the polar and steric characteristics of R upon the fungicidal activity of I was more complex than in the familiar case of anticholinergic organophosphates. Therefore, it was conceivable that the mechanism of fungicidal action of I might not even involve phosphorylation of an enzyme essential to the normal functioning of the fungus organism. This hypothesis was supported by the follo\+ingchemical and biological evidence. h study of the solvolysis of I b gave the results shown i n Table 11. They clearly indicate that the imidazolyl group on I b is a poor leaving group in the presence of a 4 &' excess of solvolysis agent. Compounds Ia, Ib, and Ih were found to have remarkably low insecticidal activity, and their mammalian toxicity, in terms of LDjo in milligrams per kilogram orally on rats, had values of about 1500, 1000, and 750, respectively. This evidence implied that the compounds were not particularly effective phosphorylating agents of cholinesterases in vivo. I n agreement with this assumption, I b and Ih were found to show very lorn anticholinergic activity. The strongest support for the hypothesis proposed was provided by the finding that fungicidal potency was not affected if the entire phosphorus group, RP(X)N(alkyl)s, in compounds of structure I was replaced by a phosphorus-free substituent of suitable, stereoelectronic character. I t was found that 1tritylimidazole gave complete control of powdery mildew and late blight at concentrations of, respectively, 10 arid 35 ppm.jb6 ( C B HC ,N ~QN
( 5 ) D. R . 11ussell and H. Tolkmith, U. S.Patent application (allowedi. (6) On the basis of the evidence described in this paper it is clear that the fungicidal activity of compounds of structure I is not critically dependent upon their phosphorylation ability. N o r e likely, their activity may arise from the fact that they are imidazole derivatires. Thus, I may react in v i r 0 hy a mechanism similar to the well-known mechanism of imidazole itself.7~ \Vhile compounds of structure I are tlieoreiically capable of functioning as ambident nucleophiles, it is known t h a t the nucleophilicity of sulfur a t phosphorus in phosphoramidothionates can easily be blocked by steric factors.'b I n fact, the S atom in I b cannot be alkylated by reaction with primary alkyl halides. As a result, t h e compound I b and I-tritylimidazole have in common the presence of only one nucleophilic atom, t h e azole nitrogen of the imidazole ring. This feature and the similarity between the stereoelectronic character of the trityl group and the phosphinamidothionate group in I b may he related t o the fact t h a t I b and 1-tritylimidaaole are nearly equal in the scope and degree of their fungicidal activity. I n view of this situation i t is postulated t h a t the mechanism of fungicidal action of I differs not only from t h e well-knon-n mechanism of action of organophosphoramide insecticidesa but also from the proposed mechanism of action of 0.0-dialkyl pl~thalimidophosphorothionate fitngicides.'n,b T h e lark of fungicidal acsucli a s 111and Ii, does not tivity foitnd with imirlazolylpl~ospliinami~lates. seem to reaiilt from a redtiction in t h e niicleophilieity of the imidazolyl g r o u p because it is well known t h a t the energy of t h e highest f i l l e d molecular orbital has the same value for various types of biologically important imidazole deriratives.'c More likely, t h e lack of activity of the phosphinamidates mentioned may arise from t h e well-kno\r I I wI\ olyrir in3tability of imidazolyl I'(0)i #,roli~,*. ( 7 ) (a) See E. .i. I3arnard and \V. D. Stein, A r l ~ n n .b'nzymol., 20, 51 (1958): (h) 1%.Tolkmith. J . Am. Chem. Soc.. 86, 3246 (19133: (c) F3, Piilli m n a n d A . Pullman, "Qiiantum Hiochemi*t,ry." Intcrxience Pulilislierb. 11ii:., Ne\$ l ' o r k , N. Y.. lY6:1, a l ~ ~ r e n d i x .
TABLEI1 HALF-LIFETIME( T I ; ?OF ) I b IS SOLVOLYTIC AIEDIA
---.I i
>>2 >>2
20
>>:io
1120''
so
I .)
l l o ~ i i u g e ~ i ~re:ic.(ioii oii~ inistiire
'8
TI ' 2 , days
Temp, 'C
Medium
n-C4HoKHt CIHsOH J1 2 0 ~
iii
