ml. of water. The resulting prec,ipit>atewas collected by filrration. The product was recrystallized from ethanol t 0 afford 1.1 g. of 4-methylarninobenzonitrile, m.p. 86". 111 the case uf ethyl-. propyl-, itnd biit3-lamiiiobenzoiiitrile; method B TKIR I x t t cr t h m method A . 4-Methylaminobenzothioamide (Table 111~.--4-~1etliyl~riiiiiobenzonitrile ( 2 g.) was dissolved in a mixture of 10 inl. of pyridine and 5 ml. of triethylamine, and the solution was treated with H28 TABLE
I11
4-~~LKYLA.\IISOBEZZOTHIOAblIDES : p-lt XHCeHdCBYIJ? .___c
(
f(,llnd--
5s. 14 60.46 61.84 61.68
63.42 ,5S,45 64.06 64 61 69 06 6S.77
-
II
(,
6.06 6.69 7.4:: 7.32 7.96 7.stn ,31 p , in p., R moles O C . O C ' \\ ater
CHJ 2 76 C2Hj 2 95 CjHi 1 h4
_ - L o
('
calcd--- -_ 1% II,O
134 4.2 61 G 09 131.5 47 15 6 60 1*30 5 3 32 6 71
__
c
--(
found -II K O
16 70.995. Adding a (log P ) 2term' to eq. 4 does not result in an improved correlation. In the first r e p ~ r t ,1Ic1lahon ~ inveqtigated the demethylation of the amines (A-F) containing aromatic rings. Proceeding as described above, we obtain eq. 5-7. An I; test shows that the additional electronic term in eq. 7 is not significant even at the 0.75 level. One (7) J. I n a s a , T. Fujita, and C. Hansch, i b z d . , 8, 150 (1965). Iwasa, and C. Hansch, J . A m . Chem. SOC.,86, 5175 ( 1 964).
HE,& CHa A
reason for this may br the relatively little v:wiatioii i l l pK, for these compounds compared to the variation i n log P .
~s(lFLl~ i t’ll/\
Ill(’ -7-
I>Y:CII,.
7 - b
>%CY-: I n log BK = 0.094 log P f 0.325
+ 0.665
log Bli
=
0.137(pKa - 9.5)
log BR
=
0.099 log P 0.190(pK, 9.5) 0.354
+ +
1’
9
(i 0 7 8 % 0 1 1 6 i.5)
0
0 24s
0 180 ( 6 )
A
0 853
0 112 17,
For the work in this report, P is the octanol-water partition coefficient so that the larger the value for P , the more lipophilic the compound. Thus the positive coefficients associated with log P in eq. 2-.i bear out Brodie’ij idea arid -1IcJIahon’s conclusion that the more lipophilic the compounds are, the more rapidly they are deniet hylated. Where electronic teriiis are hignificarit in the above equations, we note that a negative coefficient iz a?sociated with (pK, - 9.*5). Thi- mean- that the 1o~wr the electron density on riitrogen (a- iiieaiured by R3N+He RJ H+), the greater tlie demetliylatioii rate. An obvious interpretation of this could be thnt the lower electron deiiqil y redwes the c1i:iiire of protoriation of the riitrogen and herice the aqueous holiibility of the amine. I t 1iiii-t he kept in mind that K or log P is determined8 bo that i t 1- indeperideiit of the degree of dissociatioii ; hence 7r and pKa are independent variables. Actually, both call play a role i i i the distribution of the amines between the :tqueou+ and lipophilic, phases The role of pk’, i n thi. prows< i i difebz accurately ,-invc i t will vary n i t h the, nvironnient and tlic endobio eiiviroiinient at tlie sites of action may be different from that of t l i r external -elution. One of the most interesting aspect- of lIcl\Iahon’? htudy is the minor importance of steric effects on tlip rate of demethylation. O n e might expect that thc demethylation rate of a molecule IT ith such highly branched substituents a‘. t-amyl-t-butylmethylamine would be ho diff ererit from ?z-di~)rol)ylinethylaminethat :in equation i u c h as 4 without x -teric parameter would give good correl:ttions. It seeni- to us this would of necessity be true if any group other than a proton were involved in reaction with 1 he nitrogen lone-pair elertroni. The work of Brown9 has c.l(~irlydenionstrated that the steric requirement for a proton reacting with highly -ubstituted :tin ie- :ire uniquely low. It also clear from Browti’s worl, that the -teric requi1.c.-
+
14
(‘li
I I (‘. H r o u I i . J C’henr b d u r 36, 424 ~ l ( l j q ) .
>YCH,H t
:wizmw
+
lf.t.ll/\
1111’
( \ I
1110
1‘) 1
---+ I>NCH?
>s-((H2] + H . t , l l / \
tion of the nitrogen would iiiliibit either iiier1i:uii-in 8 or 9 by tying dowii the lone-pair elevtrons :mid thupreventing their -tabilizatioii ot rhe intcrniediatc~through re.conaii(le. Thus the role of the electron deii.;ity o i i iiitrogeii 111 the above suggested mechaiiiiiii for demethylat ion i coniplex. If it is very high, the aniirie is primnrily in the ammonium ion form arid it? lipophilic character is lowered. If it i i too low, tlicn the availability of thc electrons for qtahilizing an intermediate i5 decreased. In order to te-t this hypothe IVC have deriwd eq. 10 for compound- 1-18 in Tab1 . Thi- giw- :I -lightly Illy ‘1
NR ;)?
I’ - u 068ipl
