January 196s
KOTES
Substituent Effects on Ester Carbonyl Absorption and Chemoreceptor Responses Initiated by Tropanyl Phenylacetates‘
particular, the point as t o whether ring substituents are able to exert remote electronic effects on the a-electron distribution function of the -0C0- group, through the aryl ring and the insulating methylene linkage, arid thereby alter the strength of interaction of this highdensity locus with a potential charge site in a tissue receptor seemed amenable to probing by infrared absorption measurements of the C=O stretching vibrations in the esters. To the extent that electron supply toward or electron withdrawal from the C=O locus by substituent X changes the x-electron profile, a corresponding change in XC=o would be expected. This possibility has now been tested, n ith the results described below. l;irst, the spectra of all esters studied contained the characteristic absorption peak correspoiidiiig to the C=O stretching vibration in the expected3 XC-o region, 5.7-,5.S p . This peak for each ester appeared invariant in position as the ester concentration in CHCl, varied from 1-570 (w./v), with a reproducibility in peak wavelength of the order of 0.01 p . Aldditionally, the OH bond4 and potential H-bonding bands4 characteristic of the parent amino alcohols, tropine. and $tropine, mere missing from the ester spectra. Both of the urisubstituted phenylacetates I arid I-$ were found to display sharp absorption peaks at 3.77 I.(. This peak value n a s therefore taken as each series reference, and the XCzo values for the corresporidirig peaks of the other esters were tabulated in terms of algebraic deviations from this reference position in each amino alcohol series. This tabulation iq sumniarized in Table I, which includeq data for the available ester I-XIV in each tropanyl series, for the urisubstituted cyclohexylacetate esters, for the 2-a-tropanyl esters XY arid XYI, and finally for the dichloroacetate ester4 of
S. L. FKIESSI K D F. J. F
~ S H
Uztiszon of Biochemistry, Yaval Medzcal Research Institute, Bethesda, Maryland 20014
Recezved July 9, 1967
Recent work’ on toxic interactions of moiiosubstituted phenylacetate esters in the 3-tropanyl (tropine Hiid $-tropine) arid 2-a-tropanyl series \\ ith C S S receptor systems in the mouse has pointed to a rather systematic depeiiderice of potency 011 certain structural features of the ester. In general, the order of decreasX
Me
Me
X
fi
T
i OCOCHp
2 - Q - Tropanyl esters
3 - Troponyl esters
(Transoid 1 Group X
Series T
-
H
I
m-NO,
I1 I I1
p
-NO2 -F m-F
_O
IV
-
V
Group
JI-T
X -
I - JI 11- JI
-p - N O z -p - C H 3
111- Jr IV-
VI
P
-CI m-Br
VI1 Vlll
Vll-JI Vlll-JI
0 -CH3
IX
IX-JI X
XVI
-JI
p -CH, p-CH, M e 1
XI XI1
XI-$
m-OCH,
Xlll
Xlll-+ XIV #
p -OCH,
XV
JI
m-Cl
m-CHn
Ester
ing potency in CXS stiniulatioii/blockade arid acute toxicity at constant substitution X runs in the sequence 3-tropariyl (transoid) > 3-tropanyl ($, cisoid) 2 2-atropanyl (transoid). With progresbive change in X, it is noted that relatively electronegative substituents (X = C1, SO,, etc.) on the aryl nucleus of 3-tropanyl esters confer significantly larger increments of toxicity on the parent structure (X = H) than do electropositive substituents (e.g., OCH,). This latter aspect of the structure-activity relationship raises the question of the degree to which the aryl substituent X may alter the total electron-density profile of the ester, arid in turn the manner in which this alteration may be reflected in a change in effective interaction of a given ester with chemoreceptor surfaces controlling the onset of the convulsioii-paralT.sis syndrome in the mouse. I n (1) From Bureau of Xedicine and Surgery, Navy Department, Research task XR005.06.0002. T h e opinions in this paper are those of t h e authors and do not necessarily reflect t h e views of the N a r y Department or the naval service a t large. ( 2 ) Leading references: (a) S. L. Friess, R . C. Durant, H. D. Baldridge, Jr., and L. J. Reber, Tozicol. A p p l . P h a r m a c a l . , 7 , 694 (1965); (b) S. L. Friess, H. D. Baldridge, J r . , R . C. Durant, and L. J. Reber, ihid., 7, 794 (1965).
xr=O . \ N D
17.5
TABLEI MOUSELDjo TT.kLUES FOR TROPASYL PHESTL.lCET.lTES A N D RELATED ESTERS
Ester hydrochlorides I and I-$ I 1 and 11-$ I11 and HI-$ I V and IV-$ V VI VI1 and VII-$ VI11 and VIII-9 I S and 19-4 X-$ X I and XI-$ XI1 XI11 and XIII-$ SIV-$ XV XVI Cyclohexylacetates Dichloroacetates
Xc=o deviations from refa peak, fi Tropine $(trans- Tropine aid) (cisoid) 0.00 0.00 0.00 +0.01 -0.01 -0.01 0.00 +0.01
Arouse LDaa values,c fimoles,/kg Tropine $-Tropine 7 7 . 8 & 2.T 1 4 2 . 9 =t 5 . 4
+0.01 f0.01 -0.08’ 0.00 +0.04
+O.Ol +0.02 +0.01
0.00 0.00 -0.01 +0.02 -0.06
5 3 . 6 =t 1 . 5 18.5 i 3 . 6
65.5 6.5 7 1 . 2 =t 1 . 6
T6.9 i 0 . 6 32.7 i 1 . 2
105.5 127.5
+
7.1 1.6
f0.01 +O.Ol
-0.04 -0.03 fO.02
-0.04
+O.OZ -0.04
119.3
5.3
112.6 i 4 . 0
a Reference level of Xc-o 5.77 p as found for the unsubstituted phenylacetates I and I-$; spectra taken in CHC13 unless otherwise indicated. * Spectrum taken in 50% CHCla-50% Flriorolrtbe (vol) because of low solubility in CHCl3 alone. Previously documented; see leading references.2
(3) R . T. Conley, “Infrared Spectroscopy,” Allyn and Bacon, Inc., Boston, Mass., 1966, p 145. (4) B. L. Zenita, C. M. Martini, M. Prisnar, and F . C. Nachod, J . Am. C h e m . Sac., 74, 5564 (1952). ( 5 ) S. -4rcher and T. R. Lewis, C h e m . I d . (London), 853 (1954).
