J. Org. Chem. 1981, 46, 2330-2333
2330
Guanidinium Ion Self-Consistent Field Calculations: Fluoro, Amino, and Methyl Single Substituents L. Herzig, L. J. Massa,* and A. Santoro City University of New York, Hunter College, Department of Chemistry, New York, New York 10021
A. M. Sapse City University of New York,John J a y College, Department of Science, New York, New York I0091 Received November 21, 1980
Rotational barriers of NH2and NHX groups are calculated for the single substituted guanidinium ion, where X is F, NH2, or CH3. The geometries and the net atomic charges are also calculated. In a recent paper’ we presented a theoretical study of the electronic structure of the guanidinium ion C+(NH2)3 (la). Here we extend that work to single substituted guanidinium ions.
Our analysis of the charge carried by the amino group lends support to this hypothesis. A matter intimately related to the permeability experiments is the mechanism of action for tetrad~toxin,~ also a substituted guanidinium molecule (2). The toxin affects H
I
C+ \N/
H\N/
I
x
ti
I
0-
I
I
H
la, X = H
b,X=F c, X = NH, d. X = CH,
We chose fluoro (lb), amino (IC), and methyl (la) substituents. These model a range of electronic donoracceptor behavior that much influences the role played by guanidinium ions in several important experiments. NMR measurements2 have been used to study substituent effects on guanidinium rotational barriers. Barrier changes of a few kilocalories per mole have been rationalized partly in terms of substituent interaction with the Y-aromatic charge distribution characteristic of the guanidinium ion. The calculational results presented here illuminate such rationalizations. Moreover, we find in certain cases that intramolecular hydrogen bonding is an additional factor controlling the rotational barrier changes. In a series of voltage-clamp experiments3 with giant squid axons it has been shown that amino-substituted guanidinium, as well as guanidinium itself, is capable of passing through sodium channels in the nerve membrane. Methylated guanidinium ion, however, is incapable of passage. This fact has been central to the structural model hypothesis for the sodium channel “pore” controlling selective ion passage. In the case of free guanidinium, which is planar, the molecule fits neatly through the rectangular 3 X 5 A “pore” in the sodium channel. A methyl substituent increases the molecular width and prevents passage. As our results indicate, however, the geometry of amino-substituted guanidinium is remarkably similar to that in the methylated case. Presumably the amino-substituted guanidinium can reduce its effective width by forming strong hydrogen bonds on passing through the sodium channel. (1) A. M. Sapse and L. J. Massa, J. Org. Chem., 45, 719 (1980). (2) A. Santoro and G . Mickevicius, J. Org. Chem., 44, 117 (1979); V. Bauer, W. Fulmor, G . Norton, and S. Safir, J.Am. Chem. Soc., 90,6846 (1968);H. Kessler and D. Leibfritz, Chem. Eer., 104, 2158 (1971). B. Hille, J. Gen. Physiol., 59, 637 (1972). R. Keynes, Sci. Am., 240, 126 (1979). L. Packer, S. Tristam, J. M. Hem, C. Russell, and C. L. Borders, FEBS Lett., 108,243 (1979). T. Oja, J. Chem. Phys., 59, 2668 (1973). W. J. Hehre, R. F. Stewart,and J. A. Pople, J. Chem. Phys., 51,2657 (1969). R. Weast, Ed.,“Handbook of Chemistry and Physics”, Chemical Rubber Publishing Co., FL 1965, pp F-218-9. (3) B. Hille, J. Gen. Physiol., 59, 637 (1972).
0022-3263/81/1946-2330$01.25/0
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nerve function. The guanidinium moiety enters a sodium channel, and the “substituent fragment” attaches by hydrogen bonds to a protein in the cell wall of the nerve membrane. The net result is blockage of the sodium channel to the passage of ions and hence inhibition of nerve function. It often occurs that apparently trivial substitutions dramatically affect the biological activity of chemical compounds. Therefore, one wishes to know whether such changes are capable of affecting the geometric and/or electronic structure of the guanidinium moiety which is presumed to bring the toxin into position in the sodium channel. Our results indicate that even strong substituent effects leave the geometry of the guanidinium moiety essentially unaffected. The electron distribution, however, can show large reorganizations over the fixed geometrical framework. The amino acid arginine is also a substituted guanidinium. Light conversion by bacteriorhodopsin involves motion of protons across the purple membrane of “Halobacterium halobium”. A guanidinium carboxylate complex (attached to arginine) is thought to act as a charge-transfer relay for protons5 (3). (Interestingly the a-
/H
et
H
H
3
carboxylate ion group seems to be involved in the inter(4) R. Keynes, Sci. Am., 240, 126 (1979). (5) L. Packer, S. Tristam, J. M. Herz, C. Russell, and C. L. Borders, FEES Lett., 108, 243 (1979).
0 1981 American Chemical Society
J. Org. Chem., Vol. 46, No. 11, 1981 2331
Guanidinium Ion SCF Calculations Table I. Fixed Geometrical Parameters planar amine
-"!
Table 11. Selected Optimized Geometrical Parametersa parameter
