SEPTEMBER, 1947
THE CONCEPT OF ISOSTERISM H. LEON BRADLOW, CALVIN A. VANDERWERF. and JACOB KLEINBERG University of Kansas, Lawrence, Kansas
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lir (~, 1 ) first introduced the concept of isosterism, the meaning of the term has undergone considerable modification and extension. In general, it appears that inorganic chemists have adhered to Langmuir's original restricted definition, whereas organic chemists have found it useful,to employ the term .in a broader sense. The present paper constitutes an attempt to trace the development of the concept of isosterism, to indicate the definitions now in use, and to suggest how these definitions have been valuable in demonstrating previously unrecognized relationships among compounds and in pointmg the way to new areas of investigation. Langmuir proposed that molecules or groups which have the same number of atoms and the same total number of electrons arranged in the same manner be described as "isosteric." He called attention to the fact that when isosteres are also isoelectric, i. e., when they have the same total charge, then they possess strikingly similar physical properties. Classic examples of pairs of isosteres showing extraordinarily close agreement in physical constants are carbon monoxide and nitrogen and carbon dioxide and nitrous oxide, as illustrated in Table 1 ($1. In his rather unsuccessful attempt to explain isomorphism, Grimm (3) broadened the concept of isosterism to include molecules or groups possessing the same number of valence electrons whether or not the
same number of atoms were involved. According to Grimm's definition, groups of the following types are classed as isosteric: fluoride, hydroxyl, amino, and methyl; oxide, amethylene, and imide; and acetylide and cyanide. Shortly after Grimrn's work appeared, Erlenmeyer beean an extensive series of investieations dealiie with the application of Grimm's interpretation of isosterism to organic chemistry. In his initial paper (4) Erlenmeyer pointed out that the dyes obtained by the coupling of &naphthol with
-
u
-
exhibit almost identical absorption spectra where X = He also called attention to the similar chemical behavior of a number of isosteric substances (2). In what is perhaps Erlenmeyer's major contribution in extending the concept of isosterism, he proposed (6) that the aromatic -CH=CHgroup and the ring sulfur atom are isosteric. Erlenmeyer arrived a t this conclusion by arguing that only.the boundary electrons, i. e., the outer electrons of the group, should be counted in determining isosterism. Thus in the case of the -CH=CHgroup, for example, the two electron pairs shared by the carbon atoms are not to be counted, as they are considered to be within the group or "pseu-
-0- or its isostere -CH2-.
TABLE 1 N.
Critical temperature Critical pressure atmospheres Density of liquid Viscosity Magnetic susce tihility Formula of hy&ate Heat of formation of hydrate
-127' 33 0.796 166 X lo-"
. . . . . . .. . . .. ... . ..... . . .
CO
NLJ
CO?
JOURNAL OF CHEMICAL EDUCATION
doatom." In this connection, he called attention to the fact that benzene and thiophene possess very similar physical properties, such as boiling point, molecular refraction, parachor, certain crystallographic constants, and size and shape of the molecules in the liquid state. In a striking investigation, Erlenmeyer and coworkers (5) found that even in the exceedingly specific antigenantibody reactions, certain corresponding derivatives of henzene and thiophene proved to he indistinguishable. The antigens :
:
N
-
> C-co - H N
.
horse serum
.
horse serum
and cO
for example, gave identical precipitin reactions with the antisera to the former. Despite the fact that benzene, thiophene, and furan differ in structure only in the substitution in the molecule of one supposedly isosteric group for another, the expected similarities in properties extend only to the first two compounds and to their derivatives, and not to furan and its derivatives. I t appears, therefore, that some additional factor must play a part in determining whether or not the properties of such compounds hear a close resemblance to each other. Erlenmeyer and Leo (6) attributed the apparently anomalous properties of furan to the fact that the intermolecular forces of furan are considerably smaller than those of henzene and thiophene.: More exactly, the diierences in the physical and chemical nrooerties of thioohene and furan., oarticularly the lesser aromaticity of the latter, are best explained on the basis of the smaller degree of resonance stabilization in furan. Shomaker and Pauling (7) have shown that the degree of resonance stabilization of the thiophene molecule, like that for henzene, is significantly larger than that for furan. The increased stabilization of thiophene as compared with furan is attributed in part, a t least, to the contribution of resonance structures in which ten electrons exist in the valence shell of the sulfur atom, as illustrated here.
. .
+
HC-CH HA
.
H-H JH
N 5-/
HA
\s/+-
CH I
HC=CH I HC
AH
NsJ
Corresponding resonance structures for furan are ruled out because of the inability of oxygen to expand its valence shell.
* Proponents of the principle of isasterism do not point out the fact that by definition pyrrale is &Is0isosteric with benzene, thiophene, and furan. Its physical constants differ rather widely from those of the above three compounds, perhaps because its molecules can associate through hydrogen bonding involving the amino-hydrogen atom. It is apparent, therefore, that the principle of isosterism can be used with success to predict similarities only hen applied with great caution and after careful eonsiderat,ionof ot,herpertinent factors.
Similar considerations apply to thiazole and oxazole in their relation to pyridine. An interesting example of this fact is provided by Erlenmeyer's observation (8) that the hydrogen atoms of the methyl group in the sodium salt of 4-methyl-thiazole-5-carboxylic acid undergoeexchange with deuterium when the compound is dissolved in deuterium oxide, whereas the analogous reaction does not occur with the corresponding oxaeole derivative. Presumably the methyl hydrogen atoms in the sulfur-containing compound exhibit appreciable acidity because of the fact that the anion (three resonance structures shown below) resulting from the loss of a proton is stabilized by the contribution of resonance structures (b and c ) in which the sulfur octet is expanded.
Resonance structures of type b and c are obviously impossible for the corresponding oxazole anion, and it would be expected, therefore, that the acidity of the methyl hydrogen atoms in the oxazole compound would be considerably less than that in the thiazole derivative. From these exceptions to the general principle of isosterism, it is apparent that the broad definition which classifies atoms or groups containing the same number of boundary electrons as isosteric does not necessarily provide a valid basis for the prediction of similarities in physical and chemical properties. One must take into account, in any given case, such factors as resonance possibilities and opportunities for hydrogen bonding. It is also noteworthy that perhaps without exception the only cases in which isosteric groups do actually confer similar properties to substances are those in which the groups involved differ little in weight. In the light of these considerations i t appears that the present expanded definition of isosterismt is too broad to be of much practical value. As applied to certain specific groups whose similar effects have been well established, however, the concept of isosterism is playing an important role in suggesting the possibilities of new physiologically active agents which differ from compounds of tested value only in the substitution of one such isosteric group by another. Many examples of this fact appear in the literature, only a few of which will be cited here..t t Certain authors, notably Ficser and coworkers [see L. F. FIESERA*ND E. B. HERSHBERG, J. Am. Chen. Soc., 62, 1640 (1940)], have employed the term "isolog" in the sense that isostere is generally used. 1 For additional examples see: (a) BLICKE,F. F., AND J. H. B. BURCKHALTER, J. Am. Chem. Soe., 64,477 (1942); ( b ) RHODEHAMEL, H. W., AND E. F. DEQERI~G, Amer. Phann. Assoe., 31, 281 (1942); (c) ERLENMEYER, H., Helv. Chim. Ada, 21, 1013 (1938); ( d ) BARGER, G., AND A. P. T. CASSON, J. Chem. Sac., (Continued on nert ~ o 0 4
SEPTEMBER. 1947
435
A classic case of this type of approach, as Northey
isosterism to the study of synthetic medicinals are appearing regularly in the current, literature. It is likely that the concept, applied with proper consideration of its limitations, will continue to find its chief use in the field of physiological chemistry.
(9) has pointed out, is that of sulfapyridine, sulfadiasine, and sulfathiazole. Steinkopf and Oshe (10) found
that the replacement of the benzene by the thiophene ring in cocaine produced a compound closely resembling cocaine in its physiological effect. Another interesting example is that of the alkylamine esters of p- LITERATURE CITED I., J. Am. Chem. Sac., 41,1544 (1919). fluorobenzoic acid, which have anesthetic properties ( 1 ) LANGMUIR, H., AND M. LEO,Helu. Chim. Acta, 16,897similar to those of the corresponding derivatives of p- ' ( 2 ) ERLENMEYER, 004 . 11033). ~ -. ~ hvdroxvbenzoic acid (11). Curiouslv. when the ~ v r i - ( 3 ) GRIMM,H. G., M. G~~NTHER, AND H. TITTUS,2. physik. dyne riAg was substitited for the th&ole ring in %a2.Elelctrochem., Chem., 14B, 169 (1931); H . G., GRIMM, min, the resulting compound was found to have antiNaturzisseenchaften, 17, 31, 474 (1925); H. G. GRIMM, 535 (1929). thiamine activit;(lB).- Presumably, this is a result of ERLENMEYER, H., AND M. LEO,Helu. Chim. Acta, 15, 1180 (4) the fact that although the pyrithiamin is absorbed like (1932). thiamin, nevertheless it cannot enter into the same . ( 5 ) ERLENMEYER, H., E. BERGER,AND M. LEO,ibid., 16,733-8 metabolic processes. (1033,. ~----,. (6) ERLENMEYER, H., AND M. LEO,ibid., 16, 1381-9 (1933). Further examples of the application of the concept of V., AND L. PAULING, J . Am. Chem. Soe., 61, ( 7 ) SHOMAKER, 1777 (1939). 1938, 2100; (e) ENGLISH,J. P., R. C. CLAPP, Q.P. COLE,et al.9 H., AND H. M. WEBER,Helv. Chim. Aeta, 21, J . Am. C h a . Soc., 67,295 (1945); Lf) GRAHAM, J. D. P., Quart. ( 8 ) ERLENMEYER, 864 (1938). J . Pham. Pharmacol., 13,305 (1940); (g) TAINTER,M. L., ibid., E . H., Chem. Reus., 27,103 (1940). W.. AND W. OHSE.Ann.. 448.205 3.585 (1930): ( 9 ) NORTHEY, ., Ih), STEINKOPF. (i926); (i)WARREN,M. R., D. G. MARSH,et al.; J. ~ & n z c o l . , (10) STEINKOPP, W., AND W. OSEE,Ann., 437,14-22 (1924). L. S., AND E. E. COMPAIONE, J . Am. Chem. Soe., 79, 189 (1943); 0') DANN,O., Ber., 76,419 (1943); (k) BLEKE, (11) FOSDICK, 63,974 (1941). F. F., AND M. U. TSAO,J. Am. Chem. Sac., 66, 1645 (1944); D. W., AND A. G . C. WHITE,J. Bid. Chem., 149, (1) ERLENMEYER, H., AND H. MEYENBERG, Helu. Chim. Acta, 20, (12) WOOLLEY, 285 (1943). 204 (1937).
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0 ON A CHEMIST
C U R I O U S Here l ~ t hto di*,
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u p urh.r GODPREY, CKTYIL~; A man who in thi earthly Pursued various ~ ~ O ( . N I ro I Qbuin Ananm wim, or the secret to live; Also, a v m vifn Or the art of gctfing rather than nuking p11. Alchymtc like-& saw All his labom and m o i a i o a . As -a in the firc, rr$p;ard & hme. When T c dg&d to his $,a# p/n~$Lr, H e d c p a d w poor As the last d r o p o f ac oln.6;~; For riches =re not pomed On the ldcpu of thi world Though fond of novelty, he c ~ l avoided l ~ The fir-fdiw, rfovfitwt, a d LrripMkn. Of this life.
and H@ i& ' ..fw; Brhg it me to th M= of the nbr( Of cbt gloh i Rncc it in a proper mgia, Or r a#& d. Amoogrbelm thcprvrn./B'+d;
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l?Il the gcnml n n r r i d , C ~ P . I " ~ %, A d n6Lmafim of all chiup ! Courtesy of the American Phil~ophlcalSociety
The Above Epitaph fa An Anonymous E.srnL.1. of Early Amsrican Humor. It First Appe-d in The Columbian M = p a r i n e , Volvms 3, Page 367. in 1789.-Wyndham M i l a
