Guanidine, Trimethylenemethane, and "Y-Delocalization"
Peter Gund
Princeton University Princeton, N. J. 08540
I
Can acyclic compounds have "aromatic" stability?
b a n i d i n e (I) tends to be mentioned in modern chemistry textbooks, if at all, only as an example of the power of resonance theory to qualitatively explain its strong base strength-the cation (11) possesses three equivalent resonance forms, while the free base (I) has three nonequivalent resonance structures, two of which have separated charges.
Yet guanidine and its derivatives are industrially and biologically important ( I ) , and possess undervalued significance for chemical theory. Guanidine has many unique chemical properties. Thus, the free base (I) is the strongest organic base, approaching hydroxide ion in its proton affinity (pK. 13.6). It is not a well characterized species, since it absorbs COI and water from air (typical strong base behavior). On the other hand protonation furnishes a cation (11) which may qualify as the world's most stable carbonium ion, since it is inert t,o boiling water. Guanidine and biguanide derivatives are often useful drugs, and cyanoguanidine is used by the ton in making melamine plastics. A guanidine derivative (arginine) is a natural amino acid, and another (creatine) is important to muscle activity. The human body is capable of synthesizing guanidines by transamidination of amino acids (2). The guanidine structure is incorporated in many biologically important compounds, including many of the purines.
the structure of I1 in terms of perturbation theory, starting from the corresponding hydrocarbon, trimethylenemethane. CHz
ii
0l 7I
Trimethylenemethane (111) possesses a central carbon atom with the maximum possible amount of pi-character, overlapping its p-atomic orbital with three others (4). Nevertheless, despite its large resonance energy (DE = 1.46 P, or -24.2 kcal/mol), the molecule is predicted to be unstable. As illustrated in Figure 1, HMO theory predicts an unfilled shell of pielectrons in 111, with unpaired electrons in non-bonding orbitals leading to a diradical ground state. The pattern of pi-MO's in I11 is qualitatively very similar to that of t,he unstable, "antiaromatic" (4 pi-electron) cyclobutadiene system. The high resonance energy of I11 is manifest to a certain degree, however, since it is unusually stable for a hydrocarbon diradical-it may be kept for weelm at liquid nitrogen temperat,nres (4). Is there any way for nature to take advantage of the stability of the Y-structure without the destabilizing
Heteronuclear Analogs of Trimethylenernethane
Why does guanidine have such great stability? Pauling (3) used valence bond theory. to estimate a resonance energy of -47 kcal/mol for guanidine free base, and he calculated that the cation was 6-8 kcal more stable due to the gain in resonance energy. (For comparison, the resonance energy of benzene is 30-35 kcal from valence bond theory.) We prefer to discuss
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Figure 1. Ekcfronic conRgvrrrtion lH&kckel molecvlor orbitold of trimethyl. enernethane (Ill), guonidinium ion (Ill,and guanidine 111.
effect of the unfilled shell? Borden (5) has pointed out that distorting the structure by moving two of the "arms" closer together removes the degeneracy of the nonbonding orbitals, allowing the electrons to pair up in a slightly bonding orbital while the other, empty orbital becomes somewhat antihonding in character. While such behavior might be predicted by the JahnTeller effect, the slight gain in bonding energy is opposed by the correlation energy required to pair the electrons, and little over-all stabilization appears to result. Alternatively, as pointed out by Hoffmann (6), putting a heteroatom on one of the "arms" splits the degenerate orbitals, making one bonding, and one antibonding in character. A structure such as oxyallyl (IV) should therefore be more stable than the hydrocarbon (111), and indeed IV has been proposed as an intermediate in the Favorski reaction, and in many reactions of cyclopropenones V (7). Nonetheless oxyallyl seems not to be stable enough to he isolated, and Hoffmann has calculated that the ground state of IV is still a triplet, although the singlet state is much lower in energy for IV than for 111 (6). However, the calculations are open to question, since they predict that the open form (IV) should be more stable than the rina-closed form (V), . . . and this is in conflict with experimeit (7). The final method of stabilizing the Y-structure consists of adding two electrons to form a closed-shell configuration, much as non-aromatic, nonplanar cyclooctatetraene forms an aromatic, planar dianion. For the parent hydrocarbon (111), electron repulsion effects are expected to offset the advantage of forming a closed electronic shell, and indeed the trimethylenemethane dianion bas apparently not yet been prepared (4). However, if the additional electrons are added from heteronuclear lone pairs, the molecule retains neutrality and the filled orbitals are all bonding in character. The perfect example of this type of stabilization is guanidinium cation (II), which is isoelectronic and isosteric with t,rimethylenernethane dianion, yet has strong bonding character to its highest occupied molecular orbitals (Fig. 1). If the orbitals of the 4 pi-electron trimethylenemethane system (111) resemble those of the antiaromatic cyclohutadiene, the filled orbitals of the 6 pi-electron guanidinium ion (11) resemhle those of benzene. Indeed, the calculated delocalization energy (DE) for guanidinium ion is 1.60 p (-26.4 kcal/mol), or 0.40 p per pi-center, compared to a DE of 2.0 p for benzene (-33 kcal), or 0.33 p per pi-center (8). We may remove a proton from the guar~idiuiumion (11) in the plane of the molecule, orthogonal to the pielectron system, thus perturbing but not fundamentally altering the 6 pi-elect,ron system. Figure 1 illustrat,es the resulting orbit,als for guanidiue free base (I), reflecting the loss of symmetry of the molecule but retaining most of the Y-stabilizat,ion with a D E of 1.20 p (19.8 kcal). This is a loss of DE of -0.6 0 or 6.6 kcal/mol on deprotonation of ion 11, in good agreement with Pauling's estimate (3) of 6-8 kcal/mol. Other Examples of Y-Delocalized Systems
It appears, then, that the Y-shaped configuration of 6 pi-electrons as found in guanidine derivatives is an
carbonic acid
L+H+
carbamic acid (unstable)
urea
1+~+ guanidine
p+
boric acid
Figure 2.
Y-Delocolired carbonic acid congeners.
exceptionally stable one. As might be expected, nature has taken advantage of such an energetically favorable closed-shell configuration to stabilize many other important chemical species. Most notably, all the carbonic acid derivatives may he collected in this category, with increasing pi-delocalization as nitrogen replaces oxygen. In particular, the chemical and physical properties of urea are indicative of a large amount of pi-electron delocalization. Although the site of protonation and deprotonation in such species bas often been controversial, most evidence suggests (9-12) that these species ionize in such a way as to preserve the Y-delocalized system, as summarized in Figure 2. Note that the trihydroxycarhonium ion has recently been discussed as a species of possible physiological importance (11). Boric acid and nitric acid derivatives may also fit this category, although protonated nitric acid is apparently unstable with respect to dehydration to the nitronium ion. Other Volume 49, Number 2, February 1972
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Figure 3.
5-pi eledmn, Y-dolcealized systems.
tracted the attention of early chemists by their resistance to saturation of the ring, undergoing substitution rather than addition reactions. Rather similarly, guanidine was first isolated from degradation of an "aromatic" natural product. Peruvian guano (an early fertilizer consisting mostly of seafowl excrement) was found to contain the purine compound guanine (VII), and this material on oxidative degradation afforded guanidine (18).
VII
As with benzene, guanidine tends to react by sub-
Y-delocalized species include thiourea, boron trihalides, carbonyl halides, dihaloethylenes, ethylene ketals, 1,l-diaminoethylene derivatives, trihalocarbonium ions, aci-nitromethane, and carbanions derived from nitroalkanes, esters, amides, and amidines. A survey of the chemistry of all these and other Y-delocalized species is obviously beyond the scope of an article of this size. Suffice it to say that such structures are important in many different branches of chemistry, and generally are associated with systems of enhanced st,ability. On the other hand, Y-systems with fewer or more than 6 pi-electrons are decidedly less stable. For example, the 5 pi-electron species listed in Figure 3 are stable only under special conditions (13, 14). The corresponding 4 pi-electron systems are generally even less stable; the ones listed in Figure 4 are either postulated intermediates, or are stable only a t extremely low temperatures as diradicals (4, 6, 7, 11). Interestingly, calculations on the unstable carbon trioxide (VI) favor a closed ring ground state, but suggest that a Y-delocalized pi-system is present, with no pioverlap between the sigma-bonded oxygen atoms (15). Consistency requires that 7 pi-electron, Y-delocalized systems be destabilized, due to the presence of electrons in antibonding pi-MO's. Interestingly the order of stability of trihalocarbanions is: CI3- > CRra- > CC13-, in the order of decreasing effectiveness of pioverlap, and opposite to the order predicted from inductive effects (16). Of course these carbanions are undoubtedly near-tetrahedral rather than planar in conformation; however, destabilization of the planar form (which after all is the transition state for anion inversion) may somehow affect total ~tabilit~y.Similarly, the tendency of the trihalocarbanions to expel halide ion and form dihalocarbenes under relatively mild reaction conditions may be related to the instability of the planar conformation (17). Can Acyclic Compounds be Aromatic?
Historically, benzene derivatives were often isolated from natural oils and aromatic essences; hence the term "aromatic" compounds. Such derivatives at102
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stitution rather than addition, and to resist further degradation (I). The development of the concept of aromaticity has had an interesting history (19). KelcuM originally suggested that the chemical stability of "aromatic" compounds was due to the presence of the benzene ring ($0). However the following year Erlenmeyer proposed that nonbenzenoid compounds with special chemical stability might also be termed "aromatic" (21). Later, Iiermack and Robinson suggested that the "aromatic sextet" of electrons conferred reduced unsaturation and the tendency to retain the type in compounds in which it occurred (22). With the forrnulation of Hiickel's famous rule, "aromatic" stability became expected for all monocyclic, planar polyolefins containing 4n 2 pi-electrons ($3). The concept has continued to be transformed as more exotic "aromatic" systems were discovered. Some representative aromatic systems which do not strictly fit Hiickel's rule are shown in Figure 5. Thus, pyridine
+
Figure 5. rule.
"Aromatic" sompounds which do not strictly fulfill Hiickel'r
and thiophene contain hetero-atoms, naphthalene is not monocyclic, ferrocene is non-planar, homotropylium ion is nonplanar and not fully conjugated, and the cyclopropeuone merely contains 4n 2 pi-electrons in one resonance form. However, the cyclic criterion for application of Hiickel's rule generally is retained. As such esoteric systems came to be considered ',aromatic," the chemical stability criterion had to be modified, since many of these materials are unstable except in solution, or at low temperatures, or in the absence of air (for example, the fully aromatic cyclopentadienide anion ignites in moist air). Spectral criteria for aromaticity have become popular; ultra-violet spectra and more recently the demonstration of a ring current in the nmr spectrum are among the favorite methods.
+
Despite recent trends, it would appear useful to designate systems as "aromatic" if they represent a delocalized system exhibiting peculiar chemical stability, in order to focus attention on such systems even when they are buried in complex structures. Since guanidine and its derivatives appear to possess really exceptional stability, and since their physical and chemical properties appear to be dominated by the tendency to retain the closed-shell, Y-delocalized 6 pi-electron configuration, we suggest that it is profitable to consider such substances as possessing a special type of "aromatic character," despite their acyclic nature.'
N-N
H~N--(
+,
NE=N
Uses af the Concept of Y-Aromaticity
We believe that not enough notice is paid to the presence of "Y-aromatic" structures in complicated molecules as a chemically stabilizing influence. Thus, aminoguanidine derivatives appear to have more in common with arylamines than with hydrazines (24). Heterocyclic systems containing Y-aromatic centers may prove to be exceptionally stable. The significance of Y-delocalized moieties in purines, proteins, and other bio-molecules appears to be seldom considered in a unified manner, although chemical stability, coulombic, and hydrogen-bonded interactions of such materials are profoundly affected by such structural features. In addition, formation of a Y-delocalized intermediate may act as a driving force for chemical transformations. Reaction of carbodiimides with oxygenated materials, to form a urea and a dehydration product, is a case in point. Many ~eactionsof cyanamide derivatives may also be interpreted in thismanner. Finally, we note that Y-delocalized systems may be coupled or fused together to make larger stabilized systems, just as benzene may; some stable derivatives of this type are illustrated in Figure 6 (26-28). Ten pi-electron systems of the tetra(dialky1amino)ethylene (VIII) type may be considered to be derived from the pi-system of the known tetramethylene-ethane dianion (29). The S pi-electron, diradical hydrocarbon (IX) in this series has also been studied ($0).
H2N+m-NH/'hHs Typical complex derivatives of Y-delocolired ryrtomr
Figure 6.
( 6 ) (4 H o s a l a ~ mR., , J . A m r . Chcm. Eor., 90,1475 (1968). (b) Gberre~, R., A N D HOFFMAIN, R., A W Y . Chem. I n t . E d . . 8 , 2 1 4 (1969). 171 Review: Tnnno. N. J.. Acoaunts Chem. Res.. 2 . 2 5 (1969). i8j G u m . P.. unpubliahsd calculations. ( 9 ) OLAH.G . A,. A N D CALIN,M., J . A m ? . Chcm. Soe.. 9 0 , 4 0 1 (1968). ( l o ) OLAH.G . A,, A N D WHITE,A. M.. 3. Amer. Chem. Soc., 9 0 , 1884 ( 1 9 6 8 ) . (11) Review: OLAX.G . A,, W m m , A. M . . A N D O'BRIEN.D . H.. Chsm. Re%. 7 0 , 5 6 1 (1970). R., and M a m s ~ nL. ~ J., . Con. J . Chern.,3 9 , 401 (1961). (12) STEWART. 113) SOLOWAY. S.. ROBENBTOCK. H . M.. AND SAATOBO. A,. J . O w . Chem.. . . 23, 1042 (1958). . . C., Gmscou. D. L., m n BRAY,P. J., J . Chcm. Phua., 5 4 , (14) T~rfionP
. - ~ .~. ~ ,
J.. BURSRB,N . w.. H & : M . A N O LANOFORD, P.,?.J . ~ m c r . Cham. Soo., 7 9 , 1406 (1957). See also G o u m E. S., Mechanism and structure in Organic Chemistry." H d t , Rinehart and Winston. N. Y.. 1959, p. 381. H m e , J.. B u r ~ e n w o n ~ aR., . AND, LANOPORD P. B . , J . A m ? . Chcm. Sor., 8 0 , 819. 824 (1958); HINE,J.. EBRENBON, S. J.. J . Amw. Chem. Soc., 8 0 , 824(1958). STREOKER. A,. Ann.. 118, 151 (18611. Reviews: Lsouo. D.. "Carboovolic Nonbenrenoid Aromatic Com-~~ pounds." EI~.&. ~materdam,1966; JONEB,A. J.. Pure and Appl. Chem., 18, 253 (1968); B n e s ~ o w ,R., Chcm. and Enp. Ncws, June 28. 1965. p. 9 0 ; FIQEIB. H . P.. i n "Topicsin Carboavolio Chemistry." V o l . I . (Editor: LLOYD,D . ) Plenum Press, N. Y., 1969, P. 269: Sraarrwrma~a. "Mnleeular Orbital Theorv for Oreanic ~---- ~A.. ,~ ~-~~~ .~, . Chemists." Wiley, N . Y . , 1961,che.p. 10. K a a n ~ B ,F. A,, Bull. Soc. Chim. Fr., ser. 2 , 3 , 98 (1865); sas also ref. HIND.
~
~
~
\."",. ,.O",
Acknowledgment
The HMO calculations which led to this article were largely carried out while the author was at the Agricultural Research Division of American Cyanamid Company. The author wishes to thank Professor Paul von R. Schleyer for helpful criticism. Literature Cited ( 1 ) "The Chemistry of Guanidine:' American Cysnamid Co., Wayne. N . J. (1950). See d s o Beilstein article on guanidine. ( 2 ) VAN TXOAI.N.. i n "Comprehensive Biochemistry" (Editors: Fm% XIN. M.. A N D STOTZ. E. H.) V o l . 6 . Elsevier. Amsterdam, 1965, p . 228. ( 3 ) PAUL IN^, L.. "The Nature of the Chemical Bond." Cornell Univ. Press, Ithioa, N. Y . , 3rd ed., 1960, p. 286. See also Pnmnm, L., i n "Organic Chemistry: ao Advanced Treatise" (Editor: Oilmao., H . ) . V o l . 2 , 1943,p.213. ( 4 ) Review: Wmss, F.. Quart. Rcu.. 2 4 , 278 (1970). . T . . Tetrohedron L d t . . 259 (1967). ( 5 ) B o n o x ~W.
(21) (22) (23) (24) (25) (26) (27) (28) (29) (30)
ERLENMEIZR. E., Ann., 137.327 (18661. See eap. P. 341 tf. KsnMAca. W . 0.. AND Ronrmon, R., J . Cham. Soc., 121,427437, (1922). HUcaw+ E.. 2.Physik. 7 0 , 2 0 4 (1931). Kunzsn. F . . AND Goorner. L. E. A , . Chem. and Ind., 1584 (1962); and Anpam. Chem.. Inl. Ed.. 2 , 459 (1963). (a) H O P P M A N N R., , Annew. Chem. I n t . Edit.. 7 , 754 (1968). (b) WIa e m . N.. Anww. Chcm. I n t . Ed., 7 , 766 (1968). R m a n n . R., Bcr., 101, 174 (1967). KURZER.F.. A N D PITCXIORI, E, D.. "The Chemiatry of the Biguanidea." in Fortachr. Chem. Forsch., 10, 376 (1968). K n ~ u m s m a r nA,. . J . Amer. Cham. Soc., 81, 6017 (1965). B ~ m o N, . L., A N D STBYENSON, G . R., J . A ~ B IChem. . Soe.. 9 1 , 3675 (1969). D o w o . P.. J . Amar. Chcm. Soc.. 92,1086 (19701.
' There appears to be no greater than additive gain in resonance energy in traversing the series: HrC=NHlf, H2N-CH= NH,+, (HIN)~C=NHI+such &S is observed in the progression: cyclohexene, 1,3-cyclohexadiene, benzene. Nevertheless the guanidinium ion represents a maxhum delocdilis~tionfor acyclic systems, with a closed-shell pi-electron configurrttion and resonance energy of the same order of magnitude as benzene.
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