Concertedness of 1,3-dipolar cycloadditions
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Concertedness of 1,3=Dipolar Cycloadditions M. Serajul Haquel New York University, Washington Square, New York, NY 10003
The 1.3-dipolar cvcloaddition is the union of a 1,3-dipole with a &tiple hond sysrrm (adipolarophilej to form a five- membered rina. The process is remarkably useful and is re- garded as one i f the most general methods for the synthesis of five-membered heterocycles. Its versatility in the synthesis of heterocycles is comparable to that of the Diels-Alder re- action in the formation of carbocyclic systems.
The formation of the triazole (I) from phenyl azide and dimethyl acetylene dicarhoxylate indicates this type of reac- tion was known even in the late nineteenth century (1).
L. I. Smith (Z), in an extensive review, illustrated the open chain and cyclic 1,s-additions of several typical dipole species, such as aliphatic diazo compounds, azides, nitrones, nitrile oxides, furoxans, iso-oxazoline oxides, azoxy compounds, etc. The generality and possihle extension of the reaction was, however, not considered. During the last several decades, al- most all aspects of the 1,3-dipolar cycloaddition process have come under extensive study, hoth theoretically and experi- mentally. Perhaps the most outstanding contribution has come from the brilliant work of Rolf Huisgen of the University of Munich, West Germany. His efforts have helped transform the 1,3-dipolar addition from an almwt obscure phenomenon into a major reaction type (3). 1,3-Dipoles
l,3-Dipoles can he represented by zwitterionic octet reso- nance structures (4). The compounds display electrophilic as well as nucleo~hilic reactivity. Each molecule has at least one resonance str&ure which indicates a separation of charge in a 1,3-relationship (5). The great majority of these compounds are isoelectronic either with ozone or nitrous oxide and un- ambiguously contain a three-orbital system occupied by 4 a-electrons (3). Some of the more common 1,3-dipoles, with resonance structures, are listed (4,5) in Table 1. Dipolarophiles
Dipolarophiles are usually olefins or acetylenes, hut other multiple bonds, such as the C=N hond of imines and the C=O hond of aldehydes, also can act as the dipolarophile. Several types of compounds have been used as dipolaro- philes.
Mechanism Huisgrn proposed a concerted merhanism for the 1,R-di-
~ o l a r rsrloaddition in which the two new a-hondsare formed &nultaneously, although not necessarily a t equal rates (6). Most experimental results are consistent with this mecha- nism.
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490 Journal of Chemical Education
A two-step addition process, with a zwitterionic interme- diate, in which the two new @-bonds are formed one after the other, was rejected on various grounds, such as solvent effect, stereospecificity, etc. The following example of addition of a diazoalkane to strained olefin, hicycloheptene (II), was chosen to compare the concerted one-step (A) versus two-step (B) addition.
(m) Very little effect of solvent polarity on reaction rate is Table 1. The More Common 1,3-dipoles, wlth Resonance
Structures * -
Diaraalkane &=N--c~R~ u N=N+.R. Nitrogen as . . central
Azide &=N-NR cc NEN-NR Nitrogenas central atom.
Nitrile ylide R&N-~RI CC R C E ~ ~ R , Nitrogen as central
- - atom. Nitrile imiw R&N-NR RC&NR Nitrogen as
central - + - atom.
Nitrite oxide R&N-G: RC=N-@ Nitrogen as Central
- - + .. atom. Nitrous oxide &N+: * NGN--+: Nitrogen as
central - - atom.
Nibone 6 - N * 0 Nitrogen as I I central R R atom.
Carbanyl ylide R . & ~ ; R ~ * R , C = = ~ ~ R . oxygen central as
- - atom. ~ a m n y i R . & ~ : - R&+: Oxygenas
oxide central - -- - + - atom.
NHrosimines R&+NR cc RN+NR Oxygen as central
- atom. ozone & : * :O=s: oxygenas
Vinyl R&-+RZ - R % C = C R . Carbonas ca~knes I I central
R R atom. -
Ketocarbenes R&-0: R- Garbon as
k R I atom. cenual -
Imlnmenes ~X-NR cc N+NR Carbonas I I central
R R atom.
typical for 1.3-dipolar additions. This is clearly inconsistent with the two-step addition process (B) which should exhibit a strong enhancement of rate with increasing polarity of the solvent, because the intermediate zwitterion (III), contrary to the diazoalkane itself, has nonexchangeable distant formal charges, separated by a tetrahedral carbon atom.
The 1,3-dipoles are not highly polar substances due to ex- tensive charge delocalization and so have low dipole moments. For example diazoalkane can he represented by the resonance structures shown below.
Consequently, the transition state for cycloaddition of 1,3- dipoles to carbon-carbon multiple bonds is not expected to he polar. Consistent with this and in agreement with viewing the reaction as a concerted process (6-8) is the observation that the rate is only slightly affected by solvent polarity (6). The transition state for concerted addition of a typical dipole, diazoalkane, to an olefin is depicted below.
I t is a general rule that concerted reactions should he ste- reospecific. In all known examples of 1,3-dipolar cycloaddi- tions, the configurations of 1,3-dipoles and dipolarophiles are retained in the product. No exceptions have been observed (9). For cycloaddition to olefinic dipolarophiles bearing suh- stituents at both ends the cisand trans stereochemistry of the dipolarophile is maintained in the product within experi- mental error. Thus, for example, maleic acid derivatives al- ways give cycloadducts in which the carhoxy groups are cis, whereas fumaric acid derivatives give trans products. This lends strong support to the concertedness of 1.3-dipolar cy- cloaddition.
A high degree of order is required in the transition state for multicenter or concerted reactions with the reactants heing aligned precisely with respect to each other. Consequently, these processes generally exhibit large negative entropies of activation (AS$) and only moderate enthalpy requirements (AH$). Experimentally, large negative values of AS$ have been found for 1,3-dipolar additions. The activation param- eters of some dipolar cycloadditions are shown (6) in Table 2. -~
If the 1,3-dipolar (3 + 2 - 5) cycloaddition is a concerted process then the stereochemistry of the product can he pre- dicted using the Woodward-Hoffmann rules for the conser- vation of orbital symmetry (10,l l) . The 1,3-dipole is merely a structural variant of the diene component in the Diels-Alder reaction, with four electrons heing distributed over three atoms instead of four. Moreover, the HOMO and the LUMO of a 1,3-dipole are of similar symmetryto those of a diene with respect to the twofold axis and the mirror plane which bisects the molecule (12).
n n -
diene 1,s-dipole olefin The symmetries of the HOMO of the 1,3-dipole and the
LUMO of the olefin and vice versa are such that, when the
Table 2. Activation Parameters of Some Dipolar Cycloaddltlons AHt AS%
Reactants ( k c 4 (calldeg) N-phenyl-C-methyl sydnane (in pcymene)
+ethyl phenyl propialate 18.3 -29 dimethyl acetylenedicarboxylate 14.7 -31
Cphenyl-N-melhyl "Inane (in toluene) + methyl methacrylate 15.7 -32
2-vinylpyridine 18.3 -29 Ozone (in CCl3
+benzene 13.2 -23 mesitylene 10.7 -22
reaction coordinate Energy profile for lhe Firestone mechanism
reactants approach each other with their molecular planes parallel, two new honds can he formed at the same time. Consequently, concerted cycloaddition of the 1,3-dipole with an olefin is symmetry allowed for the ground state. This concerted mechanism for 1,3-dipolar cycloadditions has been widely accepted ( 3 , l l , 13-17),
There are several reports (15, 18, 36-39) of theoretical studies about the mechanism of these reactions. Many of these calculations favor the concerted nature of the cycloaddi- tion.
Firestone proposed (19) and defended (27,28, 30) an al- ternative two-step mechanism with a discrete spin-paired diradical intermediate, the first step being rate determining. The energy profile for this mechanism is sketched (19) as path A, the figure. It is assumed that for every successful collision between two partners many others will occur in which the first bond can form, but the orientation is poor for the second (path B). In these cases the intermediate reverts to startine mate- rials, leaving no memory of itself except a reduced frequency factor. Low entropies of activation are thus to he expected.
The stereospecificity (exclusive cis addition) is explained by the low activation energy (possibly approaching zero) for
Volume 61 Number 6 June 1984 491
- ring closure of a properly disposed, spin-paired diradical. The activation enerev for a single bond rotation in the intermediate is assumed to
dipolar cycloaddition of acetylene to fulminic acid, a serious discrepancy occurs between relatively symmetrical (favoring concerted mechanism) (37 ) (nonempirical SCI.') and unsym- metrical (38) (MNDO) transition states. Houk (3fi) seems to favor thr nonempirical SCF predictions, and they may turn out to he correct. Howevrr, a number of potentially quite serious approximations have been made in the ah initiostudy (37). Komornicki, Goddard. and Schaefer (39) inyest!garrd 1.3-dinolar rvrloaddition of fulminir acid (HC=-N -01 and acetyiene toSyield an isoxazole utilizing both SCF and CI methods and suunort the view that the transition state has . . rrliltively symmetric geometry. Thrir calculations provide no indication that there is a hiradical reaction parh with a highly nonsymmetrical transition state of romparahlr or lower energy but cannot definitelv rule out such a wssihilitv in the absence of further exploration of other regions of the potential energy surface. The relatively minor energetic changes due to a two-configuration SCF treatment do suggest that there is not a very low-lying, doubly excited state as is often found to stabilize biradical species.
In an attempt to reconcile the conflicting viewpoints of Huisgen and Firestone, attention has been focused (31,321 on the im~ortance of the "s~in-uaired diradical" or "lonp-
bond" srructurei of 1,3-dipoles and the development uf "in- creased valence" in the transition swte.'l'o illusrratt. the idea, the "concerted diradical cycloaddition" (31) of a nitrone with methvl methacrvlate is shown using the following valence forml;lae. 'l'his explmatiun howevrr,has not heen rtfertndy considered by H~uiyen ( 9 ) and Firestone (30).
The "long-bond" or "spin-paired diradical" structure (XI) makes an important contribution to the ground state reso- nance description of diazoalkane (32). A generalized valence bond calculation (33) indicated CHzN2 to resemble more a diradical (e.g., XI) than a zwitterion.
-44 . -44 R~GTNTN: R,%N=N:
(W The hypothesis that for each neutral 1,3-dipole molecule there exists a "long-bond" structure like (XI) has been supported by the results (33-35) of a number of valence bond studies. Using (XI), a concekted cycloaddition mechanism, (XIII) - (XIV), may be drawn (32). The Linnett valence structure (XII) has been used by Firestone. If (XII) is used instead of (XI), a cycloaddition mechanism, (XV) - (XVI) - (XIV), that utilizes the spin-paired diradical character present in (XII), may be constructed (32). Generation of Firestone's singlet diradical (XVII) (30) seems to be unnecessary and his spin-paired diradical structure (XVIII) may be viewed as a
special form of (XVI) which is an example of an "increased valence" structure.
Firestone has not taken account (30) of the possibility that "increased valencv" mav occur in the transition state and Huisgen has rejected (9) the possibility that "spin-paired diradical structures" mav make imuortant contributions to the ground state resonance description of a 1,3-dipole mole- cule. Conclusion
There are two very different views about the mechanism of 1,3-dipolar cycloadditions to multiple bonds, one of Rolf Huisgen and the other of Raymond Firestone. The former suggested a concerted mechanism in which all bonds are made and broken simultaneouslv, though not necessarilv in perfect synchrony. The latter prbposed-a two-step mechanism in- volving the formation of a discrete, spin-paired diradical in- termediate. To reconcile the conflicting viewpoints a con- certed, spin-paired, diradical mechanism, based on valence bond theory, was proposed by R. D. Harcourt. Huisgen's arguments and experimental facts in favor of a concerted nature of the reaction seems to be more convincine. Calcula- tion with ab initio SCF or CI techniques suggests s&metrical transition states whereas MNDO methods favor unsvmmet- rical transition stares. A conclusive nnswer may come from more rigorous and suphisticated MO calculations. Literature Clted (11 Michael, A . , J Prokt Cham., (2),48, 94 (1893). 121 Smith,L. I.,Chem. RPU.,~~, 193 (1938). 13) Woodward. R. B.. and Hoffmsnn, R., Angeu. Chem. In11 Ed. Engl., 8, 781,617 (1969). (41 Huisgen, R., Angel". Chem. Intl. Ed. End.. 2,562 11983). (5) Carey, F. A.,snd Sundberg. R.J. "Advances in Organic Chemistry,Part B,"Plenum
Puhl. Carp.. New York, (1977). p. 212. (6) Huisgen, K., Angeu. Chem. ln t l Ed. En&. 2.633 (1963). (7) Kadaha, P. K., Tetrohedmn,25,3053 119691. (8) Scheinor. P.. Shoemaker, J. H., Doming, S. Libbey, W. J.. andNawaek. G. P., J. A m r
Chem Soe., 87, 306 119651. (91 Huisgen. R., J. Org. Chem., It, 403 (19761.
(10) Hoffmsnn, R., and Woodward. R. B., J A m s r Chem. Soc., 87,2046 (1965). (11) Hoffmann,K.,and Woodward, R.B.,Aeclr. Chem. Re*, 1,17(19681. (121 Norms", K. 0. C.. "Prineiplerof Orgsnie Synthe8is.l. 2nd. ed. p. 296. John Wilay, New
York, 1978. (13) Cowoil, G. W.,andIadvith,A.,Quori. Re". Chem. Soe.,24.119l1970). 1141 Houk,K.N., J. Amer Cham. Soc.,94,8953 (19721. (151 Minafo. T., Yamabe. S.,Wimato, H., and Fukui, K.,Bul Chpm Soc.Jopon,47.1619 (1974). (161 L'sbhC.G.,Cham. Reu.69.345 (1969). (171 Keishi.T..Fuiio,T., Chem. Abs.,S9:196549lI9761.
-21.79 (1978): Chem. Abs., (181 Leroy, G.,S&a,M., Ann. Soc. Sci. R~ureliesSw. 1,92[1. 0" VW,C"" ,,o,ot "".a*"""-,
(19) Firestone,R.A., J. Olg. Cham.,33,2285 11968). (201 Ekkcll,A.. Huisgen,R.,Sustrnann, R., Wsllbillieh,G., Grashey, U.,and Spindler, E.
Chem Rer., 100,2192 (1967). (21) Huisgen, R., J. Or#. Chem., 33, 2291 (19681. (221 Sustmann, R., Te t r La1.,29,2717 119711. 1231 Suatmann,R.,and Trill, H.,Angew. Chem. h l lEd . Engl., ll.838(19721. (241 Houk, K. N.,Sims. J.. Watts. C. R a n d Luakus. L. J.. J Amar Chem. Soc..95.7301
114711 ,.-.-,. (251 Ei*nstein, 0.. Lefaur, J. M., and Anh, N. T., J Chem. Sor. Chom. Comn., 969
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(29) Linnett. J. W.. J. Amor C h m Soc..83,2643 11961). (SO) Firestone, R. A,, Telrohedrorr, 33,3W9 11977). 131) Harcourt. R. D . , J MdStruc t . , l2.351 11972). 132) Narmurt, R. D., Telrohadron. 34.3125 (1978). (331 Walch, S. P. and Goddard, W. A., J. Amer Chem. Soc, 97,5319 11975). IS41 Hiberty. P. C., and Leforestie., C., J. Amer Cham....