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.

' Present address: Smith Kline Beckman, 1500 Spring Garden St., F-50. Philadelphia, PA 19101.

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 - - .. atom.

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 central atom.

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 <; greater than for either formation of the sec- ond bond (ring closure) or reversion to reactants.

Conjugation exerts some promoting effects on the dipo- larophilic activity of multiple bonds. This supports the two- step theory (19), wherein the intermediate diradical derives some stabilization through conjugation. In a concerted cy- cloaddition the situation is reversed; whatever stabilization energy the dipolarophile possesses ought to diminish steadily a l n n ~ the reaction coordinate as the n-bond is consumed. - ~ - ~ - - ~-~~ ~~~~~~ ~ ~~

Huisgen dealt with this question (6,20) by the explanation that the formation of the two new bonds is simultaneous but not necessarily synchronous.

Firestone reported that the small solvent dependence of 1,3-dipolar cycloadditions is not consistent with the concerted mechanism. but it is better exnlained hv a two-step mecha- nism in which only one bond i i partiall;formed inthe tran- sition state which might have the same polarity as the orien- tation complex of the components.

When an acetylenic dipolarophile reacts with a 1,3-dipole to produce an aromatic system directly, a portion of this ar- omatic stabilization should exist (19) in the transition state in a concerted reaction. With the same dipole then, enhanced reactivity is expected for an acetylenic dipolarophile over its ethylenic counterpart. However, no difference in reactivity is actually found. A two-step mechanism is supported by the observation that the appearance of the aromatic system is delayed substantially until after the rate-determining step. Huisgen attempted to clarify (5, 21) this discrepancy by pointing out that the transition state resembles more the or- ientation complex than the product as i t is not planar hut puckered and thus cannot profit from the aromatic resonance of the nroduct.

A c&loaddition of an unsymmetrical dipole to an unsym- metrical dinolaronhile mav take dace via two orientations # i~ ' in# two refioisomers, only one of which is generally formed. Huiseen 16) rworted that in reartions of dir~olnrouhiles with . . . carbon-heteroatom multiple bonds, the nature bf the new a-bonds can influence the orientation. Thus, benzonitrile- N-oxide reacts with aldehydes to produce exclusively deriv- atives of the l,3,4-dioxazole system (V).

Formation of the structurally isomeric heterocycle (VI) is energetically less favorable (4). With olefinic or acetylenic dipolarophiles, however, a similar amount of a-bond energy is produ,:ed in both orientations. Here the interplay of elec- tronic and steric effects, the latter usually being dominant, is responsible for the orientation. In many cases the correct orientation can he predicted by considering only steric effects. For examnle. whereas dinhenvldiazomethane reacts with . . propiolic eke; to yield only compound (VII), the same dipole reacts in the reverse orientation with phenyl propiolic ester to give compound (VIII). I t should he realized, however, that the above generalizations have exceptions for which Huisgen has put forward specific explanations.

Firestone reported (19) that the concerted mechanism and Huisgen's explanation based on electronic and steric effects are inadequate to explain the question of orientation. He as- serted that regioselectivity can be explained better with a diradical intermediate. The predominant unidirectionality of orientation exhibited by most 1,3-dipoles toward both electron-rich and electron-poor dipolarophiles is a natural consequence (28) of the diradical mechanism but conflicts with the concerted one. Huiseen. however, analvzed (21) Firestone's arguments and sho&d several inc~nsisr&es and commented that nrrdiction of reeioselertivitv using a diradical ~ ~ - mechanism is uncertain.

Several authors have reported molecular orbital calculations (14,22-24) of dipolar cycloadditions which suggest that reg- ioselectivity may be governed by the distribution of electron density in the HOMO and LUMO of the reacting molecules. The preferred orientation of addition is assumed to be the one providing maximum overlap of these two frontier orbitals. For electron-rich dipolarophiles, the HOMO is presumed to in- teract with the LUMO of the 1,3-dipole. The opposite happens for electron-poor dipolarophiies. The direction of addition will he that which provides the greatest overlap of these orbital pairs. The conclusions drawn from these calculations are consistent with the experimental results. Houk (24) also qualitatively discussed nonsynchroneity in the formation of the two new a-bonds; this nonsynchroneity seems to play a part in determining the orientation in the concerted mecha- nism (25).

~ u & & has refuted (21) the arguments and explanations for a diradical mechanism nronosed bv Firestone (19). AC- ~ ~ . . cording to him the greatest obstacle for a diradical interme- diate is the stereosprcificity of 1,3-dipolar cycloadditions. Firestone's assumptions of higher activation energy fur a single bond rotation in the intermediate diradical than that of ring closure or reversion of the diradical to reactants is highly improbable. Moreover calculation (21) of the activation energy for the formation of the diradical intermediate (IX) (from a nitrone and methyl methacrylate) has been found to he much larger than that determined experimentally (26) for the cy- cloaddition.

Firestone tried to justify (27,28) his diradical mechanism by means of a modified type of bond energy analysis using Linett's double quartet theory (29). Structure (X) is the Linett structure for the intermediate (IX). The energetics for the formation of (IX) are shown, by a detailed calculation (27), to be fairly close to the experimental values (26). However, the validity of this method of calculation of 3,5 and other odd electron bond energies and the use of Linett notations instead of the usual Lewis structures were questioned by Huisgen who, in a lengthy discussion (9) tried to disprove Firestone's arguments (27,Z.S) favoring the diradical mechanism. Con- siderine stereochemistrv. steric. solvent, and substituent ef- fects, orientation and kgioselectivity, periselectivity, ener- eetics. conformation and scission of diradicals, and hvdroeen - . . . transfer in excited diradicals, Firestone againcritically com- nared (30) the diradical and concerted mechanisms with ieference to the Drels-Alder reactlon and Cope-rearrangement and concluded that the exuerimental tacts, as a whole, favor the diradical mechanism.

Houk. Caramella, and Domelsmith (36) noted that that sort of disagreement, seen between the MNDO methods and ah initio SCF (or small CI) techniques seems to occur with reg- ularity. They point out that for a simpler system, the 1,3-

492 Journal of Chemical Education

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.

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