kinetics and mechanism of 1,3-dipolar cycloadditions

ANGEWANDTE CHEMIE V O L U M E 2 - N U M B E R I 1 N O V E M B E R 1 9 6 3

P A G E S 633-696

Kinetics and Mechanism of 1,3-Dipolar Cycloadditions [*I

BY PROF. DR. R. HUISGEN

INSTITUT FUR ORGANISCHE CHEMIE DER UNIVERSITAT MUNCHEN (GERMANY)

Criteria for the mechanism of 1,3-dipolar cycloadditions which lead to 5-membered rings are provided by the stereoselectivity observed with cis-trans isomeric dipolarophiles, by the efect of solvent and substituents on the rate constants, by the activation parameters, and by orientation phenomena. A concerted addition, which can also be described in terms of molecular orbitals and in which the two new o-bonds are formed simultaneously, although not necessarily at equal rates, ofers the best explanation of the experimental facts,

The concept of “cycloaddition” gives a formal description of an overall reaction but not a mechanistic interpretation. Any discussion of the mechanism of the 1,3- dipolar addition must be viewed against the background of mechanistic interpretation of other cycloadditions which lead to three-, four-, or six-membered rings. Recent studies have shown that cyclopropanes can be formed from an alkene + carbene via at least two mechanisms. Likewise, two reaction paths exist for the coupling of two alkenes to give cyclobutanes, and different stereoselectivities are observed. A preceding review [I], described various 1,3-cycloadditions which follow the scheme 3 + 2 -+ 5. Our studies of the mechanism of addition have been carried out exclusively with 1,3-dipoles which have internal octet stabilization according to the definition given elsewhere [ 11 ; hence the following discussion is limited to 1,3-dipolar cycloadditions of this type.

A. Confrontation of Possible Mechanisms

The principal question is whether the two newo-bonds, which lead to the uncharged five-membered ring on fusion of the 1,3-dipole a-b-c with the dipolarophile d-e, are closed simultaneously or one after the other.

d Ae

[*I Extended version of a lecture given at the Annual Meeting of the Decherna in Frankfurt/Main on June 14th, 1962, and of the MaxTishler Lecture at Harvard University on December loth, 1962. [ I ] R. Huisgen, Angew. Chem. 75, 604 (1963); Angew. Chem. internat. Edit. 2, 565 (1963).

The experimental criteria discussed below favor a multi-center or concerted reaction with a cyclic electron shift, as symbolized by the arrows in the above diagram. One-step reactions of this type (the Diels-Alder reaction and the Claisen and Cope rearrangements are well- known examples) have been referred to in the United States as “no-mechanism reactions” [2]. This terminology was born of “Scherz, Salire, lronie und tiefere Be- deutung” [**] and implies the principal impossibility of arriving at a direct mechanistic proof. The energy profile contains a single activation peak between reactants and products; it offers no opportunity for inter- ception. The fact that alternative mechanisms can be excluded from consideration brightens somewhat the pessimism implicit in the name “no-mechanism reaction”. The 1,3-dipole is always an ambivalent compound, which either displays electrophilic and nucleophilic activity in positions 1 and 3 or reacts in the 1,3-position as a spin-coupled biradical. The mesomerism of the octet and sextet resonance structures of the 1,3-dipole (formulated below for diazoalkanes) results in charge compensation or charge exchange, respectively, which makes it impossible to identify unequivocally an electrophilic and nucleophilic center. I n other words, the question whether the cyclic electron shift formulated above

Octet structures 0 0 (1 0 - N=N-C_Rz - IN=N=CKz

Sextet structures

[2] Cf. W. v. E. Doering and W. H. Rofh, Tetrahedron 18, 67 (1962). [**I Play by Ch. D. Grubhe (1827).

Angcw. Chem. internut. Edit. [ Vol. 2 (1963) I No. I I 633

takes place clockwise or anticlockwise is meaningless. Neither is it meaningful to regard the “biradical” reaction path as an alternative, as long as the event is completed within the framework of a singlet state. The example of the addition of a diazoalkane onto angularly strained, and thus energy-rich, double bonds of the bicycloheptene type [3] may be used to compare the one-step, concerted addition A with the two-step addition B in which the two new a-bonds are formed one after the other. In the latter case the energy profile for the addition shows a dip corresponding to the intermediate (/) (Figure I) . Incidentally, ordinary nonconjugated alkenes are sluggish in their reaction with diazoal kanes.

0 (1) C~HS-CO-CH-N?

0 (D />N02C6H4-CO--Cti-N~

CHj-CO.,O @ C-Nz

CzH502C’

Since the olefinic double bond is nucleophilic, the diazoalkane should function as an electrophilic reagent in the rate-determining primary process of the two-stage scheme B. Additions of nucleophilic cyanide or sulfite

slow

very slow

no addition

Reaction coordinate - rn Fig. 1 . Energy profiles for the one-step and two-step cycloaddition. The arrows denote transition states.

ion onto the outer nitrogen of diazoalkanes are known [4]; their ease is a function of the degree to which the carbanion charge at the carbon of the diazoalkane is stabilized by substituents. However, the order of reactivity of substituted diazometnanes, as displayed in their additions onto the model compounds (2) and (3) is opposite to that which would be expected for reaction path B [5 ] . The introduction of carbonyl substituents, which efficiently distribute the negative charge in the

[3] K . Alder and G. Stein, Liebigs Ann. Chem. 485, 211 (1931); K. Ziegler, H . Sauer, L. Brunr, H. Froitzheim-Kiihlhorn, and J . Schneider, ibid. 589, 122 (1954). [4] Review: R . Huisgen, Angew. Chem. 67,453 (1955). [5] R. Fleischmnnn, unpublished results, Universitlt Miinchen, 1957j58.

intermediate ( I ) , reduces the addition tendency of the diazoalkane; the presence of two carbonyl groups makes the diazoalkane completely inactive (Table 1).

Table I . Rates of addition of diazoalkanes onto the angularly slraiiicd douhlc boiitl systems (2) and (3) 151.

~ ~ _ _ - Diazoalkane I Rate of addition

- I

rapid

ratlier slow 0 01

H2C--N2, 0 a l (C~HS)IC- Nz

C ~ H S O ~ C - C H - Nz

B. Dependence on the Solvent

The result of the primary step of path B is the zwitterion ( I ) whose rather distant formal charges are, contrary to the diazoalkane itself, separated by a tetrahedral carbon atom and, therefore, no longer exchangeable. The formation of such a zwittcrion should be greatly facili- tated by good solvents for ions. Reactions which are associated with an increase in charge separation are known to exhibit a strong enhancement of rate with rising polarity of the solvent [6]. On the other hand, little or no rate change with solvent polarity would be anticipated for the case of the concerted process A.

[6] In the reaction of triethylarnine with ethyl iodide, the rate constants range over 3.5 ordcrs or magnitude, depending on the polarity of the solvent: N . Mc,nschutkin, Z. physik. Chem. 6, 41 (1890); H . G. Grirnm, H . Ruf; and t / . Wolff; ibid. B 13,301 (1931).

634 Angew. Clirln. intcrnrrt. Edit. 1 Vol. 2 (1963) / No. I 1

Table 2 contains the rate constants for two cycloadditions of diphenyldiazomethane in various solvents [7], one onto the angularly strained double bond of (3) (Reaction I), and the second onto dimethyl fumarate (Reaction 2). A function of the dielectric constant E

serves here as a rough measure of the polarity of the solvent [8]. Both series of rate constants do not exhibit the steep rise expected for the two-step path B; instead, the influence of polarity of the solvent is insignificant.

2.43 2.93 2.27 3.64 2.38 2.61 2.90

Table 2. Rate constants for the addition of diphenyldiazomethane onto the cyclopentadieneazodicarboxylic ester adduct (3) (Reaction 1) and onto dimethyl fumarate (Reaction 2) at 40 “C in various solvents [7].

1.44 1.15 1.25 3.70 1.10 2.63 2.45

Solvent E- 1 k z X LO4 kZX 102 1 2 1- 1 I (Reaction I ) I (Reaction 2)

Benzene Dioxane Ethyl acetate Methoxyethanol Acetone Acetonitrile Dimethylformamide

0.22 0.22 0.39 0.46 0.47 0.48 0.48

Is this absence of a solvent effect consistent with the concerted addition according to Scheme A (p. 634)? Should not the loss of the formal charges of the diazoalkane during the course of the reaction lesd to an inverse solvent dependence? The term “ I ,3-dipolc” should not be understood to imply that these substances have a high electric moment in the ground state. On the contrary, the charge distribution between the two resonance structures with electron octets, already referred to above, reduces the dipole moment of diphenyl- diazomethdne to 1.42 D, instead of the 6--7 D expected for a single resonance structure. The addition onto the strained double-bond system of (3) is not accompanied by an appreciable change in charge separation, as is shown by the electric moments (Scheme 1).

(3) p = 3.09 p = 1.42 p = 3.20 D

Scheme 1. Electric moments in the addition of diphenyldiazomethane onto a strained double bond.

The solvent dependence of the union of a 1,3-dipole and a dipolarophile should be z e r o , provided the following relationship applies [8,9]:

p21,3-dipole + p.‘dipolarophile - - p.‘%ransition state

MVl,3-dipole MVdipolarophilz MVtransition state (for approximation, the molecular weight can be used instead of the molar volume MV)

In the case of the diphenyldiazomethane addition cited above, the calculation gives ptransition state = 4.6 D. If the concerted addition corresponds to a continuous transition of the components into the adduct, then the moment of the transition state (which cannot be measured) should lie between that of the adduct and that of the orientation complex of the

[7] R . Huisgen, H. Stnngl, H . J . Sturm, and H . Wugenhofer. An- gew. Chern. 73, 170 (1961). [8] J . G. Kirkwood, J. chem. Physics 2, 351 (1934). [91 Cf. S. Glusstone, K . J . Lnidler, and H . Eyring: Thc Theory of Rate Processes. McGraw-Hill, New York 1941, p. 422.

componcnts. The moment of tlic Iattcr would be expected to be 4.4 D [cf. (31)l. The transition state thus appears to be only slightly more polar. The absence or small extent of solvent dependence is typical of 1,3-dipolar additions. The addition of phenyl azide (p = 1.56 D) onto (3) (p 3.09 D) to form 98 % adduct (p = 3.26) shows almost no effect due to the solvent polarity [lo]. A weak inverse dependence on the polarity of the solvent is observed, however, if the charge compensation of the 1,f-dipole is less complete than in phenyl azide, as for example in the azomethine imines

(5 ) p = 6.7 (6) 11 6.57 (7) p = 3.55 D

(5) and (6) or the nitrone (7). I n the case of (5), the rate constant for the addition onto dimethyl acetylene- dicarboxylate decreases by a factor of 6 when the solvent is changed from benzene to dimethylformamide [ll]. With (6) and (7), the solvent effects are likewise small; the addition of (7) onto ethyl acrylate may again be formulated in terms of dipole moments (Scheme 2).

CHS

(7) p = 3.55 p 1.76 p = 2.48 D

Scheme 2. Elcctric moments in the addition of Gphenyl-N-inethylnitrone onto ethyl acrylate.

A transition state with p 2 5.4 D (calculated) would lead one to expect no dependence on the solvent. The small moment of the adduct would suggest a smaller moment than 5.4 D for the transition state; if toluene is substituted for ethanol, the rate constant is lowered by a factor of 5.7 as a result ol the decrease in charge separation during the activation process [12]. Here, the values of log k for eight solvents show a fairly linear relationship to the empirical polarity function Z [13] of the solvent. In view of the low order of magnitude of the solvent effect, activation parameters have not been measured. The 1,faddition of ozone, which has a particularly low dipole moment (0.53 D), onto carbon-carbon multiple bonds is undoubtedly accompanied by an increase in charge separation. The moments of primary ozonides are still unknown. The few kinetic data available in the literature show the expected small positive influence of the solvent. Ozone reacts with benzene at -28°C in nitromethane three times fastcr than in chloroform [14], and at -t25OC in acetic acid 3.2 times faster than in carbon tetrachloride [15].

[lo] H. Stung1 and H . Wugenliojcr, unpublished results, Uni- versitat Munchen, 1960. [ll] A. Eckell, Ph.D. Thesis, UnivorsitBt Miincnen, 1962. [12] H . Seidl, unpublished results, Universitit Munchen, 1962. [13] E. Kosower, J . Amer. chern. Soc. 80, 1253 (1958). [I41 F. L. J . Sixnia, H . Boer, and ./. P . Wiliuut, Rec. Trav. chim. Pays-Bas 70, 1005 (1951). [I51 T. W. Nakaguwa, L. J . Andrrws, and K. M . Keefer, J. Amer. chern. SOC. 82,269 (1960).

Angew. Chem. internnt. Edit. 1 Vol. 2 (1963) 1 N o . I I 635

Ozonolysis of benzene in nitromethane at -28 "C is acceler- ated by a factor of 3.5 in the presence of 0.2 M aluminum chloride or ferric chloride 1141. This effect is too small as to lend any support to the assumption that the ozone enters into an initial, electrophilic two-center addition to form an open-chain zwitterion 1141. An increase in solvent polarity due to the addition of the Lewis acid is more probable.

C. Steric Course of the Addition

If the two new a-bonds are closed simultaneously during the cycloaddition, the result must be a stereoselective cis-addition. On the other hand, if the coupling with a dipolarophilic double bond d=e is accomplished in two steps, then the bond d-e should assume single-bond character in the intermediate; this applies equally to intermediates which result from electrophilic (8), nucleophilic (9), or radical (10) primary attack. The

energy required to start rotation about this single bond is relatively low. Thus, when an intermediate of type (8) to (IO) is involved, a certain proportion of the molecules should undergo rotation around the d-e bond axis prior to ring closure. If one starts with cis-trans isomeric alkenes as dipolarophiles d=e, then this phenomenon must result in non-stereoselective addition. In the extreme, geometric isomers should both yield either an identical adduct or one and the same mixture of diastereoisomeric adducts. The addition of diphenyl(nitri1e imine) (liberated from benzphenylhydrazidoyl chloride with triethylamine) to cis- or trans-stilbene yields the pure, i.e. mutually un- contaminated, diastereoisomeric Az-pyrazolines (1 I) and ( I2 ) . Both of these compounds can be dehydrogen- ated to the same tetraphenylpyrazole [16].

If a lack of stereoselectivity is observed, it must be scrutinized whether subsequent epiinerization of the primary adduct has occurred. Thus, decomposition of 2,5-diphenyltetrazole [also a source of diphenyl (nitrile irnine)] in dimethyl maleate at 165 "C, yields only 4 '%, of (14). The mixture contains mostly the trans-adduct (13), which is also formed in 88 "/, yield when

1161 R . Huisgen, M . Seidel, (2. Wallbillich, and H . Knupfer, Tetra- hedron 17, 3 (1962).

the decomposition.is carricd out i n dimethyl fumarate. It has in fact been proven that (14) is converted into the thermo- dynamically more stable compound (13) in the presence of basic catalysts. This epimerimtion, which is initiated by the removal of a proton, is no longer possible with the adduct (16) from dimethyl dimethylmaleate. Hence, additions of diphenyl(nitri1e iminc) o n t o climethyl dimethylfumaratc ond dirnethylmaleatc procccd stcrcosclcctivcly l o tbrm ( 15) and (16), respectively 1161.

The fact that a cis-addition is actually involved here is confirmed by the nuclear magnetic resonance spectra of adducts ( [ I ) to (14). The coupling of two hydrogen atoms to neighboring carbon atoms is known to depend on the dihedral angle [17]. In a planar five-membered ring, the value of this angle is 0 for the tertiary hydro- gens present at the 4- and 5-positions of the pyrazoline ring in (12) and (14). However, in (11) and (13), it is 120 O, so that the degree of coupling is smaller. In fact, the coupling constant J is 1 I .9 and 13.0 cps, respectively, for the cis-compounds (I?) and (14), and 4.9 cps for each of the trans-pyrazoiines (11) and (13). All the cycloadditions of octet-stabilized 1,3-dipoles examined so far show similar stereoselectivity. Benzo- nitrile-N-oxide gives diastereoisomeric isoxazolines on addition to fumaric and rnaleic esters, as well as to mesaconic and citraconic esters [18]. As an example of diazonium betaines, diazomethane may be cited, for it adds stereoselectively onto dimethyl dimethylfumarate and dimethylmaleate [19].

0 CH&N

t

m.p. 49-51°C m.p. 71-73°C

CH30zC CH3 CH30nC CH3

m.p. 59-60°C liquid

C-Biphenylene-"(or)-p-chlorophenyl] - N@)-cyanoazo- methinejmine'(5):combines with dimethyl fumarate.and dimethyl maleate to give diastereoisomeric, crystalline pyrazolidines in 82 % and 93 %, yield, respectively [I 11. 3,4- Dihydroisoquinoline- N- (p-nitropheny1)imine (17) reacts stereoselectively with f umaronitrile and maleo- nitrile, producing the respective adducts nearly quan- titatively with no admixturcs of their diastereomers [20]. ~

[I71 M. Karplus, J. chem. Physics 30, I 1 (1959); cf. H. Conroy, Advances org. Chem. 2,265,3 I0 (1960). [18] A. Quilico, G . Stagno d'Alwrrtrcs, and P. Griinanger, Gazz. chim. ital. 80, 479 (1950); A. Qrrilico and P . Grunanger, ibid. 82, 140 (1952). [I91 K. v . Auwers and E. Cmwr, Licbigs Ann. Chem. 470, 284 (1929); K. Y. Auwers and F. KfiniK, ibid. 4Y6, 27 (1932). [20] R. Grashey, unpublished results, Universitkt Munchen, 1959160.

636 Angew. Clwm. intcvnirt. Edit. 1 Vol. 2 (1963) No. I 1

The same is true when cis- or trans-dibenzoylethylene is used as a dipolarophile.

In the nitrone series, 3,4-dihydroisoquinoline-N-oxide (18) gives practically quantitative yields of diastereoisomeric isoxazolidines with dimethyl fumarate or maleate [20].

H COzCH3

n1.p. 89-90°C m.p. 95-96OC

In one individual case, the proof of a stereoselective cis- addition is always tempered by the possibility that ring closure of the intermediates (8) to (10) could occur more rapidly than rotation about the d-e bond axis, However, experience gained with some two dozen examples, in which a stereospecific course was observed without a single exception, weighs heavily against this hypothesis. Thus, stereoselectivity is a valuable criterion for the concerted nature of 1,3-dipolar addition. However, it may be an unwarranted simplification to say that the concerted process must necessarily be associated with the one- s tep addition scheme (A, page 634). One can also conceive of a case in which fixation of the configuration of the dipolarophile d=e results from the electrostatic attraction of the positive and negative charge centers of (8) or (9). This intermediate would be related to an oriented ion pair, and rotation about the d-e axis would be suppressed. In order to ensure stereoselective addition, the charge centers would have to be electrostatically bound right from the very beginning of the activation process. This would correspond to a concerted addition, however. So far, the. experimental data do n o t require the assumption of a trough in the energy profile of the cycloaddition corresponding to such an ion- pair intermediate. Nevertheless, it should be pointed out that participation of an intermediate in the concerted process is also conceivable.

negative entropies of activatioii (AS )and only moderate enthalpy requirements. Let us now proceed to test I ,3-dipolar cycloadditions against this general criterion for a concerted process. Cycloadditions of diphenyldiazomethane onto various activated alkenes do in fact have unusually large negative entropies of activation [7], as determined from kinetic measurements at various temperatures (Table 3). We are not dealing with a unique case, since the finding is quite general. For example, phenyl azide adds onto the angularly strained double bond of norbornene in CCl4 with AH+ = 15.2 kcal and AS - -29 cal/deg. [21].

Table 3. Eyring parameters for some 1,3-dipolar cycloadditions of diphenyldiazomethane to C=C double bonds in dimethylformamide [7].

AH*[kcal] 8,O 8,4 12,7

AS*[cal/dcg. ] -43 -39 - 34

Additions of 1,3-dipoles "without a double bond" (cf. [l] for definition) display the wme kinetic characteristics (Table 4). The high negativc entropy values leave no doubt that effective collisions with the correct orientation occur only rarely. The reactions of ozone fit well into the overall picture of thc activation parameters.

Table 4. Eyring parameters lor 1.3-dipolar cycloadditions of the azomethine imine 122,231 and nitrime series [I21 and of ozone [IS].

AS' [cal/degreel

C-Biphenylene-N(c+p-chlorophenyl- N(P)-cyanoazomethine imine (5)

(in chlorobenzene) + ethyl acrylate

styrene phenyl isocyanate

N-Phenyl-C-methylsydnone (6 ) (in p-cymene) .t ethyl phenylpropiolate

C-Phenyl-N-methylnitrone (7) dimethyl acetylenedicarboxylatc

(in toluene) -I- methyl methacrylate

Ozone (in carbon tetrachloride) 2-vinylpyridine

f benzene mesitylene

12.5 15.6 12.1

18.3 14.7

15.7 18.3

13.2 10.7

-35 -3 I ---33

-- 29 -. 31

--32 -- 29

-23 -22

D. Activation Parameters E. Activity Series of Dipolarophilic Systems

Unlike two-center reactions, multi-center or concerted reactions require a high degree of order in the transition state, i.e. at the peak of the activation barrier; the reactants must be precisely aligned with respect to each other, otherwise the reaction will not go. This is equivalent to saying that the lock will be closed with a low ex- penditure of energy only when the key is fitted into it properly. The interplay of entropy and enthalpy controls the rate-determining activation process. For the reasons mentioned, concerted processes generally exhibit largc

Comparison of the activities or dipolarophilic systems is of both theoretical and practical importance. If such relative reactivities were known, it could be predicted whether a particular I ,3-dipolar addition would be

[21] G. Sreimies, unpublished resulls, UniversilBt Miinchen, 1962. [22] M . V. George and A . S. K c i i t k , unpublished results, Uni- versitlit Miinchen, 1962. [23] H. Gofflrtrrt//, unpublished rcsulls, llnivcrsitiit Miinchen, 1062.

Awgew. Cl~enr. internut. Edit. 1 VCJI. 2 (1963) 1 N o , I I 637

possible or not. Moreover, in cases where several dipolarophilic structural elements are found in the same molecule, the reaction site could be predicted. A measure of the ability to undergo addition is the reaction rate constant. Direct kinetic measurement - a great variety of methods have been used to determine concentrations - is possible only if the 1,3-dipole is sufficiently stable and the cycloaddition is accompanied by less than 10 % side reactions. Benzonitrile-N-oxide, for example, dimerizes rapidly to diphenylfuroxan, and diphenyl(nitri1e irnine) cannot even be isolated. Hence we used a competition method: pairs of dipolarophiles were allowed to compete in a known molar ratio for the 1,3-dipole, which was generated in situ; analysis of the product, which was usually carried out by quantitative infrared technique, gave the relative rates of addition. Instead of presenting the entire bulk of material in tabular form, it is more appropriate to discuss selected kinetic data from specific points of view. In this way, similarities in the reactivity of 1,3-dipoles, as well as deviations from common behavior, will be unveiled.

1. Electronic Substituent Effects

The most striking phenomenon observed here is the promoting effect that conjugation exerts on the dipolarophilic activity of all multiple bonds. Table 5 gives a list of the rate constants for additions of various dipoles onto an alkylethylene, styrene, and acrylic ester. To facilitate comparison, all the kz values are related to that for acrylic ester, which is taken as 100.

Table 5. Relative rate constants for the cycloadditions of various 1,3-dipoles onto monosubstituted ethylenes (relative to k2 for acrylic ester = 100).

1 , fd ipole (solvent, temperature)

e e GHs-CE N-N - G H s

(benzene, 80 "C) 1241

(ether, 20 "C) I251

$ 8 NEN-C(&H5)2

(DMF, 40 "C) I71

(CCI,. 25 "C) 1261

(chlorobenzene, 80 "C) 1221

CH3

CoH5-N .A,/o \s?

N (p-cymene, 140 "C) I231

\ (IdCH3 H

C6Hs /c=N\oO

(to tuene, 120"C)[121

kz (relative) for dipolarophile HzC=CH--R

R = alkyl

0.30

3.9

0.01

2.4

I .8

5.8

0.67

3.2

14

0.2

4.1

5. I

8.0

3.0

-COlalk

100

100

100

100

100

LOO

I00

[24] G . Wullbillich and E. Spindler, unpublished results, Universi- tat Munchen, 1961/62. [25] W. Muck and E. Kudertr, unpublished results, UniversitLt Miinchen, 1960j61. [26] L. Mobiur, unpublished rcsults, Universitiit Mhchen, 1962.

Ordinary olefins react so sluggishly that their very small rate constants cannot be measured satisfactorily in all cases. The aromatic nuclcus in styrene accelerates the rate 1.5- to 20-fold. The activating influence of a neighboring ketone group, a carboxylic ester, or a nitrile function is considerably greater. The rate constants for acrylic ester exceed those for nonconjugated olefins by one to four orders of magnitude.

Addition of a l,3-dipole onto a double bond saturates the latter so that it can no longer participate in conjugation. The loss of conjugation energy reduces the exo- thermicity of the cycloaddition onto a conjugated double bond compared with that of an isolated one. How, then, does conjugation bring about a reduction of the activation barrier?

One important reason is the stabilization of partial charges, or possibly even of a partial radical character of the transition state involved in the 1,3-dipolar addition. The term "concerted addition" is not to be taken to imply that the two new a-bonds form in the transition state to exactly the same extent. This "marching-in-step" principle is merely a limiting case. Normally the two bonds begin to form simultaneously but are developed to different extents in the activation configuration. Thus, if the closure of one bond occurs somewhat more rapidly than that of the other, then one center of the dipolarophile becomes the carrier of a partial negative or positive charge (or of a partial radical character), as the case may be. When neighboring substituents are present, they can take over and distribute such partial charges, which results in a reduction of the overall energy level.

The decrease in electron density of the double bond under the influence of ;I phenyl or alkoxycarbonyl residue cannot, however, be the only controlling factor, for chlorinated or fluorinated alkenes are especially poor dipolarophiles. Thus, without discussing all of the available experimental material, it may be suggested that yet another factor, namely polarizability, contributes to the high dipolarophilic nature of conjugated systems. The so-called exaltation of the molar refraction of conjugated systems demonstrates the magnitude of a special contribution to pohrizdbility in such cases [27]. The Kerr effect offers convincing evidence that the additional polarizability ol' conjugated systems is local- ized in the x-electron cloud. This increased mobility of the bonding electrons should correspond to an en- hanced tendency to enter into cyclic electron shifts. When one intends to determine the optimum electron density at the reaction site, a substiluted phenyl compound is used so that the effect of nuclear substituents on the rate constant can be measured. The evaluation of the data by means of the well-known Hammett equation yields the p-value specific to the reaction; the sign and magnitude of p indicate whether and to what extent the activation process requires a supply or withdrawal of electrons [?ti].

[27] Cf. the Table i n C. K. I / /go /d: Structure and Mechanism. G . Bell, London 1953, pp. 12.5 -137; W. Huc'kcl: Theoretische Grundlagcn der Organischen Chcmic. 8th Edit., AkademischeVer- lagsgesellschaft, Leipzig 1956, Vol. 1 1 , pp. 181-205.

[28] L. P. Hummcrt: Physical Organic Chcrnistry. McGraw-Hill, NewYork 1940,p.184; H . H.Jtrffk,C:hcm. Reviews53, 191 (1953).

638

We have measured the rates of addition of various I ,3-dipoles onto p-substituted styrenes (some examples in Table 6). The rate depends only slightly on the nature of the p-substituent, attaining a factor of 6 with C-phenyl-N-methylnitrone. It is only in this case that the Hammett equation is satisfied with a value of p = +0.83.

Diphenyl(nitri1e imine) (80 'C) [24] Benzonitrile oxide ( 2 O O C ) [25] Diphenyldiazomethane (40 "C) I71 Phenyl azide (25 "C) [21,26]

'Table 6. Rate constants f o r 1,3-dipolar cycloadditions onto styrene and its n-substituted derivatives.

24 9 I 3 0 99

l.3-Dipole (solvent, leniperature)

2.9

2.7

CnH4 , @ , C ~ H ~ P C I

CoH4 N-CN (chlorobenzene. 80 "C,)

' ,C=N\o

CH3 v21

5.6

5.1

(p-cymene, 140 "C) [231

0.87 \

H

c6n5 /C=N\oD

(toluene, 120°C) [ I21

0.'

kzx lo4 [I/mole/sec] for p-RGH&H=CH2

93

1 1.17

1,3-Dipole

Diphenyl(nitri1eimine) (80 "C) [24] Benzonitrile oxide (20°C) [251 Diphenyldiazomethane (40 "C) [71 Phenyl azide (25 "C) 121,261 Azomethine imine (5) (80 " C ) 1221 N-Phenyl-C-methylsydnone

(I40 "C) [23]

The dipolarophilic character of the CEC t

kAHzC=CH-C6Hs) k2(HzC=CH-COOR) kz( HC F- C--Cn H 5 ) k2( H C C-COO R)

12 8.5 9 2 5.1 1.2 0.67 1.4 0.95 0.64 0.22

1.4 0.38

is similar in magnitude to that of the C- C dou ble bond. Table 7 gives a comparison of the rate constants for styrene and phenylacetylene, as well as for acrylic and propiolic esters. Aromatic pyrazoles, isoxazoles, and 1,2,3-triazoles result in the additions of dipolarophilic triple bonds onto diphenyl(nitri1e imine), benzonitrile-N- oxide, and phenyl azide, respectively, but not by addition onto the other 1,3-dipoles of Table 7. It is remarkable that the reactions leading to aromatic rings do not proceed at a faster rate. Evidently, the transition state of the cycloaddition does not profit from the aromatic resonance of the product. This surprising phenomenon will be discussed further below.

The high dipolarophilic activity of a n g u 1 a r 1 y s t r a ined double bonds, such as those in trans-cyclooctene or in bicyclo[2,2,1]heptene and its derivatives, has already been mentioned. The rate of reaction of norbornene with nitrilium and diazonium betaines is 24-99 times faster than that of cyclopentene. The highest value is attained with phenyl azide (Table 8). Remarkably, this advantage vanishes in the case of 1,3-dipoles "without a double bond" [I]. With azomethine imines and nitrones, the ratio kz(norbornene) / k2(cyclopentene) is only 0.13-6.0; this phenomenon is as yet unexplained. There are differences as well as similarities in the activity series. The ratio of the rate constants of ethyl

Table 8. Katios of dipolaruphilic activities loward nitrilium and diazoniuni betaines.

__ ~

15

244 0.68

0.052

acrylate and norbornene (Table 8) might perhaps be taken as a quantitative measure of' the affinity of 1,3- dipoles toward conjugated, clectron-attracting substituents in the dipolarophile. Possibly this ratio increases with the magnitudc of the partial negative charge which resides on the dipolarophile during the transition state of the 1,3-addition. Perhaps this is a key to the unravelling of the above-mentioned problem of the unequal rate of bond closure i n the transition state.

2. Influence of Steric Factors

The greater the steric requircnients of the transition state, the more sensitive the system is toward disturban- ces. The rates of concerted processes are often dramati- cally affected by steric factors. Table 9 shows the decrease in rate associated with the introduction of methyl groups into the a- or $-position of acrylic ester.

Table 9. Inlluencc 01' methyl groulis on the rate constants for additions onto acrylic ester.

I ,3-Dipole

Kelativa k z values based on k2 for acrylic ester = 100

IlzC-. C - - C O * R HCxCH-COzR I

CH, 1 CH3

Diphenyl(nitri1e imine) (85 "C) [241 Benzonitrile oxide (20 "C) 1251 Diphenyldiazomethane (40 "C) 171 Phenyl azide (25 "C) [261 Azomethine imine (5 ) (80 "C) 1221 3,4-Dihydroisoquinoline-N-

phenylimine (50 "C) [291 C-Phenyl-N-niethylnitrone (85 "C) I12 I

34 4x

7.2 7.4

I 2

3.5 3 0

2.1 1.52 0.35 2.6

35

0.9 8.4

The effect is greatest with diphcnyldiazomethane; the rate constants for its cycloaddition onto niethacrylic and crotonic esters are 14 and 280 times Iuwcr, respectively, than the values obtained for acrylic ester. 'This is in conformity with a phenomenon frequently observcd in I ,3-dipolar additions, namely that steric hindrance in I. 1 -disubstituted ethylenes is more pronounced than in the I ,2-disubstituted types. We sus- pect that the polar effect of the nicthyl group is less significant than its steric influence. The differing effects exerted by methyl groups, as apparent from the rate constants in Table 9, are caused by the varying spatial requirements of the 1,3- dipoles. Thus, with C-phenyl-N-methylnitrone, the decrease in the rate constant becomes rapid only when the acrylic ester is heavily substituted with methyl groups [I21 (Scheme 3).

Ozone and nitrous oxide arc the two 1,3-dipoles with the lowest steric requirements. With ozone, introduction of the first two methyl groups into ethylene is ac-

[29] R . Srhiffur, unpublishcd rcsnlls, Univcrsitiit Miinchen, 1962.

Atigew. Chrm. internut. Edir. 1 Vol. 2 (1963) / No. I I 639

CHa\ FO2CzHs cH3\ /COzCzHs ,c=c ,c =c,

CH3 H CH3 CH3

2 1 1.0

Scheme 3. Rate constants k z x I06 [I/mole/secl in toluene at 120°C for 1.3-dipolar addition of C-phenyl-N-methylnitrone onto methylated acrylic esters.

companied by an increase in reaction rate, while the third and fourth methyl groups induce a slight rate decrease [30] (Scheme 4).

HzC=CH2 CHs-CH=CHz CH~-CH=CH-CHS

1.0 2.8 9.0

(CH&C =CH-CH~ ( C H ~ ) Z C = C ( C H ~ ) ~

6.4 7.5

Scheme 4. Relative values of kp for the addition of ozone onto methylated ethylenes at 20 "C in the gas phase [301.

These antagonistic tendencies of accelerating electronic and impeding steric effects are also encountered with phenylated ethylenes. Introduction of a second phenyl group into the a- or @-position of styrene is always accompanied by a decrease in reaction rate. Thus, the rate constant for 1 , l - diphenylethylene is lower than that of styrene by the following factors: with diphenyl(nitri1e imine) 15, with diphenyldiazomethane 8, and with C-phenyl-N-methylnitrone 12.

3. Rates of Addition to cis-trans Isomeric Alkenes

Kinetic studies of the stereoselective addition of 1,3- dipoles onto geometrically isomeric alkenes indicate a higher reactivity for the trans-isomers. Thus, truns- stilbene adds diphenyl(nitri1e imine) 27 times faster than does cis-stilbene [24]. The ratios of the rate constants for additions onto dirnethyl furnarate and maleate range from 58 to 2.9 (Table 10). Is this not surprising, because the addition of bromine or sulfite onto the energy-richer maleic ester is faster than that onto fumaric ester ?

Table 10. Effect of configuration on the dipolarophilic activity of dimethyl ethylenel ,Z-dicarboxylates.

kZ (fumaric ester)

kz (maleic ester) _...I..__

~

Diphenyl(nitri1e irnine) (80 "C) 1241 Benzonitrile oxide (20 "C) [25] Diphenyldiazomethane (40 "C) 13 I I Phenyl azide (25 "C) [261 Azomethine irnine (5) (80 "C) [22] C-Phenyl-N-methylnitrone (85 "C) [I21

36 58 36 25

5.2 2.9

cis-Stilbene and maleic ester both have angles of 120 at the spz-hybridized carbon atoms and show some overlapping of the van der Waals radii of their cis- substituents even in the ground state. The result is a

[30] T. Vrbaski and R . J . Cvetanouii, Canad. J. Chem. 38, 1053 ( I 960). [31] R. Huisgen, H . J . Sturm, and H . Wngenhofer, Z. Naturforsch. 176, 202 (1962).

steric hindrance of resonance, which can be detected in theultraviolet spectra of the cis- and trans-forms; the 7c-

electron system can be coplanar only in the trans-form. The hindrance of mesomcrism in the cis-isomer weakens the activating effect of the phenyl or carboxylic group in the cycloaddition.

However, there is a second factor of even greater importance. Comparison or Tables 9 and 10 shows that the rate constants for thc reaction of maleic ester with 1,3-dipoles which are especially sensitive to steric hindrance in the dipolarophile are particularly much lower than the rate constants for the reaction with fumaric ester. During the concerted addition of a 1,3- dipole, ubc, hybridization of the central carbon atoms of the olefinic dipolarophile changes gradually from sp2 to sp3. Even though the CC distance is thus somewhat lengthened, the attendant shrinkage of the bond angle from 120 to 109' results in considerable compression of the van der Waals radii of the eclipsed cis-substituents as illustrated convincingly by the scale drawing(Figure2). Thus, an increase in the van der Waals repulsion results during the activation process. This increase leads in turn to a higher activation energy for the cycloaddition to the cis-isomer, whereas the addition onto the trans-isomer is free from this disadvantage.

Fig. 2. Steric changes occurring during the cycloaddition of a I ,3-dipole, abc, to a ci.s-I,2-disubstituted ethylene.

If this explanation is corrcct, then the ratio of trunslcis ratefactors should increase as the bulk of the substituents R colliding in the cis-configuration increases. This is indeed the case, as is confirmed by the rates of addition of diphenyldiazomethane [3 I ] (Table 11). Thus, the bulky benzoyl residues of dibenzoylethylene cause the ratio to rise to 110, while in the case of ethyl crotonate,

Table 1 I . Ratios of rate constatits for the addition of diphenyldiazomethane onto geometrically isomeric alkenes at 40°C; R and R' are substituents on ethylene [311 (cF. IGg. 2) .

R I I k2 k2(frrms) (cis)

640 Angew. Chern. ; n t w t w t . Edit. 1 Vol. 2 (1963) 1 No. I 1

where the smaller methyl and ethoxycarbonyl groups interact, the trans-form reacts only 2.6 times faster. Incidentally, the same phenomenon has also been reported by J. Sauer [32] for the Diels-Alder synthesis. The ratio of the tramlcis rates offers an elegant and theoretically clear criterion for concerted additions leading to five- and six-membered rings.

1,3-Dipole (solvent, temperature)

4. Principle of Maximum Gain in .r-Bond Energy

~ ~ ( C ~ H S - C E C H ) k2(HC=C-COOR) --

k2(CnH5 - c ~ N ) k2(NEC-COOR)

Is there a universal activity sequence of dipolarophiles in the 1,3-cycloaddition? Unfortunately, a closer inspection of the results outlined above destroys any such illusions straight away. Instead, it is necessary to elaborate the specific sequence of dipolarophilic activity for each new I ,3-dipole. A significant determining factor is reached by including dipolarophiles containing hetero - atoms in the comparison. The ability of such systems to undergo addition is often inferior to structurally analogous (1,C-dipolarophiles; however, the highly polarizable C -S double bond frequently constitutes an exception. The kinetic data for the addition of diphenyl(nitri1e imine) and benzonitrile oxide onto acetylene derivatives and the related nitriles may serve as an illustration. The ratios presented in Table 12 disclose the higher activity of the C C triple bond.

o f 3

(benzene, 80 "C) [241 0 0

C ~ H S - C E N - N - C ~ H S

C6HS-C=N-0 (ether, 20 "C) [25!

15

20

4.2

9.9

The superiority of the C,C - dipolarophile becomes even greater if, for example, benzaldehyde or glyoxylic ester are compared with styrene or acrylic ester. l h e 1,3-dipoles of Table 12 add onto carbonyl compounds only very slowly. The lower activity of the hetero-dipolarophiles is shown still clearer in their behavior towards phenyl azide, i. e. nitriles barely react, whereas aldehydes and ketones do not add a t all. The two-step scheme presented on p. 634 would predict higher activity for hetero-dipolarophiles, since the oxygen or the nitrogen atoms present in position d of the intermediate (9) should readily assume a negative charge.

An explanation of numerous activity ratio data is supplied by the principle of maximum gain in o-bond energy. Thus, the driving force behind the 1,3-dipolar addition is the stronger, the more the loss of 7r-bond energy in the reactants is overcompensated by the energy of the two new o-bonds. A part of this o-bond energy contributes already to the transition state of the concerted cycloaddition. Thus, the 1,3-addition of ozone yields primary ozonides only with olefinic or aromatic C=C bonds whereas cycloadditions onto C - 0 or C-N double bonds are un-

[32] J . Suuer, H. Wiesr, and A. Mielert , Z . Naturrorsch. /7b, 203 (1962); J. Sauer, D. Lung, and ti. Wiest. ibid. /7/1, 206 (1962).

known. The reason is readily apparent. Two new C -0 single bonds are closed in the addition to the alkene; this corresponds to a bond energy of 170 kcal. Addition

C - O 85 +R2C=CR2

c-0 85 170 kcal

0 0 0 @ o=o* - 043=0

C-O 85 O* 35

120 kcal

onto a carbonyl group would yield one C-0 single bond and one 0-0 single bond; the attendant gain of only 120 kcal of a-bond energy does not provide sufficient driving force for the cycloaddition since the reactants would have to sacrifice their x-bond energy. Of course, the activation configurations for the two ozone additions will not differ by this full amount of 50 kcal, but the difference will certainly constitute an appreciable fraction of this value. Thegain ino-bond energy is perhaps the most important reason for the difference between the activity scales of the dienophiles and dipolarophiles. As an example, azo- dicarboxylic ester displays a very great readiness to add dienes at the N- N double bond; the gain ino-bond energy associated with this process amounts to 146 kcal. In contrast, the addition of cliphenyf(nitri1e irnine) or phenyl azide onto azodicarboxyIic ester is sluggish. However, this is not surprising if we remember that these reactions are associatcd with o-energy gains of only 1 I2 and 78 kcal, respectively.

F. Orientation Phenomena

All unsymmetrically bonded d i polarophiles can add the 1,3-dipole in two directions, since with few exceptions 1,3-dipoles lack bold symmetry. To what extent can the orientation phenomena be explained, and the direction of the addition he correctly predicted?

1. In Dipolarophiles with Hetero-Atoms

The nature of the new o-bonds not only influences the activity series of dipolarophiles, but also determines the orientation. Dipolarophiles with multiple bonds including a hetero-atom usually add the dipole in only one of the two possible directions. Thus, the addition of benzonitrile-N-oxide onto aldehydes yields exclusively derivatives of the 1,3,4-dioxiizole system [33]. The formation of the structurally iwmeric heterocycle would involve a gain of o-bond clicrgy which is smaller by 52 kcal. I n the addition of ~Ii~~hcnyl~nitrile imine) onto azomethines [34], a difference in o-bond energy of the

[33] R . H u i s g ~ u and W. M u c k , I'clrahcdron Letters 196 / , 583. (341 R. Huisgew, R . Grushey, M. . S P ; ~ P / , a n d H. Knuitfer, unpublished results, 1959/62.

Angew. Chem. intevncrt. Edit. Vol. 2 (1963) N o . I 1 64 1

products of 24 kcal is sufficient to direct the reaction entirely into the channel leading to A2-1,2,4-triazolines. As already stressed above, the energy of the newo-bonds becomes only partly (estimated at 20-40% of the total) available in the transition state of the cycloaddition.

H

C - C 83 0-035

118 kcal

I

C - C 83 N-N 2

122 k c a l

C-N 73 C-N 3

146 kcal

In contrast to the numerous cases in which the maximum gain in a-bond energy dictates the direction of addition, there are a few exceptions of special interest. It is reasonable to postulate a change in mechanism for these cases. One example is the dimerization of nitrile oxides to form furoxans, whereby one C-C and one N-0 bond are closed. A dynamic equilibrium between benzofuroxan and a modest concentration of o-dinitrosobenzene has been detected a t room temperature [35]. The existence of this equilibrium suggests a two-step mechanism for furoxan formation: in the first step, the nitrile oxide, which can be represented by a nitrosocarbene structure, dimerizes to a dinitrosoethylene. This multistep path naturally no longer obeys the principle of maximum gain in a-bond energy.

Benzonitrile oxide appears to add onto the C-N double bond of benzhydroxamoyl chloride in a “normal” fashion; in any event, spontaneous decomposition of the latter leads to the derivative (19) of the isomeric 1,2,4-oxadiazole [36], during the formation of which C 0 and C N single bonds are closed.

[35] G. Englert, 2. Naturrorscli. 16h, 413 (1961); A. R . Kn- tritzky, S. Oksne, and R. K . Harris, Chem. and Ind. 1961, 990; P . Diehl, H . A . Chrisi, and F. B. Mnllory, Helv. chim. Acta 45,504 (1 962). [36] H . Wieland, Ber. dtsch. chem. Ges. 40, 1667 (1907).

2. In Dipolarophiles of the Alkene and Alkyne Series

With alkenes or alkynes ;IS dipolarophiles, both directions of addition produce, of course, the same amount of o-bond energy. The intcrplay of electronic and steric substituent effects - the latter usually being dominant - is responsible for the orientation here. The large amount of factual material on the subject may be illustrated with a few examples. Diphenyldiazomethane adds onto propiolic ester in one direction only. This direction is favorable both from the steric and electronic points of view. The latter statement is based on the experimental evidence that the central carbon atom of the diazoalkane is more strongly nucleophilic than the outer nitrogen. In the case of phenylpropiolic ester, the direction of addition is re- versed with respect to the carboxylic ester group [37].

The spatial requirements of the phenyl residue are greater than those of the inethoxycarbonyl group and the steric effect is dominant i n this addition. This is suggested by experiments with diazoalkanes in which the steric demand of the central carbon is lower, With phenyldiazomethane or diazoacetic ester, a mixture of products resulting from both directions of addition is obtained, although the sterically favored isomer (2I) is the principal one [37].

25-30% CsH, 70-7570 little l?. COzCH, much

Benzonitrile-N-oxide combi ties with all monosubstituted ethylenes or acetylenes to I‘orm 5-substituted 3-phenyl- isoxazolines or -isoxazoles; the substituent may be an alkyl or an aryl residue, and have either an electron- attracting or an electron-donating character [38]. At- tachment of the dipolarophilic carbon of greater spatial

0 0 Ic~H,-c tH2C=CHR

C6115--C=N=0

H c6H5&

H R

1371 E. Buchner and M . Fritsth, Bcr. dtsch. chcm. Ges. 26, 256 (1893); E. Buchner and W. B~hiigheI, ibid. 27, 869 (1894); R. Hiit- tel, J . Riedl, H. Martin, and K . F ~ n h , Chem. Ber. 93,1425 (1960). [38] A . Quilico and G‘. Speroni, Garr . chim. ital. 76, 148 (1946); G. Stagno d‘Alronrres and P. G/,rinrmgrr, ibid. 80, 741, 831 (1950); G. Stagno d’Alcontres, ibid. 82. 621 (1952); P. Grunnnger, ibid. 84, 359 (1954); P . Griinanger and M . R . Lcingella, ibid. 89, 1784 (1959); G . Gaudinno, A. Quiliro. and A. Ricccr, Tetrahedron 7, 24 (1959).

642 Angew. Chenr. interiwi. Edit. I Vol. 2 (1963) / No. 1 I

requirements with the oxygen of the nitrile oxide is undoubiedly the sterically more favored route.

If the anionic oxygen of benzonitrile-N-oxide is replaced by an anilino residue, the dipole becomes diphenyl- (nitrile imine), which obeys an exactly analogous orientation rule. Butadiene, styrene, acrylic ester, acrylonitrile and even the isolated double bond of n-heptene yield the 5-substituted A2-pyrazolines (23) with this 1,3- dipole; no product of the reverse orientation was detected in even a single case [16]. Can this still be a matter of steric influence?

(22) R = C5Hl1 85% R = C & , 88% R = CH=CH2 94% R = CN 85%

R = CO&It, 85%

As will be shown later, nitrile imines can attain the mesomerism characterized by formula (22) only if the geometry of the ground state corresponds to that of the nitrilium resonance structure, with sp-hybridization at the central carbon atom. In this case, the nitrogen per- mits the approach of a dipolarophilic center of a higher steric requirement noticeably more easily than does the nitrile imine carbon. Thus, even though the mesomeric effect of the ethoxycarbonyl group in acrylic ester should promote an addition resulting in the 4- substituted pyrazoline, the commanding steric influence determines the orientation.

The specificity with which even monosubstituted acetylenes add diphenyl(nitri1e imine) to yield 5-substituted 1,3-diphenylpyrazoles is astonishing [ 161. Comparison of the results obtained with propiolic ester and with phenylpropiolic ester is still in agreement with this tentative assumption of steric control. Also here, as with diphenyldiazomethane, reversal of the direction of addition occurs with respect to the ester function. The reaction path resulting in the appearance of the phenyl at the 5-position is once again the sterically more favorable route.

It should be expected that the steric preference for addition onto the nitrile imine nitrogen would vanish if the N-phenyl residue were to be encumbered with bulky substituents. This, however, is not the case, as is shown by the adducts (24) and (25) obtained from C-phenyl-N-trihalogenophenyl(nitri1e iniine) with acrylic ester and 1,l-diphenylethylene, respectively [39]. It is true that the trihalophenyl residue is twisted out of the coplanarity with the nitrile imine bond system; however,

the strictness with which the same orientation rule is followed is really remarkable and casts doubt on a purely steric interpretation.

c1

It should also be mentioned brielly that a mechanism assum- ing the existence of a spin-coupled biradical intermediate fails to offer an unequivocal interpretation of the orientation phenomena. The unidirectional addition to monosubstituted ethylenes and acetylenes can admittedly be understood in terms of the intermediate (26), since alkyl, aryl, and carboxylic ester groups are able to stabilize the radical when present in position R. However, with phenylpropiolic ester, the actual orientation does not correspond to that expected from such an intermediate, since the kinetic data of Table 5 leave no doubt that the carboxylic estcr group is far more strongly activating than phenyl.

The interplay of the factors determining orientation is thus somewhat unclear in many cases. This, incidentally, is also true of the influence of substituents on the direction of Diels-Alder addition 1401.

G. Kinetics and Structural Variation of the 1,3-Dipole

It has already been shown qualitatively (Table 1) that the ability of substituted diazomethanes to undergo cycloaddition decreases with their resonance stabilization in the ground state. When the mesomeric substituent effects of the 1,3-dipole are compared with those in the cyclic adduct, one often arrives at a reasonable correlation with the reaction rates. However, the few observations available at present are no substitute for a systematic investigation.

Although the addition of the dipolarophile usually results in higher coordination numbers at the charge centers of the 1,3- dipole, in certain situations, the cycloaddition produces release of mesomeric effects. Thus, thc octet structures of the sydnones or nitrones reveal that thc mesomeric electron-attracting effect of any substituent R at the immonium nitrogen is suppressed; however, in the adduct, the unshared electron pair at the now trivalent nitrogen becomes available for resonance with R. The gain i n rcsonance energy thus increases the driving force of the cycloaddition. Naturally this effect is proportional to the ability of tlic aromatic nucleus to take up electrons. In 1,3-dipoles “without a double bond” [I], the configuration is of primary importance. In C-phenyl-N- methylnitrone, the organic residues are trans to the C - N double bond. Fixation of the cis-configuration in dihydroisoquinoline-N-oxidc by the cyclic structure

[39] V. WeherndGffer, unpublishcd results, Universitit Miinchen, 1961162.

[40] K. Alder and M . Schuh/nnc/wr, Portschr. Chem. org. Naturst. 10, 21 (1953).

Angew. Chem. intermit. Edit. Vol. 2 (1963) 1 No. I 1 643

Table 13. Relative rate constants for the reaction of N-substituted sydnones with ethyl phenylpropiolate [23], and of N-substituted C-phenylnitrones with ethyl crolonate [ 121.

1,3-Addition

I + d=e

-e

kz(re1.) -

3.8 7.2

=10.0 18.2

2.0 7.1

=10.0 15.8

results in a 200-fold increase in the rate of 1,3-cycloaddition (Table 14). Dialkylnitrones and A’-pyrroline- N-oxide show similar behavior. The rate constant for the addition of isoquinoline-N-oxide is 40000 times smaller than that of the 3,4-dihydro derivative because the aromatic pyridine mesomerism has to be sacrificed during the cycloaddition.

Table 14. Rate constants k2X 10s Iliters/mole/secl for the addition of some nitrones onto ethyl crotonate in toluene at 100 “C [121.

1.1 240 If. 0.006

0.97 4.3 160

Polar substituent effects have relatively little influence on the specific rate of addition of a 1,3-dipole. So far we know of only one surprising exception: this occurs with the aromatic azides, whose special tendency to add onto electron-rich double bonds has already been mentioned [ 11. p-Nitrophenyl azide adds onto norbornene eight times faster than does p-rnethoxyphenyl azide (Table 15). However, the aromatic azide displays opposing substituent effects depending on whether it adds onto an olefinic dipolarophile of higher or lower electron density. In the addition onto maleic anhydride (which has an electron-deficient double bond) p- methoxyphenyl azide exceeds the p-nitro compound by

Table 15. Rate constants for I .3-additions of organic azides onto olefinic dipolarophiles in benzene at 25 “C [21,261.

0’83 R-N-NEN

R =

644

maleic anhydride

1 .3 1.2

21

-1.2

53

kzx lo7 [liters/mole/secl for

N-phenyl- nialeiniide

I I 28 67 -4J.7

95

pyrrol- idinocyclo- hexene bornene

nor- 1 1530 254 I87 -1-0.8 22

1480000 9930 3 400

f2.6 25

a factor of sixteen. The order of magnitude is especially noteworthy with the electron-rich double bond of pyrrolidinoqclohexene (an enamine): the Hammett p- value rises here to -1-2.6. It is noteworthy that the rille of addition of benzyl azide is scarcely affected by the eleclron density of the dipolarophilic double bond. Further investigation is needed to show whether a change in mechanism is involved i n this case, e.g. a transition from a “true” 1,3-dipolar addition to a process involv- ing a zwitterionic intermediate.

H. Molecular Orbital Considerations

The resonance of the two octet formulae of 1,3-dipoles “with a double bond” is no longer self-evident if the orbital hybridization of the two octet structures is

considered separately. Taking the nitrile ylides as a model system, it can be seen that accommodation of the lone electron pair at carbon atom a of formula (28) in an sp2-orbital is energetically favored over that in a p- orbital. This should result in a bending of the bond system at carbon atom a, compared with the linear sp- hybridized a-system of (27).

a b C

(27)

a b C

(28)

In terms of the MO theory, mesomerism of the structures above is equivalent to saying that delocalization of fourx-electrons in the three p-orbitals of the plane of the paper in formula (2Y) takes place. This can be achieved only in configuration (27) of theo-bond system. To a first approximation, the delocalization energy in (29) is that of the ally1 anion, which amounts in the LCAO treatment to 0.82 (3, where is the resonance integral [41]. It may be assunied that this gain in energy is larger than the loss associated with the establishment of sp-hybridization at carbon atom a in (28).

[41] Cf. A. Srreitwiuser: Molecular Orbital Theory. Wiley, New York 1961, p. 40.

Angew. Chem. interrrirt. Edit. / Vol. 2 (1963) / No. I 1

During the activation process, the linear bond system a-b-c of the 1,3-dipole must necessarily bend in order to place centers a and c in contact with the n-bond system of the dipolarophile. How much energy does it take to achieve the transition from (29) to (30), during which ihe rc-bond perpendicular to the plane of the paper disappears? An LCAO calculation by J . D. Roberts [42] for the azide system - in which the relationships are simpler because of the identity of atoms a, b, and c - has pointed out that a loss of less than I is involved in bending the linear configuration to an angle of 120”; the loss of x-bond energy is partly compensated by a gain in energy resulting from rehybridization and accommodation of a lone pair of electrons in an orbital of high s-character. The resonance energy of the “allyl anion” is not disturbed by the bending.

(331

It is highly probable that the 1,3-dipole and dipolarophile d=e orient themselves during the formation of the activated complex in the fashion shown in (31). This implies that the “allyl anion” orbitals at centers a and c interact with the n-bond of the dipolarophile. The gradual transformation of the p-orbitals into sp*- or sp3- orbitals of the new o-bonds is accompanied by an interesting change in configuration. The nitrogen is moved upwards (in the simplified picture (32) of the transition state, the path is indicated by an arrow) until it reaches the plane of the remaining four centers in adduct (33). In the course of this continuous transition, the orbital of the lone electron pair at the nitrogen in (31) attains y-character; the x-bond of the product originates from this pair of electrons. Of the four electrons of the “allyl anion” orbital, only two are utilized in the creation of the new o-bonds; the other two appear as an unshared pair of electrons on the nitrogen in the product (33). The orbital concerned in (33) is to be considered as the remainder of the “allyl anion” system. The C=N double bond of the adduct is not that of the angled 1,3-dipole in (31); this is a significant phenomenon which did not come to light by the simple valence bond notation:

Rather, theoriginal delocalizedx-bond of (31) disappears during the progress of the reaclion while a new x-bond is formed. This now explains why the rates at which nitrile imines, nitrile oxides, or azides add to triply bonded dipolarophiles do not profit from the aromatic resonance of the product (Tablc 7). The new p-orbitals, which later become part of the aromatic x-electron cloud, are still insufficiently developed in the transition state. Moreover, the rapid decrcase in x-interaction with increasing distance contributes to the absence of any aromatic resonance in (32); in the transition state, the new 0-bonds are still quite long.

It may be a safe assumption that the transition state (32), and hence the system at the peak of the activation barrier, is geometrically closer to the oriented complex (31) of the components than to the adduct (33). Generally, the transition state i n exothermic reactions resembles more the starting nixterial than the product [43]. In this particular case, thc entire loss of activation entropy has already been achieved on orienting the components into configuration (31); it has been stressed on p. 637 that decrease in entropy accounts for a considerable part of the free energy of activation.

1,3-Dipoles “without a double bond” are already bent in the ground state; thus, therc is no problem of initial bending here. All of these 1,3-dipoles are capable of forming a delocalized 4-electron system of the allyl anion type in a manner similar to that outlined above, so that the picture given for the course of cycloaddition holds here without limitation. It is clear by now that the terminology “biradical” or “ionic” cannot be applied to this mechanism.

We shall nor discuss here an altcrnative description of the concerted addition which postulalcs that the five centers are aligned within the plane of the ring produced during the transition state. There is evidence against such a geometry of the activated configuration, e.g. with cyclic 1,3-dipoles such as those of the sydnones, the dipolarophile must necessarily approach at a right angle to the ti-h-c plane of the 1,3-dipole.

The tendency to explain new reactions in the light of theoretical principles even at :in early stage is undoubtedly greater today than ever before. If each individual experimental result is thought or as one stone in a mosaic, then many of these are needed before one is cognizant of the picture. The temptation is strong to start inter- preting the picture even before the entire array of the mosaic stones is unveiled. I t is possible, then, that future studies of 1,3-dipolar cycloadditions will bring to light further new colors and contours.

Received, March 28th, 1963 [A 3081116 IE]

German version: Anpew. Chem. 75, 741 (1963).

[42] J. D. Roberts, Chem. Ber. Y4, 273 (1961). [43] G . S. Hammond, J . Amer. chcni. Soc. 77, 334 (1955).

Angcw. Cheni. infernnt. Edit . Vol. 2 (1963) 1 No. 11 645

kinetics and mechanism of 1,3-dipolar cycloadditions

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