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Kinetics and Mechanism of 1 3-Dipolar Cycloadditions.

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ANGEWANDTE CHEMIE
-
VOLUME 2 NUMBER I 1
NOVEMBER 1963
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 experimentalfacts,
The concept of “cycloaddition” gives a formal description of an overall reaction but not a mechanistic interpretation. Any discussion of the mechanism of the 1,3dipolar 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
carbene via at least two
formed from an alkene
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-cyclo2 -+ 5. Our
additions which follow the scheme 3
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-dipolea-b-c with the dipolarophile d-e,
are closed simultaneously or one after the other.
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 wellknown examples) have been referred to in the United
States as “no-mechanism reactions” [2]. This terminology was born of “Scherz, Salire, lronie und tiefere Bedeutung” [**] 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 interception. 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
N=N-C_Rz
d Ae
(1
0
IN=N=CKz
Sextet structures
[*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).
Angcw. Chem. internut. Edit. [ Vol. 2 (1963) I No.
II
[2] Cf. W . v. E. Doering and W.H. Rofh, Tetrahedron 18, 67
(1962).
[**I Play by Ch. D. Grubhe (1827).
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.
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
H2C--N2,
0 a l (C~HS)IC-Nz
rapid
0
01
C ~ H S O ~ C - C HNz
0
ratlier slow
(1)
C~HS-CO-CH-N?
slow
0 (D
/>N02C6H4-CO--Cti-N~
very slow
CHj-CO.,O
@
C-Nz
no addition
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
rn
Reaction coordinate
-
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.
634
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 facilitated 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).
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.
Table 2. Rate constants for the addition of diphenyldiazomethaneonto
the cyclopentadieneazodicarboxylicester adduct (3) (Reaction 1) and
onto dimethyl fumarate (Reaction 2) at 40 “C in various solvents [7].
1
Solvent
Benzene
Dioxane
Ethyl acetate
Methoxyethanol
Acetone
Acetonitrile
Dimethylformamide
E-
2
I
1
1- 1
0.22
0.22
0.39
0.46
0.47
0.48
0.48
k z X LO4
(Reaction I )
2.43
2.93
2.27
3.64
2.38
2.61
2.90
I
p = 3.09
kZX 102
(5)
1.15
1.25
3.70
1.10
2.63
2.45
Scheme 1. Electric moments in the addition of diphenyldiazomethane
onto a strained double bond.
The solvent dependence o f 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
MVl,3-dipole
+ p.‘dipolarophile
MVdipolarophilz
- p.‘%ransitionstate
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. Angew. 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.
Angew. Chem. internnt. Edit.
p = 6.7
(6)
11
6.57
(7)
p = 3.55 D
1.44
p = 3.20 D
p = 1.42
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
(Reaction 2)
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 diphenyldiazomethdne 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)
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.
1 Vol. 2 (1963) 1 N o .
II
(5) and (6) or the nitrone (7). I n the case of (5), the
rate constant for the addition onto dimethyl acetylenedicarboxylate 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
p = 2.48 D
1.76
Scheme 2. Elcctric moments in the addition of
Gphenyl-N-inethylnitroneonto ethyl acrylate.
A transition state with p
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 o l 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].
2
[lo] H. Stung1 and H . Wugenliojcr, unpublished results, Universitat 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).
635
Ozonolysis of benzene in nitromethane at -28 "C is accelerated 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.
the decomposition.is carricd out i n dimethyl fumarate. It has
in fact been proven that (14) is converted into the thermodynamically 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.
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 uncontaminated, diastereoisomeric Az-pyrazolines (1I)
and ( I 2 ) . Both of these compounds can be dehydrogenated to the same tetraphenylpyrazole [16].
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 hydrogens 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 .9and 13.0cps, respectively,
for the cis-compounds (I?) and (14), and 4.9 cps for
each of the trans-pyrazoiines ( 1 1 ) and (13).
All the cycloadditions of octet-stabilized 1,3-dipoles
examined so far show similar stereoselectivity. Benzonitrile-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
m.p. 49-51°C
m.p. 71-73°C
t
CH30zC CH3
liquid
CH30nC CH3
m.p. 59-60°C
C-Biphenylene-"(or)-p-chlorophenyl] - N@)-cyanoazowith 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 maleonitrile, producing the respective adducts nearly quantitatively with no admixturcs of their diastereomers [20].
methinejmine'(5):combines
~
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, Tetrahedron 17, 3 (1962).
636
[I71 M. Karplus, J. chem. Physics 30, I 1 (1959); cf. H. Conroy,
Advances org. Chem. 2,265,3I0 (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.
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].
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]
H COzCH3
m.p. 95-96OC
n1.p. 89-90°C
In one individual case, the proof of a stereoselective cisaddition 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.
AS*[cal/dcg.
8,O
] -43
12,7
8,4
- 34
-39
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].
However, it may be an unwarranted simplification to say that
AS'
the concerted process must necessarily be associated with the
o n e - s t e p 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 ionpair intermediate. Nevertheless, it should be pointed out that
participation of an intermediate in the concerted process is
also conceivable.
[cal/degreel
C-Biphenylene-N(c+p-chlorophenylN(P)-cyanoazomethine imine (5)
(in chlorobenzene)
ethyl acrylate
styrene
phenyl isocyanate
N-Phenyl-C-methylsydnone ( 6 )
(in p-cymene)
.t ethyl phenylpropiolate
dimethyl acetylenedicarboxylatc
C-Phenyl-N-methylnitrone(7)
(in toluene)
-I- methyl methacrylate
2-vinylpyridine
Ozone (in carbon tetrachloride)
f benzene
mesitylene
+
12.5
-35
15.6
12.1
-3 I
---33
18.3
14.7
-.31
15.7
18.3
--32
-- 29
13.2
10.7
-23
-22
-- 29
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 expenditure 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
Awgew. Cl~enr.internut. Edit.
1 VCJI.2 (1963) 1 N o , I I
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, Universitlit Miinchen, 1962.
[23] H . Gofflrtrrt//, unpublished rcsulls, llnivcrsitiit Miinchen,
1062.
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(nitri1eirnine) 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, f d i p o l e
(solvent,
temperature)
kz (relative) for dipolarophile
HzC=CH--R
R = alkyl
-COlalk
e e
GHs-CE N-N - G H s
(benzene, 80 "C) 1241
0.30
3.2
100
3.9
14
100
0.01
0.2
100
2.4
4.1
100
I .8
5. I
100
(ether, 20 "C) I251
$ 8
NEN-C(&H5)2
(DMF, 40 "C) I71
(CCI,. 25 "C)1261
(chlorobenzene, 80 "C) 1221
CH3
.A,/o
CoH5-N
5.8
8.0
LOO
0.67
3.0
I00
\s?
N
(p-cymene, 140 "C) I231
H
\
(IdCH3
C6Hs/c=N\oO
(to
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 exothermicity 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 localized in the x-electron cloud. This increased mobility of
the bonding electrons should correspond to an enhanced 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].
tuene, 120"C)[121
[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.
638
[27] Cf. the Table i n C. K. I / / g o / d : Structure and Mechanism.
G . Bell, London 1953, pp. 12.5 -137; W. Huc'kcl: Theoretische
Grundlagcn der Organischen Chcmic. 8th Edit., AkademischeVerlagsgesellschaft, Leipzig 1956, Vol. 11, pp. 181-205.
[28] L . P. Hummcrt: Physical Organic Chcrnistry. McGraw-Hill,
NewYork 1940,p.184; H . H.Jtrffk,C:hcm. Reviews53, 191 (1953).
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.
'Table 6. Rate constants f o r 1,3-dipolar cycloadditions onto styrene
and its n-substituted derivatives.
,
@,C~H~PCI
' ,C=N\o
CoH4
5.6
N-CN
(chlorobenzene. 80 " C , )
CH3
v21
2.9
(p-cymene, 140 "C) [231
H
\
c6n5
/C=N\oD
0.87
Diphenyl(nitri1e imine) (80 'C) [24]
Benzonitrile oxide ( 2 O O C ) [25]
Diphenyldiazomethane (40 "C) I71
Phenyl azide (25 "C) [21,26]
24
~
15
0.68
9I
30
99
244
0.052
0.'93
1.17
2.7
acrylate and norbornene (Table 8) might perhaps be
taken as a quantitative measure of' the affinity of 1,3dipoles 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.
5.1
2. Influence of Steric Factors
1
(toluene, 120°C) [I21
The dipolarophilic character of the CEC t
is similar in magnitude to that of the C-C d o u 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(nitri1eimine), benzonitrile-Noxide, 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.
1,3-Dipole
__
kzx lo4 [I/mole/sec] for p-RGH&H=CH2
l.3-Dipole (solvent,
leniperature)
CnH4
Table 8. Katios of dipolaruphilic activities loward nitrilium and
diazoniuni betaines.
kAHzC=CH-C6Hs) k2(HzC=CH-COOR)
kz( HC F-C--Cn H 5 )
Diphenyl(nitri1eimine) (80 "C) [24] 12
Benzonitrile oxide (20°C) [251
92
Diphenyldiazomethane (40 " C )[71
1.2
1.4
Phenyl azide (25 "C) 121,261
Azomethine imine (5) (80 " C ) 1221 0.64
N-Phenyl-C-methylsydnone
1.4
(I40 "C) [23]
k2(
H C C-COO R)
8.5
5.1
0.67
0.95
0.22
0.38
The high dipolarophilic activity of a n g u 1 a r 1y s t r a i n e d
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
Atigew. Chrm. internut. Edir.
1 Vol. 2 (1963) / No. I I
The greater the steric requircnients of the transition
state, the more sensitive the system is toward disturbances. The rates of concerted processes are often dramatically 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.
Kelativa k z values based on k2 for
acrylic ester = 100
I ,3-Dipole
IlzC-. C - - C O * R
CH,
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
34
4x
7.2
7.4
I2
1
HCxCH-COzR
I
CH3
2.1
1.52
0.35
2.6
35
3,4-Dihydroisoquinoline-Nphenylimine (50 "C) [291
C-Phenyl-N-niethylnitrone
(85 "C) I12 I
3.5
30
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 suspect 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 1,3dipoles. Thus, with C-phenyl-N-methylnitrone,the decrease
in the rate constant becomes rapid o n l y 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.
639
CHa\
,c=c
FO2CzHs
H
CH3
/COzCzHs
cH3\
,c =c,
CH3
21
CH3
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-methylnitroneonto 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~
(CH~)ZC=C(CH~)~
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.
steric hindrance of resonance, which can be detected in
theultraviolet spectra of the cis- and trans-forms; the 7celectron 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 1,3dipole, 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 convincinglyby 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.
3. Rates of Addition to cis-trans Isomeric Alkenes
Kinetic studies of the stereoselective addition of 1,3dipoles onto geometrically isomeric alkenes indicate a
higher reactivity for the trans-isomers. Thus, trunsstilbene 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
dimethylethylenel ,Z-dicarboxylates.
Fig. 2. Steric changes occurring during the cycloaddition of a I ,3-dipole,
abc, to a ci.s-I,2-disubstitutedethylene.
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,
kZ (fumaric ester)
_
.
.
.
I
.
.
_
_
kz (maleic ester)
~
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
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(frrms)
k2 (cis)
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 cissubstituents 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).
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.
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
+R2C=CR2
C-O
85
c-0 85
0 0
o=o*
-
170 kcal
0 @
043=0
4. Principle of Maximum Gain in .r-Bond Energy
C-O
O*
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(nitri1eimine) 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.
1,3-Dipole
(solvent, temperature)
~ ~ ( C ~ H S - C E C Hk2(HC=C-COOR)
)
k2(CnH5-
of3
C ~ H S - C E N - N - C ~ H S 15
(benzene, 80 "C) [241
0
cN )~
--
k2(NEC-COOR)
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, azodicarboxylic 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.
4.2
F. Orientation Phenomena
0
C6HS-C=N-0
(ether, 20 "C) [ 2 5 !
20
9.9
T h e 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 a d d onto carbonyl compounds only very slowly.
T h e lower activity of the hetero-dipolarophiles is shown still
clearer in their behavior towards phenyl azide, i. e. nitriles
barely react, whereas aldehydes a n d ketones do not add
a t all. T h e two-step scheme presented o n p. 634 would
predict higher activity for hetero-dipolarophiles, since the
oxygen o r 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. / 7 b , 203
(1962); J. Sauer, D. Lung, and ti. Wiest. ibid. /7/1, 206 (1962).
Angew. Chem. intevncrt. Edit.
85
35
Vol. 2 (1963)
No. I 1
All unsymmetrically bonded d i polarophiles can add
the 1,3-dipole in t w o 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 ~ uand W. M u c k , I'clrahcdron Letters 1 9 6 / , 583.
(341 R. Huisgew, R . Grushey, M . . S P ; ~ P / a, n d H . Knuitfer, un-
published results, 1959/62.
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
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.
Diphenyldiazomethaneadds 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 reversed with respect to the carboxylic ester group [37].
I
C - C 83
N-N
122 k c a l
2
C-N
C-N
73
3
146 k c a l
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.
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%
little
l?.
70-7570
CsH,
COzCH,
much
Benzonitrile-N-oxidecombities with all monosubstituted
ethylenes or acetylenes to I‘orm 5-substituted 3-phenylisoxazolines or -isoxazoles; the substituent may be an
alkyl or an aryl residue, and have either an electronattracting or an electron-donating character [38]. Attachment of the dipolarophilic carbon of greater spatial
Ic~H,-c 0
0
tH2C=CHR
C6115--C=N=0
c6H5&
H
H
[35] G. Englert, 2. Naturrorscli. 16h, 413 (1961); A . R . Kntritzky, 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).
642
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. Hiittel, J . Riedl, H. Martin, and K . F ~ n hChem.
,
Ber. 93,1425 (1960).
[38] A . Quilico and G‘. Speroni, G a r r . 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).
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 1,3dipole; 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 = CH=CH2 94%
R = CO&It,
R
R
= C & , 88%
= CN 85%
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 permits 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 4substituted pyrazoline, the commanding steric influence
determines the orientation.
The specificity with which even monosubstitutedacetylenes 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,
[39] V. WeherndGffer,unpublishcd results, Universitit Miinchen,
1961162.
Angew. Chem. intermit. Edit.
Vol. 2 (1963) 1 No. I 1
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 assuming 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 t o 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 1,3dipole, 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-Nmethylnitrone, the organic residues are trans to the
C - N double bond. Fixation of the cis-configuration in
dihydroisoquinoline-N-oxidc by the cyclic structure
[40] K.Alder and M . Schuh/nnc/wr, Portschr. Chem. org. Naturst.
10, 21 (1953).
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
kz(re1.)
3.8
7.2
=10.0
18.2
+ d=e
I
a factor of sixteen. The order of magnitude is especially
noteworthy with the electron-rich double bond of
pyrrolidinoqclohexene (an enamine): the Hammett pvalue 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-dipolaraddition to a process involving a zwitterionic intermediate.
2.0
-e
results in a 200-fold increase in the rate of 1,3-cycloaddition (Table 14). Dialkylnitrones and A’-pyrrolineN-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.
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 porbital. This should result in a bending of the bond
system at carbon atom a, compared with the linear sphybridized a-system of (27).
0.006
160
4.3
0.97
H. Molecular Orbital Considerations
7.1
=10.0
15.8
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) pmethoxyphenyl azide exceeds the p-nitro compound by
a
b
C
a
(27)
b
(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).
Table 15. Rate constants for I.3-additions of organic azides onto olefinic
dipolarophiles in benzene at 25 “C [21,261.
kzx lo7 [liters/mole/secl for
0’83
R-N-NEN
maleic
R=
an-
644
hydride
N-phenylnialeiniide
bornene
nor-
1.3
1.2
21
II
28
67
-1.2
-4J.7
53
95
1530
254
I87
-1-0.8
22
1
pyrrolidinocyclohexene
1480000
9930
3 400
f2.6
25
[41] Cf. A. Srreitwiuser: Molecular Orbital Theory.
York 1961, p. 40.
Wiley, New
Angew. Chem. interrrirt. Edit. / Vol. 2 (1963)
/ No.I 1
C
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 sp3orbitals 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 t h e 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 interpreting 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 N o . 11
645
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