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Capto-dative Substituent Effects in Syntheses with Radicals and Radicophiles [New synthetic methods (32)].

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(981 R. K. Smalley, H. Suschitzky, J. Chem. SOC. 1963, 5571.
1991 R. K. Smalley, W . A. Strachan, H. Suschitzky, Tetrahedron Lett. 1974,
825.
[lW] M . I . Chohan, A . 0. Fittan, B. T. Hatton, H. Suschitzky, J , Chem. SOC.C
1971, 3079.
(1011 B. Iddon, H. Suschitzky, D. S. Taylor, M . W Pickering, J. Chem. Soc. Perkin Trans. I f 974, 575.
1102) E. B. Mullock, H. Suschirzky. J. Chem. Soc. C 1968, 1937.
11031 R. Garner, H. Suschitzky, J. Chem. SOC. C 1967, 74.
[lo41 Ch. L. Zirkle. C. Kaiser in A . Burger: Medicinal Chemistry. 3rd Edit., Part
I t Wiley. New York 1970, pp. 1410, 1470.
[lo51 Z. U. Khan, E. F. V. Scriuen, H. Suschitzky, unpublished work.
(1061 J. I . C.Cadogan, I . Cosney, E. Henry, T. Naisby, B. Nay, N. J. Stewart, N.
J. Tweddle, J. Chem. SOC.Chem. Commun. 1979, 189;J. I. G. Cadogan, N.
J. Stewart, N . J. Tweddle, ibid. 1979, 191.
11071 A. M. Jeffrey, D. M . Jerina, J. Am. Chem. SOC.97, 4427 (1975).
(1081 F. L. Rose, Nature 215, 1492 (1967).
Capto-dative Substituent Effects in Syntheses with Radicals and
RadicophilesI**]
methods (32)
By Heinz Gunter Viehe, Robert Merenyi, Lucien Stella, and Zdenek Janousek‘’]
Dedicated to the double anniversary: 100 years Wurster’s salts and SO years Paneth’s radical
reactions with metal mirrors
The 100 years old Wurster’s salts have long been recognized as compounds with radical cations. Their unusual stabilization derives partly from capto-dative (cd) substitution. This principle is now discussed as one factor of radical stabilization and it is applied to simple methine
derivatives. cd-Substitution has synthetically useful applications: cd-substituents on a carbon
atom allow its selective dehydrodimerization. Olefins with geminal and thus cross-conjugated
cd-substituents are “radicophilic” and permit twofold carbon radical addition. cd-Substituted
olefins are useful antioxidants, polymerization inhibitors and are promising agents in the control of biological radical reactions. Generally, many reactions of cd-substituted molecules appear to involve radicals.
1. Introduction
In 1879, Wurster’s salts (1) were discovered[’]but their radical nature was recognized only about half a century later[*I.
tramethyllead when exposed to a stream of methyl radicals
generated by thermolysis from other organometallic compounds such as trimethylbismuth (Fig. 1).
CHP
r
7PblCH,),
IS0
Pb
Bi
Fig. 1. Paneth’s methyl radicals dissolving lead mirrors: 1929.
f7J
Wurster’s salts: 1879
In 1929, the surprising stability of (1) as isolable salts with
radical cation structure was contrasted with the unstable methyl and phenyl radicals when Paneth published his famous
mirror experiment^[^]. Thus, when tetramethyllead was decomposed thermally in a glass tube it produced ethane, and
lead as a deposit. This lead mirror could be dissolved as te[‘I
Prof. H. G. Viehe, Dip[.-Ing. R. Merenyi, Dr. Z.Janousek
Universite de Louvain, Laboratoire de Chimie Organique
Place Louis Pasteur 1, 1348 Louvain-la-Neuve (Belgium)
Dr. L. Stella
Laboratoire de Chimie Organique B, Universite d’Aix-Marseille
Rue Henri Poincare, F-13 397 Marseille Cedex 4 (France)
[**I
Capto-dative Substitution Effects, Part 5.-Part
Angew. Chem. Int. Ed. Engl. 18, 917-932 (1979)
4 (671.
With these historical events of organic and particularly of
radical chemistry in mind, it now appears appropriate to report on a general principle in radical chemistry which partly
explains the stability of Wurster’s salts: the capto-dative (cd)
substituent effect[.‘I.
In the past, organic free radicals have been divided into
two classes: 1)The long-lived radicals which are stabilized by
resonance, and for which, as for Wurster’s salts (I), one can
formulate several mesomeric forms with the lone electron in
different positions. 2) The short-lived radicals like methyl or
phenyl which do not enjoy such stabilization and for which
only one mesomeric form is possible.
Later, the notion of stabilization was dissociated from that
of persistencelsl.The persistence of a radical Ro refers to its
0 Verlag Chemie. CmbH, 6940 Weinheim, 1979
OS70-0833/79/1212-0917
$ 02.50/0
917
lifetime under specified experimental conditi~ns'~J,
while the
stabilization has been definedr6]in terms of dissociation energies of the R-H bond. Thus, a persistent radical is not necessarily stabilized, e. g. the 2,4,6-tri-tert-butylphenyl
radical
(2), while a stabilized radical can often be transient, such as
the benzyl radical (3).
111
I21
131
(1): Salt with persistent stabilized radical cation
(2): Persistent destabilized radical
(3); Short-lived (transient) stabilized radical
Another definition"' of radical stabilization is based on
equilibrium constants derived from polarographic redox potentials in reversible systems. Spin density delocalization also
reflects the thermodynamic stabilization of radicals[*].
The capto-dative (cd) substituent effectc4]derives from a
logical extension of the principles governing the stabilization
of cations and anions: whereas carbocations (4) are stabilized
by electron donor-substituents, and carbanions (6) by electron acceptor-groups, electroneutral radicals (5)-formally
situated between (4) and (6/-enjoy particular stabilization
when they are substituted simultaneously by a donor and an
acceptor group.
Kinetic studies indicate that substituents such as CN
stabilize an adjacent radical to a large extent[10].Substituents
with heteroatoms of the first Period such as -OR have a
smaller stabilizing effect1'1.12,131
, those with heteroatoms of
the second Period such as - SR display an intermediate effect"'.121.
~
Although the data for stabilization energies are derived
principally from kinetic experiments, they reflect the substituent effects for the stability of the radical. Bond dissociation
energie~l'~'
reveal the same trend. The oxidation of ethers or
amines gives an example of selective radical formation in the
a-position to the heteroatom [see (7) and (8)J.
This selectivity can be explained by electronic assistance
of the donor group which stabilizes adjacent radicals by resonance, but charge separation in the resonance forms (7b)
and (Sb) leads to an increase in energy because it is opposed
to the relative electronegativies. The Linnett structures (7c)
and (8c)["] lead to the same conclusion: spin-delocalization
imparts double quartet electron configuration to all atoms,
but the polarization is unfavorable.
v,o 1/,Q
/8al
I
d
14 I
c= electron acceptor group
I51
I61
("capto'l
d = electron donor group ("dative")
The cd-substitution concept further leads to the notion of
radicophilicity as a complement to nucleophilicity and electrophilicity. Moreover, this concept represents a practical
tool for organic chemistry and biochemistry. Its application
enables, e. g., the design of new radical inhibitors, antioxidants and spin-traps. cd-Substituent effects can also be useful
in polymer chemistry and organic synthesis and appear in
many chemical processes where radical reactions are involved. In biochemistry, the cd-systems are omnipresent,
since they occur, for example, in amino-acids, sugars, and vitamins C and E. In biology and medicine cd-substituent effects are linked to photosynthesis, the radioprotection of organisms and to enzymatic dehydrogenation. They appear to
play an important role in controlling mutagens['] and in the
processes of ageing.
2. Radical Stabilization
Substitution
by
Capto-dative
1861
l8cl
If these radicals are further substituted by an electron acceptor group, and hence are cd-substituted, then the resonance becomes greatly enhanced since the negative charge is
delocalized over the electron-acceptor group. Hereby the radicals such as (9) and (10)with cd-substitution derived from
alkoxyacetic esters or from 1,2-diaminoethyIenesenjoy particular dipolar resonance stabilization and the "right" polarization.
0.
r
(cd)
17Ob1
R\@@
.i'-CH=CH-
N,
IlOdl
It is well known that free radicals are stabilized by both
electron acceptor groups (c) and by electron donor groups
(4.
c=-CN, -CO-R,
-COOR,
d=--OR, -NR2, -SR, --SeR,
918
-cR-RR~,
Oe, efe.
NO^, etc
More generally, the substitution by neutral or charged acceptor c and donor d groups in (11) leads to cd-stabilization
if n is an odd number. Conversely, the diamagnetic species
(12) and (13) obtained from (11) by one-electron release or
Angew. Chem. Ini. Ed. Engl. 18, 917-932 (1979)
uptake, respectively, are destabilized by the opposite polarization effect of the two substituents (Scheme 1).
crease in stabilization with increasing strength of the acceptor group X ( c)["].
destabilized
It should be noted that the stable diphenylpicrylhydrazyl
radical (DPPH) (1 7), R = H, X = NO2, can be considered as a
cd-substituted aminyl radical.
Walter tried to interpret the influence of different groups
R on the properties of (17) and related radicalsc'R1.-The radical nature of Wurster's salts (1) was already recognized by
Weitz in 1925 (cf. [I9]).
It appears that the first theoretical formulation of the stabilizing effect of a donor and an acceptor substituent, when
applied to conjugated alternate odd numbered hydrocarbon
radicals, was made by Dewar in 1952[201.
Linnett formulated the double quartet rule which explains
the stability of radicals and radical ions such as nitrogen
monoxide and the nitroxides, semiquinones and Wurster's
stabilized
d
C
destabilized
diamagnetic
0
neutral
neutral
O=C-C-O-R
I
positive
neutral
neutral
negative
I
;E,C<=N<0
I
1
paramagnetic
0
0-CX-0-R
I
0
I
0
;N=c<-N:
I
1
0
O=C-C=O
I
1
O=C-C-O~
I
I
diamagnetic
0
O=CX-O-R
I
I
>N-c=c-N:
l
l
@o-c=c-o~
I
1
Scheme I . Stabilization and destabilization by cd-substitution
On the other hand, the species (11) in which n is an even
number are stable diamagnetic compounds such as amides,
esters, etc. The groups c and d act in a synergetic way. Only
radicals ( l l ) , n = 1, are dealt with in this article.
Many examples of vinylogous radical ions, like Wurster's
salts (1) and their oxa-analogues, the semiquinones (14), can
be found in a recent reviewc7].
In radical ions of the type (1) and (14) the cd-effect is enhanced by delocalization in the TT system of the aromatic
ring. Such delocalization is more profound than that in benzyl (15) or phenoxyl (16) radicals where only alternate carbon atoms are involved. In (1) and (14), however, the delocalization effectively takes place over all the six carbon
atoms of the benzene ring and thus leads to much greater stabilization (Scheme 2).
-
Based on the analogy between merocyanines (19) and radicals of the type (18), Katritzky developed the principle of
merostabilizationc2'].
,CR=O
/(CR=CR'n
R2N
1191
1181
Balaban introduced the term push-pull stabilization for nitrogen-centered radicals, like (20)[*'].
(201
,N-N-CN
2
2
2
Scheme 2. Stabilization of radicals and radical ions by delocalization. The number of resonance structures for different positions of the unpaired electron is given under the formulas.
3. Historical Development
After Gomberg's discoverylf61of triphenylmethyl as the
first stabilized free radical great efforts were made to determine the factors governing the stability of radicals. For triphenylhydrazyl radicals (17) Goldschrnidt observed an inAngew. Chem. int. Ed. Engi. 18, 917-932 (1979)
Hiinig (cf. c71)studied the one-electron redox systems
which involve a semiquinone (SEM) between the reduced
(RED) and oxidized (OX) form. The semiquinones (21), (22)
and (23) correspond to radicals which are stabilized by c,dsubstitution.
{ 'Y'CCH=CH+Y?
-
?
( ;;CCH=CH+~
-
?
YCCH=CH+?
0
YCCHXH~Z
]
/Zl/
}
/23/
The thermodynamic stabilization is expressed by the
equilibrium constant K.
K = [SEMI2/[RED][OX]
De V r i e ~ [detected
~~]
the radicals (24) and (25) and A ~ r i c h l ~ ~ ]
919
/NMe2
H-C@
'CN
IZLI
Aryl
I
A r y l i C@
N/ 'CN
Aryl"
/NMe2
NC-C@
C' N
I261
1251
generated those of type (26); both authors recognized the stabilizing effects discussed by Katritzky and Balaban.
4. Radicophilicity of Olefins as a Consequence of
cd-Substitution
Since electron-rich olefins such as enamines (27) are nucleophilic and electron-poor ones like acrylonitrile (29) are
electrophilic, the a-cyano-substituted enamines (28) and all
cd-substituted olefins (30) can be considered as radicophilic
[4]. The stabilized cd-substituted radicals (31) formed in the
addition step do not undergo typical reactions such as polymerization or hydrogen abstraction but rather they trap another radical R' or dimerize.
The adducts of radicals to simple olefins such as propene
or isobutene are not sufficiently stabilized or are too polar to
be able to couple with themselves or with other radicals.
Usual reactions are polymerization (Route A), H-abstraction
as chain reaction (Route B) as well as disproportionation and
chain termination.
In contrast to simple olefins, a radicophilic olefin can undergo twofold radical addition; the usual chain reactions do
not take place.
I
I
-N
Similarly, electrophilic addition of carbenium ions (and X')
to olefins results in both C and X addition:
>=
1271
nucleophile
-NL
NeCr
1281
r a d i c o p h i le
1291
electrophile
R"
C
C
'R
1301
1311
Although this definition of radicophilicity corresponds
mainly to the thermodynamic stabilization of the radical adit is not excluded
duct (31) by capto-dative sub~titution[~',
that the kinetic aspects of addition, which depend primarily
on steric and polar factors, may also be favorably influenced
by cd-s~bstitution[~~]
(cf. Section 12).
Because of cross conjugation of the cd-substituents, the TT
orbital of the double bond in (30) must have a marked degree of dissymetry. "One-electron conjugation" in the adduct
(31) replaces the original cross conjugation in the cd-olefin
(30).
Moreover, radicophilic olefins, because of opposite substituent polarization, should trap any radicals regardless of
their polarity.
This concept of radicophilicity is in many ways useful for
syntheses. Most obvious is the possibility of twofold carbon
radical addition to cd-substituted olefins. This is practically
impossible for ionic reactions except for polymerization and
cycloadditions.
Nucleophilic addition of carbanions (and H') to electrophilic double bonds leads only to C and H addition:
Variation of the nature of both the groups c and d should
make it possible to establish a scale of radicophilicity of different cd-substituted olefins and even a scale of stabilizing
effects on radicals. The experimental approach is equally attractive for the organic chemist because of its potential in
syntheses.
5. c,d-Substituent Effects and Orbital Correlation
5.1. cd-Substituent Effects on Radicals
The effect of a-substituents on the stability of radicals has
been rationalized in terms of one-electron molecular orbital
theory''"'. Interaction of a radical with either an electronacceptor group ( c = -C=N, -CO- R, - C02R etc.) or an
electron donor group (d= -OR, -NR2, - -SR etc.) leads to
stabilization (Fig. 2).
@
C
C-CH,
la1
a
@
-CH,
-CH,
@
CHd,
d
Ibl
Fig. 2. Orbital interactions involved in the stabilization of a radical by a) an unsaturated group c, and b) by a group d with an heteroatom of the first or second
period.
920
Angew. Chem. Int. Ed. Engl. 18, 917-932 (1979)
If we consider a radical H8cdZ71whose substituents have
opposite effects and can interact with the singly occupied
atomic orbital pc we can construct the correlation diagram
0
for HCcd by the successive combination of ---CH2 with c and
d. Considerin first the union with c (see Fig. 2) and next the
8
union of H2Cc with d (Fig. 3), the interaction between the
two filled orbitals Ql and x will be antibonding while that
between the filled orbital x and the singly occupied one of
0
H2Cc (a2)
will be bonding.
$3
- .......-
5.2. cd-Substituent Effects in Olefins
..-+
4
+..-.
HZc
H:cd
will be more bonding because only the singly occupied MO
will interact effectively with the orbital of the heteroatom. In
addition, the singly occupied orbital Q2 of the cyanomethyl
radical is lower in energy than AOpc of methyl. Consequently in the construction of NC-CH-d
the net stabilizing effect of d will be higher than it would be on methyl itself. Under these conditions one substituent augments the effect of
the other.
As mentioned above, it should be emphasized that the first
theoretical hint of such an effect was already given in 1952[’01
(see Section 3).
The cd-substituent effect on frontier orbitals T and T* of
an olefin is now considered. In agreement with qualitative
notions of substituent effects on orbital energies’”], electron
donating substituents d raise both frontier orbital energies,
but the HOMO more than the LUMO, and electron accepting substituents c lower both frontier orbital energies, in this
case the LUMO more than the HOMO (Fig. 5).
.+
d
I
Fig. 3. Orbital interactions involved in the stabilization of a radical by an unsaturated group c and a group d with an heteroatom.
-..I
A
.................................
-
E
The net result will depend on the relative magnitudes of
these two apparently conflicting effects. The magnitude of
the interaction between x and the two MOs Qi and Q2 will
then be determined by the orbital coefficients of the carbon
atom adjacent to d. These in turn will depend on the extent
of the coupling between the c orbitals T and T* and the singly occupied atomic orbital pc.
Comparing for example an allyl radical with a cyanomethy1 radical (Fig. 4), it is well
that for the latter
there are two main consequences arising from the additional
electron-acceptor effect of the nitrogen atom:
1) The energy levels of all the MOs in the cyanomethyl radical are lowered and so the C=N triple bond affords a stabilization energy greater than that of a C=C double bond,
In addition, the SOMO bearing the unpaired electron is lower in energy than in the allyl radical.
2) The orbital coefficients in the bonding MO Ql increase
strongly towards the nitrogen atom, and inversely decrease in
the nonbonding MO Q2[291.
9
92
-.I
d
...............
gc
c
-.f...
-id
.....................
Fig. 5 . Frontier orbital energies and coefficients for olefins with electron
CO R, erc.) and electron donor (d= OR, NR?.
acceptor ( c = C-N,
err.) substituents.
Thus geminal cd-substitution on olefins reduces the frontier orbital separation.
In general, radicals which have a low-energy SOMO show
electrophilic properties and react more easily with nucleophilic olefins which have a high energy HOMO. On the other hand, radicals which have a high energy SOMO show nucleophilic properties and react more easily with electrophilic
olefins which have a low energy LUM0[261.
Reducing the frontier orbital separation in cd olefins
cdC1-CZH2 makes them radicophilic by drawing the SOMO
of the radical near to both the LUMO and the HOMO of the
olefin. The relative magnitudes of the coefficients can also be
deduced from qualitative consideration~[~’].
Electron donor
groups increase the remote coefficient in the HOMO and the
nearby coefficients in the LUMO. Electron acceptor groups
have exactly the opposite effect from that of donor groups if
they interact only inductively (e. g. CF3), but since most of
the substituents of this type are also conjugating, the magnitude of the remote coefficients in the LUMO is strengthened,
while the difference in the HOMO coefficient values is diminished or reversed. Consequently, the combined action of
~
4
$1
[H*C=CH -C H ~ J ~
3
2
1
[N
=C-CH,]a
3
(a I
Fig. 4. Orbital coefficients in MOs @, and
cyanomethyl radical.
2
1
(bl
m2 of a) the ally1 radical and
b) the
t
-1.......................
c
-
d
El
c
This implies that the unpaired electron will be strongly localized on carbon 1, where the orbital coefficient is
Under these conditions the net interaction resulting from the
next union with the heteroatom in the donor substituent d
Angew. Chem. Inr. Ed. En@. 18, 917-932 (1979)
.....
d
..................
Fig. 6. Frontier orbital energies and coefficients for radicophilic olefins compared with those of ethylene.
921
donor and acceptor groups on olefins must lead to an increase of the remote coefficient in both the LUMO and the
HOMO (Fig. 6).
In this way it becomes evident that radical addition to the
unsubstituted carbon of a cd olefin is thus favored by both
polar and steric factors.
On the other hand, the radicophilic olefins (30) react with
AIBN at 80 "C in benzene to form either bisadducts (37) or
adduct-dimers (38)[321,which can be isolated in moderate to
very good yields (see Table 1).
Table 1. Formation of bisadducts (37) from radicophiles (30) and IBN'
(7%
AlBN
H$=C<;
6. Syntheses by Radical Addition to Radicophilic
Olefins
:
p
NC-C-CH,-C-C-CN
I
I f
3
80'C
6.1. General Remarks
As already explained, geminal cd-substituted olefins (30)
are excellent radical traps over a wide temperature range (see
Section 4); the adducts (32) and (33) can be isolated in good
yields. The meso and DL forms of the "adduct-dimer" (32)
are obtained.
R"
C
d
1-/
(37)
Yield
c
d
(37)
Yield
CN
CN
C02Me
CN
CN
Morpholino
MezN
Et2N
Me,SiO
MeS
68
38
31
33 P O I [a1
18[bI
[%I
CN
C02Me
C02Me
C02Me
CONMe2
+
d
tBuS
tBuS
MeS
Me0
Me2N
[%I
88
16
35
49
40
d'
I I
/R
c c
I321
Additive radical dimerizations from monoolefins other
than those bearing cd-substituents are practically unknown.
1,l-Diphenylethylene behaves as a radicophile towards isobutyronitrile (IBN) radicals giving the bisadduct (39) (see
Section 6.2).
A l l e ~ ~ eand
[ ~ ~1,3-b~tadiene'~~1
'
may occasionally lead to
adduct-dimers via the corresponding resonance stabilized allyl radicals (34) and (35). Butadiene also forms oligomers.
It should be noted that the bulky IBN' adds only to cdolefins bearing a free methylene group.
1,l-Diphenyl- and 1,l-bis(p-dimethylaminopheny1)ethylenes behave also as good radicophiles giving 55% and 65%
yields, respectively, of bisadducts (39) and (40)[32,411.
R
FH3
FH3
0
CH,
FH,
I
NC-C-H,C-C-C-CN
I
CH3
@
NC-C--5-C-C-CN
I
I
CH3
'3
R
ILlI
1391. R :H j 1401, R Me2N
SH3
1341
NC-
R-CH,-CH=CH-CH,
1351
"1 -
IBN radicals conveniently generated thermally or photochemically from azodiisobutyronitrile (AIBN) are used as initiators of polymerization and as very mild hydrogen abstractors e. g. from t h i o l ~ [and
~ ~ trialkyltin
]
hydride~[~
Homolytic
~].
substitutions with IBN radicals are very uncommon[371and
so is their addition to multiple C-C bonds. Thus, 4-vinylcyclohexene reacts with IBNO to give a mixture containing addition, substitution and adduct-dimer products in low
yield[381.
According to a patentc3'l butadiene affords the bisadduct (36) in satisfactory yield.
922
QCH2
AlBN
yH3
NC-F-Hg
,CH=CH
p
- C,-
3
y
3
S - C -C N
1421
Oimer +..,
6.2. Addition of Isobutyronitrile (IBN) Radicals
CH-CH
c\"3
F - S C-,
,cH,-+-CN
CH,
Radicophiles do not have to be olefins. The radicophiles
thiobenzophenone and thioacetophenone react exclusively to
give the bisadduct (41) and the adduct-dimer (42), respecti~ely[~*'.
Nitrones (43), the well known spin traps, are necessarily
radicophilic and consequently they add to IBNa in stoichiometric amounts[431leading to the bisadduct (45) via the
nitroxide (44). CIDNP signals could be observed during this
addition["].
Galvinoxyl, which is known as a highly efficient radical
scavenger, traps IBN' in 63% yield[45].Radicophilic olefins
of type (46) and (48) afford, besides the bisadduct, the adAngew. Chem. Int. Ed. Engl. 18, 917-932 (1979)
duct-dimers (47) and (49) as a mixture of
forrn~[~~.~~'.
/SR
H&=C
80.C
\C N
mally by oxidation with di-tert-butyl peroxide (DTBP)1461.
Unlike with IBNO these additions lead in the majority of
cases to adduct-dimers (S8) which are particularly attractive
for synthetic organic chemistry as new valuable highly functionalized intermediates (see Table 2).
y
-
AlBN
and meso
DL
$Ha R ?
y 3
N C - C -H2C-C-C-CH,-C-CN
I
I I
I
CH,
NC SR
CH,
I461
Table 2. Radical addition to a-(tert-buty1thio)acrylonitrile (57) [46]
H,C=C
/0Si(CH3)3
'CN
-
HC
,
(CH,),SiP
FN
\
NC-C -CH2-C-C-CH2-
AlnN
/
80 'C
I
NC
H3C
/CH3
I
OSi(CH,),
C-CN
\
CH,
RH
'SePh
/
-
1501, R = CN
/51/,R = C02CH3
Al%N
7
HBC\
FPh
NC-C-CH2-C-C-CH2-C-CN
I
/
1
/
H3C
-
'c=c'
R'
R
Yield [%]
N,N-Dimethylaniline
Trimethylamine
Triethylamine
PhNMecH2
Me2N $H2
Et2N CHMe
,R
,CH3
\CH,-C,-CN
IBNO adds only to olefins bearing cd-substituents or aryl
substituents. Accordingly, electron-rich olefins, namely enamines, vinyl ethers, ketene acetals ( 0 , O - , N,S- and N,Oacetals) fail to react altogether under the above conditions.
Electron-poor vinyl compounds, e. g. acrylonitrile, acryl esters and methylene malonates lead only to oligo- and polyme r i ~ a t i o n [ ~The
~ ] . latter reaction, however, is prevented by
the presence of radicophilic olefins, which demonstrates their
usefulness as inhibitors of polymerization and of radical
processes in general.
IBNO does not react with the olefin (S4), and reaction with
a-tert-butylacrylonitrile (55) leads to only very low yields of
the bisadduct (S6)1321.This indicates that it is the thermodynamic stability of the adduct rather than its persistency
which is responsible for radicophilicity.
59
c:
CH,-C(CH,),C
N
CsN
1561, r3 "1.
6.3. Addition of Other Radicals to Radicophiiic Olefins
The little reactive and highly selective IBNO adds preparatively only to radicophilic olefins. These compounds could
be anticipated to smoothly add both electrophilic and nucleophilic radicals. This has been borne out in practice, although most of the work was done with a-(tert-butylthi0)acrylonitrile (57) and the radicals were generated therAngew. Chem. Inl. Ed. Engl. 18, 917-932 (1979)
41
1,CDioxane
[12]Crown-4
[lS]Crown-5
[18]Crown-6
~
~~
~
~
[a] Together with disproportionation products.
In the absence of a radicophile, radical dimers are obtained in very good
e. g.
Q-w
8 0 "1.
1551
33
30
(M~ZN)~PONM~EH
60~
Me C6% NMe CH2 46
Me 0 $H2
51
Et 0 SHMe
55
MeCHOCMe2
60
THF Tetrahydrofuran
Tetrahydropyran
t-
50
70
Hexamethylphosphoric triamide
g-Methyldimethylaniline
Dimethyl ether
Diethyl ether
Diisopropyl ether
-PhSeSePh
NC(CH,),C-?
f5WS
RO
N-Methylpymole
\
CH3
I
H3C,
NC-C-H,C,
RH
,CH3
1
PhSe
H3C
R
\
1581
Yet another feature is encountered with a-(phenylseleno)acrylonitrile (SO) and the ester (51). The adduct-dimers
spontaneously lose diphenyl diselenide to afford olefins (S2)
and (S3)[321.
/
R-CH,-C-C-CH2-
1571
lG91, 12011.
I48J
H2C=C
(R@)
oTnp
140-180 C
Q-0
0
YA
-k 0
k
A
7 3%
Pyrrolidine adducts of type (58) could not be obtained.
The behavior of the N-methylanilinomethyl radical towards a number of different radicophilic olefins has been
studied in some detail[461.The results show clearly the influence of substituents on the fate of the intermediate radical. Thus a-aminoacrylonitrile and diphenylethylene[471adducts tend to undergo exclusively disproportionation. It is
puzzling that replacement of the cyano group by an ester
group in a-(alky1thio)acrylic derivatives leads to the formation of bisadducts with only a trace of adduct-dimers (Table
3).
Electrochemically generated methyl radicals from the
Kolbe reaction could be trapped by a-(tert-buty1thio)acrylonitrile (57) to give a low yield of the adduct-dimer (60)[481
which can also be obtained in better yield from the thermal
decomposition of DTBP dissolved in (S7)'491.-The main
923
Table 3. Addigon of N-methylanilinomethyl radicals to radicophilic olefins (30).
Ro = PhNMeCH2.
RO+
H,C.C/
-
d
?
RCH,C-R
‘c
1301
?
dI d1
+
RCH~-C-C-CH*R
RCH,C-H
+
I I
c c
1321
C
I331
+
C
d
RCH=C\I
C
1591
C
d
(33)
CN
CN
C02Me
CN
CN
C02Me
Ph
fBuS
EtS
tBuS
Morpholino
Me2N
Me0
Ph
-
Yield [%]
(32)
-
30
-
Pyridinyl radicals and their importance in biology have
been extensively re~iewed’~’].
(591
50
45
traces
-
-
45
35
-
The 4-pyridine carbonitrile adducts (67) of silyl, germyl
and stannyl radicals have recently been in~estigatedl~~’.
-
12
18
-
-
-
50
7. Dehydrodimerization of compounds with
cd-Substituted Methylene or Methine Groups
Numerous examples of dehydrodimerization, also known
as “oxidative dimerization” or “oxidative coupling” reactions have been reported in the literature[581.
R
product (60%)of the electrochemical reaction is the diacetate
(61)1481.
+s
CN
35%
t611
H3C-C-O-CH2-C-O-C-CH3
I
CN
‘
1621
The terminal CH2 group in radicophilic olefins can be replaced by heteroatoms e. g. 0, S, and N(R). Thus, when 1,4oxazin-2-one (63) is irradiated in isopropanol as solvent it
undergoes reductive dimeri~ation~~”
to (65), apparently via
the cd-substituted radical (64).
2R’-R-R
As expected, the hydrogen atom is abstracted mostly, but not
necessarily, from a carbon in the a-position to a heteroatom,
a cyano or an ester group. Di-tert-butyl peroxide (DTBP) has
an advantage over other oxidizing species since it forms first
very efficient, electrophilic tert-butoxy radicals which may
further decompose to acetone and (nucleophilic) methyl radicals. The methyl radicals can abstract hydrogen atoms very
well, even in the cases where tert-butoxy radicals fail, e.g.
from malonic esters. It is possible to determine which path is
operative by measuring the acetoneltert-butyl alcohol ratio.
The phenyl radical from the thermal decomposition of dibenzoyl peroxide could also be trapped with a-(tert-butylthi0)acrylonitrile (57) to give the adduct-dimer (62)I5O1.
157)
+ ROH + R‘H + R’
C,H,O-OC,H,
-
H,C,-O@
H,C-CO-CH,
+
2
%
H,C,OH
C H F L CHL
+
R@
4P1,
Table 4. Reactions of proradical methylene derivatives (68) with di-tert-butyl
peroxide (DTBP).
-??+
d\
H-C--C-H
160°C
c
(68)
924
Re
In this review we are concerned only with substrates bearing cd-substituents on methylene or methine groups. The
available evidence clearly shows that such sites are attacked
preferentially and can therefore be considered as “proradical”.
This principle is illustrated by the examples given in Table
2 ctCK2-d
The dimer (65) exists in equilibrium with the radical (64);
the enthalpy of dissociation in ethanol (11 kcal/mol) is about
the same as in the case of the triphenylmethyl dimerI5*’.The
central C--C bond in (65) is unusually long (1.591
This lengthening and the extremely easy dissociation were
attributed to steric strain only, which does not seem to be justified in this case.
The trapping of radicals by a-diketones and 1,2 and 1,4
quinones leads also to cd-substituted radicals (66)[54s551.
+
/
/c
\
d
169)
C
d
(691, Yield (W]
COIMe
C02Me
C02Me
CN
CN
CONMe2
Me0
Me2N
MeC02
Me0
Me2N
Me2N
91
2s
83
51
52
31
Even in cases where the yields are low, owing to side reactions, only products arising from attack at the cd-substituted
site could be isolated.
Photochemically generated tert-butoxy radicals effected
the dimerization of methyl N-acetylglycinate (70) to (71) and
of methyl pyroglutamate (72) to (73), respectively[601.
Angew. Chem. I n l . Ed. Engl. 18, 917-932 (1979)
H3C02C\
to-o+
CH,
hv
-
H
F02CH,
AcHN-C-C-NHAc
H,C02C
1701
I
1
H
1711. 51"10
l82al
I8 ll
R@!
R
R
f82bt
1831
1731, 6L"I.
R-R
+
a-Aminobenzyl cyanides (74) undergo a very easy hydrogen abstraction with alkoxy and aminyl radicals in benzene;
the persistent radicals (75) are formediz41[cf. (2611.
anionic rearrangement~1~~.~~].
The conclusion that such processes proceed via radical pair pathways is based on CIDNP
results. The isolation of escape products such as (87) formed
from radical pair intermediates, strong dependence upon solvent viscosity and temperature effects support this mechanism.
1751
1741
Dimethylaminomalononitrile (76) decomposes at room
temperature to give the persistent radical (77), radical (78)
and HCN. The abstracting species here is thought to be dimethylamino(cyan~)carbene~~~~.
1841
I861
1851
COFh
PhCg
~ 2 c - d ~
2 (H,C),NCH
\
1761
-
lCN
CN
-HCN
Me,"
(H3CI,N-CdCN
'CN
1771
+
(H,CI,N-C@
/CN
RLR'
1871
'H
1781
In another study[611,
the relative rates of hydrogen abstraction from substituted phenylacetonitriles by the trichloromethy1 radical were measured. This work revealed that p-methoxyphenylacetonitrile (79), which can be regarded as cdsubstituted phenylogous methoxyacetonitrile, reacts three
times faster than phenylacetonitrile.
1791
+
"Me,
The high degree of stereo~electivity~~~~
in rearrangements
of (84) when R' is a chiral group seemed at first to be inconsistent with a radical pair process but such stereoselective recombination of radical pairs is now widely accepted. It is a
consequence of the limited translational movement required
within the radical pair before they recombine to the [1,2]
coupling product. More racemization occurs in the competitive [1,3] coupling mode.
An unusual ring-closure of radicals (88), observed recentl ~ ' " ~leads
,
to the more stable cd-substituted radicals (89).
I801
-
An ESR study disclosed an enhanced spin delocalization
in (80) owing to the presence of a p-methoxy groupi211.
8. Rearrangements Involving cd-Substituted Radicals
An increasing number of rearrangements previously
thought to be concerted or ionic are now recognized as being
of a radical or diradical nature. These rearrangements may
proceed with unexpected ease when the radicals involved
possess the stabilization imparted by cd-substitution.
Thus, the benzothiazoles (81), R = benzyl, are unstable
and undergo a [1,3] benzyl shift to give the rearranged product (83). A careful investigation[621
has revealed that the first
step involves a dissociation to (82) and R' followed by recombination to (83). The cd-substitution in (826) is obvious.
Considerable efforts have been made to establish the
mechanism of the Stevens rearrangement and related [1,2]
Angew. Chem. Inl. Ed. Engl. IS, 917-932 (1979)
C : E N , CO,CH,
Chlorine attached to a carbon bearing cd-substituents as in
(90) undergoes a peculiar [1,3] migration to the N-methyl
groupV
lCH,)fl-
CI
I
C-CO,CH,
I
-
CI
I
CI
1901
1911
1921
This reaction might also conceivably proceed through a
radical pair (91).
The intermediate (93), which resembles (90) and is itself
unstable even at low temperatures, apparently rearranges in
the same fashion to give (94), which then undergoes loss of
925
methyl chloride and finally forms the imidazolium chloride
(96) via (95)[67J.
Ct0/
-
’;1
Me,
,ct
,N-$-C+@
CI-CH,
I931
c[
CL’
NMe,
-HeCI
more likely to develop radical pairs if the compounds carried
cd-substituents.
is the spontaneous and reversiOne pertinent
ble dimerization of a-(arylthiofacrylonitriles (104) to cyclobutane derivatives (106).
SArvl
,SArvl
1961
11061
11061
11051
ci
1951
1961
The covalent amide chloride (97) can be isolated, but it
rearranges to (99) when heated above 100 0C[681.
CL
F,C-C-NMe,
-
The analogous dimerization of acrylonitrile also involves a
radical process because it leads to a head-t~-head-dimer[~*l,
but it proceeds at much higher temperatures and the yields
are low.
A further example is the dimerization of the a-cyano-substituted enamine (107)[751.
-
CL
1971
1981
1991
Even more elevated temperatures are necessary for ahaloalkyl sulfides (100) bearing various electron acceptor
groups. During the flash-pyrolysis, secondary reactions become predominant with accompanying loss of HX and sulfur
to give olefins (103)[691.
I
I
CH3
CH,
IlOBl
11071
Cyanodithioformate salts (109) readily dimerize to fumaronitriles (lll)[761.This reaction might also be envisaged as
proceeding via a 1,4-diradical to give a dithietane (110) followed by loss of sulfur.
I 1701
11091
-R2/\c=c
R’
Z,
Z = CI,Br,H
X = CI, Br
\Y
Y CN,CO$I, C O R
11031
9. Cycloadditions
An understanding of the mechanism of cycloaddition
reactions has been one of the most challenging problems in
modern organic chemistry. Of particular interest is the question whether cycloadditions, retrocycloadditions and related
rearrangements are fully concerted, involve a considerable
degree of charge separation in the transition state or involve
spin-paired diradical~[~~l.
Polar intermediates can be readily
discounted if there is little change in the rate of reaction in
different solvents or if the presence of either electron-donating or withdrawing groups leads to an increase in rate. It is
much more difficult to distinguish between a concerted process and one in which a spin-paired diradical is formed. In
many cases the solvent and substituent effects found, as well
as negative values of A S + , are consistent with either process17’1. Recent st~dies~’~1
discuss the possibility of a “concerted-diradical” mechanism for 1,3 dipolar cycloadditions
and it was suggested that a more appropriate term for “1,3dipolar” compounds would be “zwitterionic diradical hybric[721.
No matter how important diradical intermediates may be,
it is obvious that cycloadditions (or their reversal) would be
926
CN CN I
CH,
11111
Yet another interesting exarn~lel~~1
is the thermal dimerization of the aziridine ester (112) leading to a “head-tohead” adduct (115). The dipolar intermediate (114) should
lead to the other geometric isomer (116) but the observed regiospecific formation of (115) is consistent with assumption
of the existence of diradical (113).
5‘
AC02R
111ZJ
R’
11151
‘12
R’
CO,R
CO,R
(1
R’
10. Radical Formation by One Electron Transfer
Processes Involving cd-Substituted Anions and
Cations
Contrary to radicals, anions are destabilized by cd-substitution when the donor groups are amino or alkoxy groups;
Angew. Chem. Ini. Ed. Engl. 18, 917-932 (1979)
cations are destabilized by poor donors such as alkylthio
groups in the presence of electron-acceptor groups.
Consequently these very reactive ions should be prone to
one-electron transfer reactions:
I
I
-e
c
fQ\
c
I
+e
-
lo\
r:\
This scheme should enable many classical reactions and
certain mechanistic puzzles to be more readily understood.
The well known benzoin
for example, and
its recent extension to vinylogous b e n z o i n ~ are
[ ~ ~known
~
to
pass through cd-substituted anions. The high reactivity of
these carbanions might be suggestive of one-electron transfer
followed by radical coupling.
0
4
Aryl-
c,
C No
H
/OH
Aryl-co
OO\
o C - Aryl
+
‘CN
-
-
..e
0:
/”
Aryl-C-H
\
CN
-
,OH
Aryl-CQ
\CN
Q
-
-c
I
CCN
i!i
&
K
N
I CN
CH3
11171
X:C1,4DoL.,
X=Br,8O%;X=I,80%
1118~
a-Alkylthionitrile anions (119), which have already been
used in substitution reactions with alkyl h a l i d e ~ [ ’ ~ ,can
~~l,
also be alkylated in high yield with tert-butyl iodide[”’
(LDA = lithium diisopropylamide).
..Q
S, Et
:Q:
SEt
1)LDIIIHF
I
- or-+CN
H
17191
This interpretation is supported by the high nucleophilicity of a-cyano-a-alkoxy substituted anions, even towards tertiary halides[”] (Table 5).
BUX
I
CH3
1
Aryl-C-C-Aryl
-HEN
m
11 B u l i
21 t
11
Aryl-C-C-Aryl
H’
A~~I-CHO
evidence that strongly polar transition states may develop in
some casesIx31.
Anions derived from a-arninonitriledw1 or a-aminoesters[”l have also been used successfully as synthetic equivalents to nucleophilic acyl anions, even in cases where dithiane
anions[861do not
The classical SN2 mechanism does
not suffice to explain some recent results, as for example in
the reaction of (117)[ssi.
11201
Table 5. Formation of kelones via cd-substituted anions.
Ethyl 2-lithio-1,3-dithiane-2-carboxylate(121), Schlessinger’s reagentC9*],
reacts stereoselectively via 1,4-addition with
a#-unsaturated ketones, whereas 2-lithio-1,3-dithiane requires the presence of a copper saltrg31.The alkylation of
Substrate
Yield
Electrophile
Product
Ref.
1%1
FN
CH,-CH
I
0 y - m
is0 C,H7-
I
CH3-$-isoqH7
80
[811
0
CH3
aCH2CH+3r
CH3-i-CH2CH2a
84
is0 C,H,-I
95
t Bu-I
85
OSi(CH313
One-electron transfer followed by radical coupling could
explain this puzzling but highly useful ditertiary carbon-carbon bond formation.
X :Halogen
Aryl- ?-C(CH3),
I
CN
It should be kept in mind that these reactions do not always proceed through radical pairs and there is compelling
Angew. Chem. Int. Ed. Engl. 18, 917-932 (1979)
(122) has been described as being very easy and yields are
very high even with isopropyl iodide (91%)Kg4].
The dianions (123) of (pheny1thio)acetic acid and the
monoanion (124) have been reported to react very smoothly
with alkyl halides and carbonyl compounds[95].The resulting
a-(alky1thio)carboxylic acids (125) can be transformed into
ketals (126) using the procedure of T r o ~ t [ ~which
~ ] , involves
an oxidative decarboxylation. An alternative method involves electrolysis under very mild conditions; the ketones
(127) corresponding to (126) are obtained[971.
927
0-S-CHQ
-CO,
The conversion of indoxyl into indigo by the action of oxygen in basic solution proceeds via indoxyl radicals (131) followed by coupling to give leucoindigo (132)1t051.
Q
11231
R'
\
p C -
I
CO,H
*
S- R3
17261
R'R2C(OCH,),
\
11251
11311
The dianion of phenoxyacetic acid (128) also reacts with
remarkable ease with alkyl halides and
Furthermore, besides substitution reactions which proceed
via radical anion intermediate~f~~],
there are only a few wellauthenticated examples of SN2 displacements at a tertiary
carbon atom1""'].
Since the tendency towards reduction of alkyl halidesrto1]
decreases in the order C-I > C-Br> C-Cl, electron transfer reactions from cd-anions to alkyl halides must follow the
same trend.
The high probability of one-electron-transfer from cd-anions is also supported by their great ease of oxidation. Thus
a-(dimethylamino)-, a-methoxy- and w(methy1thio)benzyl
cyanides (129) mostly lead quantitatively via phase transfer
catalysis (PTC) to the amides, esters and thioesters (130), respectively, under conditions which do not affect phenylacetonitrile~'021.
RX =
11301
11291
p,
OCH,
=
SCH,
e l
R-C
+
,1
4,
d
SMe
SEt
SiPr
928
-
-+
c
Br2
hv
d- CHBr- c
C
d
Yield [%]
COzMe
CN
CN
C4Et
COMe
Me0
Me0
MeS
EtS
EtS
91
87
94
95
92
R-C-C-R
/
R
A
r
Me2N-E-i?-NMe2
I137a, b I
+
c
Yield
[%I
N
0
-,n
Ref.
- CH,- to- CH,
x=0,56%
X=S.65%
1?38a,bl
1.55%
8 . 52%
-
CN-$-!-CH,
r
3
111Ol
11391
~~
C02Et
Piperidinocarbonyl
C02Et
CONMe2
PO(0Et)z
C02Et
CN
C02Et
[R-yC]
-
Table 7. Photochemical bromination of cd-substituted methylene compounds.
X
Me2N-CH2-kNMe,
d
C
~
-
Other oxidizing agents like halogens and sulfur are also
very good reaction partners for cd-substituted rnethylene
compounds. Photochemical bromination proceeds very
smoothly and yields are very
except when d is an
amino group (see Table 7).
A number of cd-substituted methylene groups have been
sulfurated using sulfur in DMF at 150 "C (conditions A) or at
Table 6. Dimerization of carbanions with iodine
d
The dihydrothiophen-3(2H)-ones (135) can be oxidized directly to thioindigo-like compounds (136)11071.
d + CH2
The well known dimerization of carbanions by iodine proceeds either through radicals formed via one-electron-transfer or through iodides which couple with the carbanion present in an S,
The latter path is less probable in
the case of cd-substituted carbanions and one-electron-transfer is a more realistic alternative (see Table 6).
d
The oxidation of the piperazinedione (133) to (134) takes
place with exceptional ease at the cd-substituted methine position[t061.
N
'CH,
=
11321
Piperidino
Piperidino
EtS
Me2N
Me2N
Me2N
EtS
Morpbolino
MeS
EtS
iPrS
H
H
H
H
H
H
Me
C02Et
SMe
SEt
smr
71
80
55
60
65
80
20
40
41
86
50
F)
EtS-CH,-C-CH,
17431
*
0
OnN-C-?-CH,
-I74L1
L / g
Scheme 3. Reaction of cd-substituted methylene compounds with sulfur. A, B see
text.
Angew. Chem. Int. Ed. Engl. 18, 91 7-932 (1979)
room temperature with sulfur, DMF and morpholine (Route
B). The results are summarized in Scheme 3['OSl.
11. cd-Substituted Radicals in ESR Spectroscopy
Table 9. ESR data of radicals with a-cyano-, a-amino and a-alkylthio substituents.
(1456)
RO
a:'
,n
.
N
/. uQ
C-CH -C
H,C/LN
\CN
2.94
H3C\
Three routes have been used for the generation of cd-substituted radicals in an ESR cavity:
A
t
Abstraction
R-C-H
+
c
RO
+
d
RH
-
5.2
1.99
10.25
-
19.28
d
/'
+
Addition
RO
t
f
R-CH2-C
@
t
'd
d
c
c
+
I
C R-C-C-R
Dissociation
+ I
d
7.9
3.41
t
t
8 =
F
R-CO
Ref.
aEcCH2
O
CH3-CHCN
(146)
C
a:"'
-
C
1
2 R-CO
f
(9121
d
d
Thus formed, many cd-substituted radicals can be detected
by ESR at unusually high temperatures. If d = N R 2 or SR,
the signal disappears on cooling and reappears reversibly
upon heating. ESR data of radicals generated by method B
are presented in Table 8.
Table 8. ESR data of cd-substituted radicals (145) in chlorobenzene at 130 "C [4,
1091.
CJ
(150)
HC
,
- CH- SEt
2.6
1.6
[113]
2.0
[114]
The double-quartet of electrons is realized for each atom
in (145b), and the molecule is polarized in the favorable direction. This occurs even more so in radical (148).
11,"
:1,
'w. CH-R
/
(1450)
(145b)
(145c)
(145d)
(145ej
C02CH3
CN
CN
CN
C02CH3
OCHi
Morpholino
N(CH3)2
SCHi
SCH3
-
-
2.94
3.0
2.75
7.9
8.0
-
-
9.82
10.12
7.4
9.14
7.9
2.65
7.12
6.2
3.68
4.1
1.19
-
0.9
If we compare the hyperfine coupling constants on nitrogen atoms of the amino group and of the cyano group in radicals (14.5) with those observed for a-cyano or a-amino radicals (Table 9), it is clear that:
a) Introduction of a donor (morpholino) group on the radical already substituted by a cyano group [(146)+(145b)],
decreases the spin density on the cyano nitrogen atom.
b) Introduction of an acceptor (cyano) group on the radical already substituted by an amino group [(147)-,(145b)]
increases the spin density on the amino nitrogen.
c) Introduction of a second cyano group [(145b)+(148)]
on the cd-radical again increases the spin density on the amino group nitrogen atom.
The same trend is observed for cd-systems with an alkylthio substituent as donor group (Table 9).
Linnett structures are in agreement with these facts: the
stabilization by electron sharing gives an unfavorable polarization in the radical (147) and a favorable one in (146). Thus,
considering the cd-substituted radical (145b), the gain in spin
delocalization is more important relative to (147) than to
(146).
Angew. Chem. Int. Ed. Engl. 18, 917-932 (1979)
t
-
Sz"
R -CH- C+ N
.V2Q
I1461
According to their radicophilic nature, cd-substituted olefins can trap radicals more or less independent of their polarization. Thus, for all of the various types of radicals listed in
Table 10, a-(alky1thio)acrylonitriles act as very powerful
scavengers['141.
Table 10. ESR data of radical-adducts in chlorobenzene at 130°C [I 14).
Ro
+
=(StBu --+
@,StBU
R-CH2-C,
CN
CN
I53)
(152)
0
(1530)
(153b)
(153c)
(1534
(1534
(nBu)&$
(CHi)2C OH
CH3Soo
(CH3hC CN
ClPCO
8.5
8.5
8.3
8.3
7.5
2.5
2.6
2.5
2.5
2.5
929
The use of a-(tert-buty1thio)acrylonitrile (152) in spin
trapping studies of transient radicals, where the unpaired
electron is located on a non-zero spin nucleus such as phosp h o r ~ ~ [ "is
~ ]complementary
,
to the trapping with nitroso
compounds and nitrones in that 31P-couplingscan be studied
up to 170°C (Table 11).
substituents. The a-CH3 coupling constants of the radical
CH3-CH-X
are proportional to the spin density on the
central carbon atom (Fischer's approach['l*I). However, to
compare spin densities in a quantitative way, planar configurations of the radical centers are required. This is certainly
the case for cd-substituted radicals; thus, the decrease in spin
density on the radical center, caused by the combined action
of an acceptor and a donor substituent, can be deduced from
the ESR parameters (Table 12).
The negative difference between the observed and calculated p values, for the planar radical (151) seems to reflect a
certain trend in the mutual interaction of the acceptor and
donor groups. This qualitative approach is in good agreement with an enhanced radical stabilization by the cd-effect.
In contrast, (pobs.- pcalc.)is positive for the bis(thioethy1)substituted radical (163). As far as the known cd-substituted
ethyl radicals (159) to (162) are concerned, this difference is
negative. Nevertheless, the latter values should be regarded
with caution since a planar configuration of these radicals
has not been proven.
Table 1I . ESR data of adducts (154) from substituted phosphorus radicals and a(terr-butylthio)acrylonitrile (152) [I 141.
L,P+ ='
-
s tsu
7'
,StBu
z,!,
'CN
t"P-c-c@
'CN
/I521
11541
aN
(154a)
(1546)
(154c)
(f54d)
(154e)
(154g)
EtZ[O
PhlPO
EtO(P$O
(Et0)zPO
(MelSiO)2P0
a>f<D
39.0
41 .o
46.8
51.5
57.2
75.0
9.2
2.6
2.6
2.6
2.6
2.6
9.5
2.6
8.7
2.6
10.0
10.0
10.0
9.7
10.0
9.2
9.2
9.5
10.0
8.7
12. Rates of Addition of Radicals to ed-Substituted
Alkenes
Another aspect of ESR studies of cd-substituted radicals
concerns the effect of substituents upon the structure["'].
Both the cyano and the alkylthio groups have been shown
to induce a planar configuration at a radical center[116,'171.
Accordingly, a radical substituted by both these groups
should be planar, since electron delocalization gives the
C-CN and C-SR bonds some double bond character. This
conclusion is supported by the experimental value of ailc for
radical (153d) and its temperature dependence:
Alkyl radicals behave like nucleophiles in addition reactions with alkenes. This polar effect has been confirmed by
positive p -values in reactions with styrene derivatives['231.
On insertion of electron-donor groups d into electron-deficient alkenes with acceptor groups c the rate of reaction depends on the opposing influences of the d-substituents on the
radical stability and the polar effect. In fact, Giese et aZ.[25.1241
found that the strong electron-donor d = morpholino hardly
changes the reaction rate in additions of cyclohexyl radicals
(164) to acrylonitriles (165), although unsubstituted enam+
anc= [(25.76k0.02)+(8.0&0.8)x 1 0 - 3 r ] Gauss (t=°C)[I'41,
The decrease in the spin density at the radical center is a
qualitative indication of the radical stabilizing effect of the
'd
ines react very slowly with alkyl radicals. Thio and seleno
groups increase the rate of addition (cf. Table 13).
Table 12. p-Orbital spin density at the center of the radical R".
a:"'
[Gauss]
R'
H,C
H,C
HIC
H3C
H,C
HIC
H3C
H3C
H,C
&C
HIC
H,C
[a]
=acH,/29.3.
[b] Calculated
the monosubstituted ethyl radicals.
930
22.61
20.2
19.8
23.05
24.98
22.5
17.88
17.1
13.92
13.33
15.0
17.6
{H OH
S H NHz
CH SEt
4 k H CN
S H COOH
S H COCH,
S(OH) CN
C(0H) COOH
&NH,) coo
{(OH) COCH
C(SE1) CN
CISEt),
according
to
Fischers
0.772
0.689
0.675
0.187
0.853
0.768
0.610
0.584
0.475
0.455
0.512
0.601
equation pCA,<
= A K H , x Ap<x Apd. ApcH,=O.919: Ap, and A p d were derived from pnh. of
Angew. Chem. Int. Ed. Engl. 18,917-932 (1979)
Table 13. Relative reaction rates of the addition of cyclohexyl radicals (164) to dsubstituted acrylonitriles (165) in CH2C12at 293 K.
CHI
H
CI
COICHl
Morpholino
SC(CH,)?
SeC6H5
CnHs
0.56
=1.00
8.5
86
0.83
5.0
9.5
18
~
[a] Mean error * 5 % ; for determination cf. 11231.
13. Outlook
The cd-substituent effect represents a challenge for theoretical chemistry, in particular for quantitative molecular orbital considerations and for ab-initio calculations. Spectroscopic studies are necessary to determine the structures and configurations of cd-substituted radicals and to measure their
lifetimes and monomer-dimer equilibrium constants.
The concept of cd-substitution sets new goals and reveals
new possibilities for organic synthesis especially in the fields
of cycloadditions, nucleophilic and electrophilic substitutions, and selective reductive or oxidative transformations via
radicals.
These applications reach far beyond the field of chemistry
into everyday life, for example in the design of new inhibitors of polymerization and oxidation. In medicine and generally in biology, there appears a possibility of controlling the
ageing of cells. The anticipated control of mutagenicity
based upon the concept of radicophilicity has been proven in
the Ames Test.
Radicals, afterall, pervade the whole of life: in photosynthesis, growth and ageing. Hence, the synthesis of radicals
and control of radical processes represents an exciting research problem both for the present and for the future.
For helpful discussions we thank our colleagues: A. T. Balaban, Sir D. H. R. Barton, J. I. G. Cadogan, R. A. Firestone, B.
Giese, R. Huisgen, S.Hiinig, K. U.Ingold, A. R. Katritzky, G.
Leroy, H. Naarmann, Nguyen-Trong-Anh, Ch. Riichardt, G.
Smets, J. M. Surzur, Lord J. M. Tedder, P. Tordo and J. C.
Walton. For their particular assistance we thank our coworkers: T. G. C. Bird, F. Hervens-Gorissen, B. Le Clex M. Demolder-Marin and L. Vertommen. We gratefully acknowledge
generous supportfrom the Institut pour I’Encouragement de la
Recherche Scientifique dans I’lndustrie et I’Agriculture (IRSIA), BASF A.G. Ludwigshafen, and the Fonds de la Recherche Fondamentale et Collective.
Received: October 17, 1979 [A 298 IE]
German version: Angew. Chem. 91, 982 (1979)
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