Distinguishing between abstraction and addition as the first step in the reaction of a nitroxyl radical with cyclohexene

Article abstract of DOI:10.1021/ol049527x

An unambiguous method for distinguishing between abstraction-addition and addition-abstraction mechanisms (and mixtures thereof) in the reaction of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl with a specifically deuterated cyclohexene, 1,2-dideuteriocyclohexene, is demonstrated.

Full text of DOI:10.1021/ol049527x

ORGANIC
LETTERS
2004
Vol. 6, No. 10
1641-1643
Distinguishing between Abstraction and
Addition as the First Step in the
Reaction of a Nitroxyl Radical with
Cyclohexene
,†
Sergiu Coseri* and Keith U. Ingold
Steacie Institute for Molecular Sciences, National Research Council,
Ottawa, Ontario, K1A 0R6 Canada
sergiu.coseri@nrc.ca
Received March 12, 2004
ABSTRACT
An unambiguous method for distinguishing between abstraction−addition and addition−abstraction mechanisms (and mixtures thereof) in the
reaction of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl with a specifically deuterated cyclohexene, 1,2-dideuteriocyclohexene, is demonstrated.
It is commonly assumed that reactions between free radicals,
X•, and cycloalkenes that yield 3-X-substituted cycloalkenes
occur by an initial H-atom abstraction to give an allylic
radical to which a second X• adds, e.g., Scheme 1. For
droxy-2,2,6,6-tetramethylpiperidine-N-oxyl, R2NO•) reacted
with cyclohexene at temperatures ranging from room tem-
perature to 70 °C to give the analogous 3-substituted
cyclohexene, 1. These workers2 concluded that this reac-
tion involved “addition of the nitroxyl radical to the double
bond followed by H-atom abstraction from the intermediate
by another equivalent of nitroxyl radical”, Scheme 2.
Scheme 1
Scheme 2
example, in 1992, Jenkins and co-workers1 reported that in
the reaction of the stable nitroxyl radical, 1,1,3,3-tetramethyl-
2,3-dihydro-1H-isoindol-2-oxyl, with cyclohexene at 25 °C,
“the hydrogen-abstraction product (3-(1,1,3,3-tetramethyl-
2,3-dihydro-1H-isoindol-2-oxyl)cyclohexene) was cleanly
produced.” Ten years later, Barbiarz et al.2 reported that
another stable nitroxyl radical, 4-hydroxy-TEMPO (4-hy-
This mechanism was based on the fact that ethylbenzene
reacted with R2NO• only at temperatures above 100 °C to
† Permanent address: “P. Poni” Institute of Macromolecular Chemistry,
Gr. Ghica Voda Alley, 41 A, 6600, Iasi, Romania.
(1) Bottle, S. E.; Busfield, W. K.; Jenkins, I. D. J. Chem. Soc., Perkin
Trans. 2 1992, 2145.
(2) Babiarz, J. E.; Cunkle, G. T.; DeBellis, A. D.; Eveland, D.; Pastor,
S. D.; Shum, S. P. J. Org. Chem. 2002, 67, 6831.
10.1021/ol049527x CCC: $27.50 Published 2004 by the American Chemical Society
Published on Web 04/16/2004

give PhCH(ONR2)CH3. This adduct could only be formed
by abstraction-addition. The addition-abstraction mecha-
nism for cyclohexene (Scheme 2) was proposed “because
the bond dissociation energy (enthalpies) for allylic and
benzylic C-H bonds is expected to be nearly the same.”
This mechanism was also claimed to be supported by
semiempirical UHF/AM1 calculations.2 Unfortunately, even
if the enthalpic (thermochemical) arguments were correct,3
entropic effects favoring H-abstraction from cyclohexene4
had been ignored. Nevertheless, both mechanisms are
certainly possible for this “simple” radical reaction and an
unequivocal discrimination between them would require an
isotopically labeled cyclohexene. 1,2-Dideuteriocyclohexene,
2, was chosen because only minimal (i.e., secondary)
deuterium kinetic isotope effects would be involved in either
mechanism, see Scheme 3.
[(1,2-dideuteriocyclohex-2-en-1-yl)oxyl]-4-hydroxy-2,2,6,6-
tetramethylpiperidine (3) and 1-N-[(2,3-dideuteriocylohex-
2-en-1-yl)oxyl]-4-hydroxy-2,2,6,6-tetramethylpiperidine (4),
whereas initial addition will give only 3. However, because
the coupling of nitroxyl radicals with carbon-centered radicals
occurs at close to the diffusion-controlled limit,8 there is a
potential mechanistic ambiguity. That is, in earlier nitroxyl/
cyclohexene reactions,1,2 the concentration of the nitroxyl
was relatively high (e.g.,2 0.85 M). The hydroxylamine
molecule formed in the initial H-abstraction could potentially
shield that end of the allylic radical system for a time
comparable to that required for the addition of an R2NO•
radical, which would, perforce, add to the other end of the
allylic system. This would produce an excess of 3 over 4 so
that even a “clean” abstraction mechanism could appear to
2
contain a contribution from an addition pathway. The H
NMR spectral parameters for the products, 3 and 4, are given
in Table 1. The signal due to the deuteron labeled Db is
Scheme 3
2
Table 1. Assignments of H NMR Signalsa,b
Compound 2 was prepared by a lead tetraacetate oxidative
decarboxylation of 1,2-dideuteriocyclohexane-1,2-dicarboxy-
lic acid,6 which was itself synthesized by an R-proton-
deuterium exchange of cis-cyclohexane-1,2-dicarboxylic
anhydride with deuteriosulfuric acid,7 Scheme 4, (see Sup-
porting Information for synthetic details).
a Based on ACD Labs NMR Prediction Software. b 1H NMR parameters
for 3 and 4 are given in Supporting Information of ref 2. c Note that Da (3)
and Dc (4) are not resolved.
unique to 3, and that labeled Dd is unique to 4. The 3/4
product ratio is therefore given simply by the integrated peak
intensity ratio, Db/Dd. In the event, reaction of 0.83 M
R2NO• in neat 29 gave Db/Dd ) 1.22 (see Figure 1B and
Table 2, column Db).
Scheme 4
Since this result might have been due to the high con-
centration of R2NO• (vide supra), the experiment was re-
peated using 0.0096 M R2NO• and 0.099 M 2 in benzene,
and the Db/Dd ratio was found to be essentially unchanged,
Ignoring secondary isotope effects, Scheme 3 implies
that initial H-abstraction should give equal yields of 1-N-
(5) Howard, J. A.; Ingold, K. U. Can. J. Chem. 1967, 45, 793.
(6) Bodot, H.; Lauricella, R.; Pizzala, L. Bull. Soc. Chim. France 1968,
3, 984.
(3) Allylic C-H bonds may actually by slightly weaker than comparable
benzylic bonds; e.g., for primary C-H, the bond dissociation enthalpies
(kcal/mol) are 88.8 ( 0.4 for propylene and 89.7 ( 0.6 for toluene. See
Table 2 in: Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255.
(4) H-abstraction from ethylbenzene requires the free rotation about the
Ph-C bond to be “frozen out” in the transition state for PhC•HCH3 radical
formation. There are no such restrictions on cyclohexene. Moreover, two
of the allylic C-H bonds in cyclohexene are perpendicular to the CCHd
CHC plane and are therefore well positioned for C-H bond rupture with
full allylic stabilization. In contrast, the two benzylic C-H bonds in
ethylbenzene lie at an angle of 30° to the aromatic plane and are not well
positioned for C-H rupture. These factors are manifest in the rate constants
for H-abstraction by the corresponding peroxyl radicals at 30 °C, viz.,5
cyclohexene 6.0 M-1 s-1, ethylbenzene 1.3 M-1 s-1, and 1,2,3,4-
tetrahydronaphthalene (where addition-abstraction is not possible) 6.4 M-1
(7) (a) Ingold, C. K.; Raisin, C. G.; Wilson, C. L. J. Chem. Soc. 1936,
1637. (b) Otvos, J. W.; Stevenson, D. P.; Wagner, C. D.; Beek, O. J. Am.
Chem. Soc. 1951, 73, 5741
(8) Chateauneuf, J.; Lusztyk, J.; Ingold, K. U. J. Org. Chem. 1988, 53,
1629.
(9) A sample containing 2 (0.4 g, 4.76 mmol) and R2NO• (0.082 g, 0.476
mmol) under nitrogen was heated at 70 °C for 72 h, cooled to room
temperature, and filtered to remove solid 1,4-dihydroxy-2,2,6,6-tetrameth-
ylpiperidine, R2NOH. The rest of this product was removed by extracting
the filtrate with 5 w/v % ascorbic acid (2 × 0.5 mL) and distilled water (2
× 0.5 mL). The organic phase was dried (Na2SO4), and volatiles (mainly
2) were removed under vacuum. The residue was purified by chromatog-
raphy (silica gel, eluent ) ethyl acetate/hexane, 1:1 v/v) to give 0.0187 g
(30.76% yield based on R2NO•) of a mixture of 3 and 4. The same procedure
was followed for the experiment with the much lower concentration of 2
and R2NO• in benzene.
s-1
.
1642
Org. Lett., Vol. 6, No. 10, 2004

2
Table 2. Reaction Conditions,9 Relative Integrated H NMR
Signals, and Percentage Abstraction in the Reaction of
1,2-Dideuteriocyclohexene, 2, with 4-Hydroxy-2,2,6,6-
tetramethylpiperidine-N-oxyl, R2NO•, at 70 °C
conditions9
relative integrated
areas
% abstractiona
[2]
[R2NO•] time
(M) (h)
(M)
Dd
Db
Da + Dc
100/Db
8.26b
0.83
72 (1) 1.22
360 (1) 1.26
2.25
2.37
82
79
0.099c 0.0096c
a This can be calculated in various ways, but the simplest is 100 × Dd/
(Db - Dd) + Dd ) 100/Db/Dd. b Neat. c In benzene.
for Db + Dd, which, in both experiments, is essentially equal
to the integrated area for the common peak due to Da + Dc
(see Table 2).
In conclusion, the reaction of R2NO• (and presumably
many other nitroxyls) with cyclohexene has been unambigu-
ously demonstrated to occur mainly (∼80%) by an initial
hydrogen abstraction and to a lesser extent (∼20%) by an
initial addition to the double bond. This duality of mechanism
has been previously reported only, so far as we are aware,
for the reactions of peroxyl radicals with certain alkenes (not
including cyclohexene).10 It will be further explored using
other deuterated alkenes and other radicals.
Acknowledgment. We thank Don Leek for valuable
NMR advice. S.C. thanks the Natural Sciences and Engi-
neering Research Council (NSERC) of Canada for receipt
of a Visiting Fellowship.
Figure 1. 2H NMR spectra in CHCl3. The signal at 7.3 ppm is
due to the natural abundance of CDCl3. A: 1,2-Dideuteriocyclo-
hexene (2). B: Neat 2 + 0.83 M R2NO• at 70 °C for 72 h. C:
0.099 M 2 + 0.0096 M R2NO• in benzene at 70 °C for 360 h.
Supporting Information Available: Experimental pro-
cedures for the synthesis of 1. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL049527X
viz., 1.26 (see Figure 1C and Table 2). An internal check
for consistency is provided by the sum of the integrated areas
(10) Mayo, F. R. Acc. Chem. Res. 1968, 1, 193.
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