Remarkable aromatic substitution by a 1,5-diradical

Article abstract of DOI:10.1016/S0040-4039(02)00158-2

Generation of 2,6-dioxa-3-phenylcyclohexylidene in benzene leads to 2,4-diphenyl-1,3-dioxane, the product of apparent insertion into a CH bond of benzene. However, that product arises from attack of a diradical intermediate on benzene.

Full text of DOI:10.1016/S0040-4039(02)00158-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1927–1929
Remarkable aromatic substitution by a 1,5-diradical
Nadine Merkley,a Darren L. Reidb and John Warkentina,*
aDepartment of Chemistry, McMaster University, Hamilton, Ont., Canada, L8S 4M1
bDepartment of Chemistry, University of Calgary, Calgary, AB, Canada, T2N 1N4
Received 15 October 2001; accepted 6 December 2001
Abstract—Generation of 2,6-dioxa-3-phenylcyclohexylidene in benzene leads to 2,4-diphenyl-1,3-dioxane, the product of apparent
insertion into a CH bond of benzene. However, that product arises from attack of a diradical intermediate on benzene. © 2002
Elsevier Science Ltd. All rights reserved.
Thermolysis of oxadiazoline 11 in benzene at 110°C
afforded 2,4-diphenyl-1,3-dioxane (11), the product of
apparent insertion of carbene 2 into a CH bond of
benzene, in about 12% yield.2 The sequence of Scheme
1 was indicated by the fact that carbene 2 could be
trapped in high yield with tert-butyl alcohol present in
the solvent.3 Compound 11 was not detectable when
tert-butyl alcohol was present but it was obtained,
together with phenylcyclopropane (5, ca. 20%) and
a-phenyl-g-butyrolactone (7, ca. 20%), in the absence of
tert-butyl alcohol. Compound 5 is derived from the
diradical intermediates 3 and 6, through a decarboxyla-
tion/coupling sequence, while 7 is a product of
intramolecular coupling of 6, Scheme 1. A control
experiment with a similar carbene (13) that cannot
fragment readily was used to distinguish between a
carbenic and a radical reaction with benzene. 4,4-
Dimethyl-2,6-dioxacyclohexylidene (13), generated at
110°C in benzene by thermolysis of oxadiazoline 12,1 did
not lead to 14 but formed dimer 15,4 Scheme 2. Analysis
by GC, with authentic 145 for comparison, revealed not
a trace of 14. That result appears to rule out insertion
of carbene 2 into a CH bond of benzene as the source
of 11, because 13 should mimic the insertion tendencies
of 2. Insertion of a dialkoxycarbene into a CH bond of
benzene is unprecedented, in any case.6
Scheme 1.
* Corresponding author. E-mail: warkent@mcmaster.ca
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00158-2

1928
N. Merkley et al. / Tetrahedron Letters 43 (2002) 1927–1929
of the CO group. When that group eventually does
rotate, those same single bonds must rotate in order to
return to a sickle-shaped 6 that, if in the singlet state,32
can cyclize to lactone 7. The net effect of those entropic
features is that cyclization to 7 can be expected to be
slower than coupling of the 1,5-diyl would be, if it were
born in the conformation 6.33 Thus, the diradical is
probably long-lived enough to attack benzene in com-
petition with decarboxylation to 4 and cyclization to 7.
Scheme 2.
We were unable to find a rate constant for addition of
an alkoxycarbonyl radical to benzene, but our product
distribution enabled us to estimate that value as fol-
lows. From that distribution, one can conclude that
decarboxylation and coupling are about twice as fast as
attack on benzene. The rate constant for H-abstraction
(kH) from HSnBu3 by alkoxycarbonyl radicals at 110°C
was estimated to be 1.8×106 M−1 s−1 from the Arrhenius
equation of Newcomb et al.34 That number, together
with the product ratio (RH:ROCHO=38:25) from
reaction of ROCO with HSnBu3,35 was then used to
estimate the rate constant for decarboxylation of pri-
mary alkoxycarbonyls at 110°C, k(CO2)=6.8×104 s−1.
Decarboxylation (of 3 and 6) and coupling of 6 are
about twice as fast as attack on benzene, permitting the
conclusion that the calculated k(CO2) ꢀ2 kbenzene [ben-
zene]. The concentration of benzene is about 10 M, and
thus the rate constant for attack of 3 on benzene should
have a value of roughly 3.4×103 or <104 M−1 s−1 at
110°C.
Homolytic fragmentation of cyclic oxycarbenes to
diradicals7 and of acyclic oxycarbenes8–19 to an alkoxy-
carbonyl radical and another radical, both in the gas
phase and in solution, is known experimentally and it
has been studied by computation for model systems.20–
25 Aromatic substitution by alkoxycarbonyl radicals is
also known.26 Thus, methoxycarbonyl radicals, gener-
ated in benzene by thermolysis of methyl azodicarboxy-
late at 130°C, gave methyl benzoate in 13% yield.27
That reaction might be considered to be a poor model
for the reaction of 3 with benzene, because diradicals 3
and 6 have not only the additional option of decar-
boxylation but also that of cyclization to lactone 7.
Could attack on benzene be fast enough to compete?
The mechanism postulated in Scheme 1 was supported
by means of computation. Conformer 3 cannot cyclize
to the lactone 7 except by converting first to conformer
6. That process is known to have a significant barrier,
as shown by previous workers who modeled a similar
isomerization of the hydroxycarbonyl radical.28 With a
combination of SCF results for the rotational barrier
and CI calculations for the stable conformations and
the in-plane inversions, the authors28 estimated that the
transition state for rotation lay ꢀ6.7 kcal mol−1 above
the cis-HOCO radical and ꢀ23.9 kcal mol−1 below the
energy of the most facile in-plane inversion pathway. In
order to obtain a better estimate for the OꢀCꢁO rota-
tional barrier in 3, the methoxycarbonyl radical was
used to model the rotational TS with the Gaussian 98,
Revision A.7, system of programs.29 Electron correla-
tion was included with the B3LYP density functional
hybrid method and the Møller–Plesset method with
correlation energy truncated at the second order (MP2).
Zero point energies were corrected using a scaling
factor of 0.98 and 0.97 for the B3LYP and MP2 results
respectively.30 Rotation is predicted to involve a barrier
of 8.0 and 8.9 kcal mol−1 from the cis-MeOCO radical,
at the B3LYP/6-31+G* and MP2(FC)/6-31+G* levels,
respectively, while the trans-MeOCO radical lies 0.5
and 0.1 kcal mol−1 higher in energy than the cis con-
former. Thus, isomerization of conformer 3 to con-
former 6, a necessary first step for cyclization, must be
relatively slow.
The literature is sparse with respect to substitution on
benzene26 by alkoxycarbonyl radicals, implying that the
substitution is too slow to be generally useful. Possibly
the reaction is slow overall because addition is
reversible36 and reversal competes effectively with the
bimolecular H-transfer step leading to substitution
product. In the case of 3 and benzene, the initial adduct
(9) has an intramolecular follow-up step to compete
with intramolecular reversal of addition and that fea-
ture could make the difference that effectively enhances
the rate of aromatic substitution by 3. We suggest that
non-sickle conformations of diradicals 3 and 6 are
largely responsible for 11 and for some of the 5,
because cyclization of the singlet via conformation 6 is
expected to occur with only a small barrier.33
The final steps of Scheme 1, from 9 to 11, are reason-
able. 6-Endo cyclization to oxygen of a carbonyl group
is known37 as are other 6-endo cyclizations of radicals.38
Neither the 6-endo nor the corresponding 5-exo cycliza-
tions require rotation about the OꢀCO bond. More-
over, 5-exo cyclization of 9, even if it were faster, is
expected to be reversible.
6-Endo cyclization of 9 would generate diyl 10, ana-
logues of which were shown by Baldwin and Shukla to
undergo the type of H-transfer that would convert 10
to 11.39 Thus, we conclude that the reaction that gener-
ates 11 from thermolysis of 1 in benzene is a diradical
process rather than insertion of a carbene.
Rotations about the other single bonds31 of 3 have
barriers smaller than 4 kcal mol−1 and therefore 3
cannot retain its sickle shape long enough for rotation

N. Merkley et al. / Tetrahedron Letters 43 (2002) 1927–1929
1929
References
24. Reid, D. L.; Hernandez-Trujillo, J.; Warkentin, J. J.
Phys. Chem. A 2000, 104, 3398.
1. 2,2-Dialkoxyoxadiazolines are now well established as
thermal sources of dialkoxycarbenes. Warkentin, J. J.
Chem. Soc., Perkin Trans. 1 2000, 2161 and references
cited therein.
25. Reid, D. L.; Warkentin, J. J. Chem. Soc., Perkin Trans. 2
2000, 1980.
26. Fiorentino, M.; Testafarri, L.; Tiecco, M.; Troisi, L. J.
Org. Chem. 1976, 41, 173.
2. As a mixture of diastereomers (3:1) that were not sepa-
rated. Synthesis of 11 by acid catalyzed reaction of
1-phenyl-1,3-propanediol with benzaldehyde gave the
major diastereomer only.
3. For trapping of carbenes with alcohols see, for example:
(a) Ho¨mberger, G.; Kirmse, W.; Lelgemann, R. Chem.
Ber. 1991, 124, 1867; (b) Belt, S. T.; Bohne, C.; Charette,
G.; Sugamori, S. E.; Scaiano, J. C. J. Am. Chem. Soc.
1993, 115, 2200; (c) Dix, E. J.; Goodman, J. L. J. Phys.
Chem. 1994, 98, 12609; (d) Kirmse, W. In Advances In
Carbene Chemistry; Brinker, U. H., Ed.; JAI Press:
Greenwich, 1994.
27. Corrected for the fact that methyl azodicarboxylate yields
two methoxycarbonyl radicals per mole.
28. McLean, A. D.; Ellinger, Y. Chem. Phys. 1985, 94, 25.
29. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria,
G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V.
G.; Montgomery, J. A., Jr.; Stratmann, R. E.; Burant, J.
C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.;
Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.;
Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.;
Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov,
B.B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gon-
zalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B.;
Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.;
Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian
98, Revision A.7, Gaussian, Inc., Pittsburgh PA, 1998.
30. (a) Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100,
16502; (b) Wong, M. W. Chem. Phys. Lett. 1996, 256,
391.
4. Identified by means of 1H and 13C NMR spectroscopy, as
well as mass spectrometry.
5. Prepared by the acid catalyzed reaction of 2,2-dimethyl-
1,3-propanediol with benzaldehyde.
6. Dialkoxycarbenes are nucleophiles that might be
expected to attack 2,4-dinitrofluorobenzene (Sanger’s
reagent), for example. Dimethoxycarbene does that, but
the substitution is inefficient. Ross, J. P.; Couture, P.;
Warkentin, J. Can. J. Chem. 1997, 75, 1331.
7. Borden, W. T.; Hoo, L. H. J. Am. Chem. Soc. 1978, 100,
6274.
8. McDonald, R. M.; Krueger, R. A. J. Org. Chem. 1966,
31, 488.
9. Crawford, R. J.; Raap, R. Proc. Chem. Soc. 1963, 370.
10. Lemal, D. M.; Lovald, R. A.; Harrington, R. W. Tetra-
hedron Lett. 1965, 2779.
31. Lowe, J. P. In Progress in Physical Organic Chemistry;
Streitwieser, A., Jr.; Taft, R. W., Eds.; Interscience Pub-
lishers: New York, 1968; Vol. 6.
32. There is approximately a 1-in-4 chance that radicals
which have become separated before encountering one
another again will be in the singlet state. Gibian, M. J.;
Corley, R. C. Chem. Rev. 1973, 73, 441.
11. Lemal, D. M.; Gosselink, E. P.; McGregor, S. D. J. Am.
Chem. Soc. 1966, 88, 582.
12. Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1971, 10,
529.
33. Radical–radical coupling of singlet 6, which should have
a small barrier at most, is expected to occur with a rate
13. Hoffmann, R. W.; Hirsch, R.; Fleming, R.; Reetz, M. T.
constant in excess of 1010 s−1
.
Chem. Ber. 1972, 105, 3532.
14. Wong, T.; Warkentin, J.; Terlouw, J. K. Int. J. Mass
Spectrom. Ion Process. 1992, 115, 33.
34. Simakov, P. A.; Martinez, F. N.; Horner, J. H.; New-
comb, M. J. Org. Chem. 1998, 63, 1226.
35. Pfenniger, J.; Heuberger, C.; Graf, W. Helv. Chim. Acta
1980, 63, 2328.
15. Suh, D.; Pole, D. L.; Warkentin, J.; Terlouw, J. K. Can.
J. Chem. 1996, 74, 544.
36. For reversibility of homolytic aromatic substitutions with
phenyl radicals, see: (a) Kobayashi, M.; Minato, H.;
Kobori, N. Bull. Chem. Soc. Jpn. 1969, 42, 2738; (b)
Henriquez, R.; Morgan, A. R.; Mulholland, P.; Non-
hebel, D. C.; Smith, G. G. J. Chem. Soc., Chem. Com-
mun. 1974, 987; (c) Henriquez, R.; Nonhebel, D. C.
Tetrahedron Lett. 1975, 3855; (d) Henriquez, R.; Non-
hebel, D. C. Tetrahedron Lett. 1975, 3857.
37. Suginome, H.; Ohtsuka, T.; Orito, K. J. Chem. Soc.,
Perkin Trans. 1 1984, 575.
38. (a) Handa, S.; Pattenden, G. J. Chem. Soc., Perkin Trans.
1 1999, 843; (b) Della, E. W.; Kostakis, C.; Smith, P. A.
Org. Lett. 1999, 1, 363.
16. Venneri, P. C.; Warkentin, J. J. Am. Chem. Soc. 1998,
120, 11182.
17. Merkley, N.; El-Saidi, M.; Warkentin, J. Can. J. Chem.
2000, 78, 356.
18. Merkley, N.; Warkentin, J. Can. J. Chem. 2000, 78, 942.
19. Merkley, N.; Venneri, P. C.; Warkentin, J. Can. J. Chem.
2001, 79, 312.
20. Altmann, J. A.; Csizmadia, I. G.; Yates, K.; Yates, P. J.
Chem. Phys. 1977, 66, 298.
21. Altmann, J. A.; Csizmadia, I. G.; Robb, M. A.; Yates,
K.; Yates, P. J. Am. Chem. Soc. 1978, 100, 1653.
22. Feller, D.; Borden, W. T.; Davidson, E. R. J. Comp.
Chem. 1980, 1, 158.
39. Baldwin, J. E.; Shukla, R. J. Phys. Chem. A 1999, 103,
7821.
23. Kakumoto, T.; Saito, K.; Imamura, A. J. Chem. Phys.
2000, 91, 2366.