Highly efficient formation of nitriles and alkoxy radicals from N-alkoxybenziminoyl chlorides in solution

Article abstract of DOI:10.1021/jo8026142

A series of N-alkoxybenziminoyl chlorides were synthesized and reacted with tributyltin hydride in the presence of AIBN to generate the corresponding N-alkoxybenziminoyl radicals. This methodology successfully generates the desired radicals, which undergo a rapid and highly efficient β-scission reaction, as shown by the formation of the corresponding nitriles and products derived from alkoxy radicals. The intermediate N -alkoxybenziminoyl radical could not be trapped by employing high concentrations of Bu₃SnH or by using a hydrogen atom donating solvent such as toluene. The fast β-scission reaction was found to be independent of the structure of the iminoyl chloride. These results are different from studies on the similar N-alkyliminoyl radicals, which typically give products from both β-scission hydrogen atom transfer pathways. Using the data from this study as well as some reported rate constants for different hydrogen atom transfer (HAT) processes, we conclude that the lower limit for the rate constant for the β-scission process (kβ)in N-alkoxybenziminoyl radicals is 2.5 × 10⁷ s^-1.

Full text of DOI:10.1021/jo8026142

Highly Efficient Formation of Nitriles and Alkoxy Radicals from
N-Alkoxybenziminoyl Chlorides in Solution
H. J. Peter de Lijser,* Cassandra R. Burke, Jonathan Rosenberg, and Jordan Hunter
Department of Chemistry and Biochemistry, California State UniVersity, Fullerton, California 92834-6866
pdelijser@fullerton.edu
ReceiVed NoVember 25, 2008
A series of N-alkoxybenziminoyl chlorides were synthesized and reacted with tributyltin hydride in the
presence of AIBN to generate the corresponding N-alkoxybenziminoyl radicals. This methodology
successfully generates the desired radicals, which undergo a rapid and highly efficient ꢀ-scission reaction,
as shown by the formation of the corresponding nitriles and products derived from alkoxy radicals. The
intermediate N-alkoxybenziminoyl radical could not be trapped by employing high concentrations of
Bu3SnH or by using a hydrogen atom donating solvent such as toluene. The fast ꢀ-scission reaction was
found to be independent of the structure of the iminoyl chloride. These results are different from studies
on the similar N-alkyliminoyl radicals, which typically give products from both ꢀ-scission hydrogen
atom transfer pathways. Using the data from this study as well as some reported rate constants for different
hydrogen atom transfer (HAT) processes, we conclude that the lower limit for the rate constant for the
ꢀ-scission process (kꢀ) in N-alkoxybenziminoyl radicals is 2.5 × 107 s-1.
Introduction
radical intermediate, however, the pathway and intermediates
involved in the formation of the nitrile remain uncertain. We
have hypothesized that the formation of nitriles from aldoximes
proceeds via N-alkoximinoyl radical intermediates.3,4 This
proposal was in part a result of experiments done with O-t-
butylbenzaldehyde oxime, which reacted to give benzonitrile
The photooxidation of oximes and oxime ethers derived from
ketones typically results in the formation of the parent ketone.1
Oximes have been proposed to react via iminoxyl radicals,
which are formed by deprotonation of the oxime radical cations
(Scheme 1).1 Iminoxyl radicals (Z) have also been proposed as
intermediates in the generation of NO from arginine, although
the involvement of radical ions in that process is not certain.2
(2) (a) Wang, P. G.; Xian, M.; Tang, X.; Wu, X.; Wen, Z.; Cai, T.; Janczuk,
A. J. Chem. ReV. 2002, 102, 1091. (b) Rosen, G. M.; Tsai, P.; Pou, S. Chem.
ReV. 2002, 102, 1191. (c) Cai, T.; Xian, M.; Wang, P. G. Bioorg. Med. Chem.
Lett. 2002, 12, 1507. (d) Koikov, L. N.; Alexeeva, N. V.; Lisitza, E. A.;
Krichevsky, E. S.; Grigoryev, N. B.; Danilov, A. V.; Severina, I. S.; Pyatakova,
N. V.; Granik, V. G. MendeleeV Commun. 1998, 165. (e) Jousserandor, A.;
Boucher, J.-L.; Henry, Y.; Niklaus, B.; Clement, B.; Mansuy, D. Biochemistry
1998, 37, 17179. (f) Sanakis, Y.; Goussias, C.; Mason, R. P.; Petrouleas, V.
Biochemistry 1997, 36, 1411. (g) Kato, M.; Nishino, S.; Ohno, M.; Fukuyama,
S.; Kita, Y.; Hirasawa, Y.; Nakanishi, I.; Takasugi, H.; Sakane, K. Bioorg. Med.
Chem. Lett. 1996, 6, 33. (h) Decout, J.-L.; Roy, B.; Fontecave, M.; Muller, J.-
C.; Williams, P. H.; Loyaux, D. Bioorg. Med. Chem. Lett. 1995, 5, 973. (i) Kita,
Y.; Hirasawa, Y.; Maeda, K.; Nishio, M.; Yoshida, K. Eur. J. Pharmacol. 1994,
257, 123. (j) Isono, T.; Koibuchi, Y.; Sato, N.; Furuichi, A.; Nishii, M.;
Yamamoto, T.; Mori, J.; Kohsaka, M.; Ohtsuka, M. Eur. J. Pharmacol. 1993,
246, 205.
Further studies involving oxime ethers have shown that these
substrates do not form iminoxyl radicals but rather react via
deprotonation at the R-position provided a proton is available
(Scheme 2).3 It was found that oxime ethers that lack R-protons
are unreactive under those conditions.
Aldoximes react to give both the corresponding aldehyde and
the nitrile.1 The aldehyde is presumably formed via an iminoxyl
* To whom correspondence should be addressed. Phone: (714) 278-3290.
Fax: (714) 278-5316.
(1) (a) de Lijser, H. J. P.; Fardoun, F. H.; Sawyer, J. R.; Quant, M. Org.
Lett. 2002, 4, 2325. (b) de Lijser, H. J. P.; Kim, J. S.; McGrorty, S. M.; Ulloa,
E. M. Can. J. Chem. 2003, 81, 575. (c) Park, A.; Kosareff, N. M.; Kim, J. S.;
de Lijser, H. J. P. Photochem. Photobiol. 2006, 82, 110.
(3) de Lijser, H. J. P.; Tsai, C. K. J. Org. Chem. 2004, 69, 3057.
(4) de Lijser, H. J. P.; Hsu, S.; Marquez, B. V.; Park, A.; Sanguantrakun,
N.; Sawyer, J. R. J. Org. Chem. 2006, 71, 7785.
10.1021/jo8026142 CCC: $40.75
Published on Web 01/15/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1679–1684 1679

de Lijser et al.
SCHEME 1. Proposed Mechanistic Pathway for the Reactions of Oximes under Photoinduced Electron Transfer Conditions
SCHEME 2. Proposed Mechanism for Product Formation in Reactions of Oxime Ether Radical Cations
SCHEME 3. Formation of an N-Alkoxybenziminoyl Radical via Hydrogen Atom Abstraction in Oxime Ethers
SCHEME 4. Competitive Hydrogen Atom Abstraction
Pathways in Oximes
SCHEME 5. Formation of N-Alkyliminoyl Radicals from
Reaction of Iminoyl Chlorides with Tributyltin Radicals
are expected to show much of the same reactivity. There are
no reports on the reactivity of N-alkoximinoyl radicals nor are
there any reported methodologies for generating these reactive
intermediates. Wirth and Ru¨chardt generated N-alkyliminoyl
radicals from N-alkyliminoyl chlorides via chlorine atom
abstraction with tributyltin radicals.6h The synthesis of N-
alkoxybenziminoyl chlorides has been reported7,8 and these
chlorides would seem like appropriate precursors for the desired
iminoyl radicals. As shown in Scheme 5, the products formed
in the reactions N-alkyliminoyl chlorides with tributyltin radicals
are the ꢀ-scission product (nitrile) and the product resulting from
hydrogen atom abstraction (imine), suggesting competitive
pathways.6h It must be noted that the yields were found to be
dependent on the temperature and the concentration of tributyltin
hydride in the addition mixture, however, with the exception
of one substrate, products from ꢀ-scission and from hydrogen
atom abstraction were formed in every single case. On the basis
of these results, we would expect that, under similar conditions,
in excellent yield.5 Since there are no R-hydrogens available in
this molecule a reasonable alternative would be hydrogen atom
transfer to yield the O-t-butoximinoyl radical intermediate
(Scheme 3).
Similarly, studies on a set of substituted benzaldehyde oximes
have suggested that the formation of aldehydes and nitriles in
these reactions are best explained by two different pathways
that involve different intermediates.4 When electron transfer is
favorable, the preferred pathway involves electron transfer,
followed by proton transfer to form an iminoxyl radical, which
eventually leads to the formation of the corresponding aldehyde.
When electron transfer is unfavorable, a hydrogen atom transfer
mechanism will be the dominant pathway. Under the conditions
of the reaction, the sensitizer, triplet chloranil (3CA), is expected
to be a very good hydrogen atom acceptor. Competition between
hydrogen atom abstraction from the hydroxyl group (to form
an iminoxyl radical) and from the iminyl carbon (to form an
iminoyl radical) would lead to the formation of the aldehyde
and nitrile products respectively (Scheme 4).4
To learn more about the pathway that leads to the formation
of the nitrile products, we decided to focus on the proposed
N-alkoximinoyl radical intermediates as the potential precursors.
These radicals have received very little attention so far. They
are similar in structure to N-alkyliminoyl radicals, which are
better known, especially their use in the synthesis of heterocyclic
rings via radical cyclization reactions.6 Several methods have
been developed to generate these types of radicals, including
hydrogen abstraction from aldehydes, radical addition to isoni-
triles, and abstraction of a suitable group such as a halide or a
selenide.6 The most commonly observed reactions of these
species are atom abstraction (e.g., hydrogen atom abstraction
from tributyltin hydride), ꢀ-scission to form a nitrile, R-scission
to form an isonitrile, or addition to unsaturated molecules (e.g.,
alkenes).6p Because of their similarities, N-alkoximinoyl radicals
(6) (a) Tokumaru, K. J. Synth. Org. Chem. Jpn. 1970, 28, 773. (b) Ohta, H.;
Tokumaru, K. Chem. Commun. 1970, 1601. (c) Ohta, H.; Tokumaru, K. Chem.
Ind. 1971, 1301. (d) Davies, A. G.; Nedelec, J.-Y.; Sutcliffe, R. J. Chem. Soc.,
Perkin Trans. 2 1983, 209. (e) Leardini, R.; Pedulli, G. F.; Tundo, A.; Zanardi,
G. J. Chem. Soc., Chem. Commun. 1984, 1320. (f) Leardini, R.; Tundo, A.;
Zanardi, G.; Pedulli, G. F. Synthesis 1985, 107. (g) Leardini, R.; Nanni, D.;
Pedulli, G. F.; Tundo, A.; Zanardi, G. J. Chem. Soc., Perkin Trans. 1 1986,
1591. (h) Wirth, T.; Ru¨chardt, C. Chimia 1988, 42, 230. (i) Leardini, R.; Nanni,
D.; Tundo, A.; Zanardi, G. J. Chem. Soc., Chem. Commun. 1989, 757. (j) Bachi,
M. D.; Denenmark, D. J. Am. Chem. Soc. 1989, 111, 1886. (k) Surran, D. P.;
Liu, H. J. Am. Chem. Soc. 1991, 113, 2127. (l) Guidotti, S.; Leardini, R.; Nanni,
D.; Pareschi, P.; Zanardi, G. Tetrahedron Lett. 1995, 36, 451. (m) Dan-oh, Y.;
Matta, H.; Uemura, J.; Watanabe, H.; Uneyama, K. Bull. Chem. Soc. Jpn. 1995,
68, 1497. (n) Nanni, D.; Pareschi, P.; Rizzoli, C.; Sgarabotto, P.; Tundo, A.
Tetrahedron 1995, 51, 9045. (o) Nanni, D.; Pareschi, P.; Tundo, A. Tetrahedron
Lett. 1996, 37, 9337. (p) Fujiwara, S.; Matsuya, T.; Maeda, H.; Shin-ike, T.;
Kambe, N.; Sonoda, N. J. Org. Chem. 2001, 66, 2183. (q) Tokuyama, H.;
Fukuyama, T. Chem. Rec. 2002, 2, 37. (r) Minozzi, M.; Nanni, D.; Walton,
J. C. Org. Lett. 2003, 5, 901. (s) Coote, M. L.; Easton, C. J.; Zard, S. Z. J. Org.
Chem. 2006, 71, 4996. (t) Bowman, W. R.; Fletcher, A. J.; Pederson, J. M.;
Lovell, P. J.; Elsegood, M. R. J.; Lo´pez, E. H.; McKee, V.; Potts, G. B. S.
Tetrahedron 2007, 63, 191.
(7) Liu, K.-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45, 3916.
(8) (a) Coda, A. C.; Tacconi, G. Gazz. Chim. Ital. 1984, 114, 131. (b) Uchida,
Y.; Kozuka, S. Bull. Chem. Soc. Jpn. 1984, 57, 2011. (c) McGillivray, G.; Ten
Krooden, E. S. African J. Chem. 1986, 39, 54.
(5) de Lijser, H. J. P.; Rangel, N. A.; Tetalman, M. A.; Tsai, C. K. J. Org.
Chem. 2007, 72, 4126.
1680 J. Org. Chem. Vol. 74, No. 4, 2009

Efficient Formation of Nitriles and Alkoxy Radicals
FIGURE 1. Preparation and structure of the N-Alkoxybenziminoyl chlorides (2) used in this study. (i) NaOH, C8H17Br, solvent, reflux; (ii) H2N
OR HCL, NaOH, EtOH, reflux; (iii) NCS, DMF.
TABLE 1. Products and Percent Yields in the Thermal Reactions
of N-Alkoxybenziminoyl Chlorides 2a-e in Argon-Purged Benzene
in the Presence of AIBN (0.005 M) and Different Concentrations of
Bu3SnH
SCHEME 6. Reaction Scheme for the Generation of
N-Alkoxybenziminoyl Radicals
conversiona
3b
4c
5d
1e
0.025 M Bu3SnH
f
f
2a
2b
2c
2d
2e
71
69
51
48
73
74
73
77
92
100
-
-
-
-
-
-
<1g
<1g
<1g
<1g
<1g
f
f
f
f
89
92
3
7
the generation of N-alkoximinoyl radicals will result in the
formation of both nitriles (ꢀ-scission) and oxime ethers (hy-
drogen abstraction). Interestingly, no kinetic studies have been
carried out on reactions involving iminoyl radicals, nor have
there been any systematic studies on the reactivity of N-
alkoximinoyl radicals, thereby limiting their use in synthetic
applications.
To further investigate the involvement of N-alkoxybenzimi-
noyl radicals in the formation of nitriles from aldoximes and
aldoxime ethers and to learn about the reactivity of these reactive
intermediates, we have used the known methodologies from
studies on N-alkyliminoyl radicals to generate the radicals of
interest. Here we present our results on the studies of these novel
intermediates and report, for the first time, estimated rate
constants for some of the observed reactions.
0.25 M Bu3SnH
f
f
2a
2b
2c
2d
2e
100
100
90
100
100
100
100
88
76
100
-
-
-
-
<1g
<1g
<1g
<1g
<1g
f
f
f
-
f
-
69
92
1
1
a Conversion of
2
determined by calibrated GC-FID. b Yield of
benzonitrile. c Yield of alcohol (4a-e) product. d Amount of aldehyde
(5a-e) product. e Amount of oxime ether (1a-e) product. f Products
could not be detected by gas chromatography due to volatility. g Amount
below the detection limit.
TABLE 2. Products and Percent Yields in the Thermal Reactions
of N-Alkoxybenziminoyl Chlorides 2a-e in Air-Saturated Benzene
in the Presence of AIBN (0.005 M) and Different Concentrations of
Bu3SnH
conversiona
3b
4c
5d
1e
Results and Discussion
0.025 M Bu3SnH
Product Formation in the Reactions of N-Alkoxyben-
ziminoyl Radicals. Because N-alkoxybenziminoyl radicals have
received little attention, we decided to generate these radicals
via chlorine atom abstraction by the tributyltin radical. This
method had been successfully used for the generation of
N-alkyliminoyl radicals as described by Wirth and Ru¨chardt.6h
The required N-alkoxybenziminoyl chlorides (2a-e; Figure 1)
were prepared from the corresponding O-alkyl benzaldoximes
(1a-d) via reaction with N-chlorosuccinimide (NCS) as reported
by Howe.7 Oxime ethers 1a-d were prepared from reaction of
benzaldehyde with the appropriate O-alkyl hydroxylamine
hydrochloride salt.3,5 Oxime 1e was prepared from reaction of
benzaldehyde oxime with sodium hydroxide, followed by
addition of 1-bromooctane.
The desired N-alkoxybenziminoyl radicals were generated via
reaction of the corresponding N-alkoxybenziminoyl chloride
with tributyltin hydride and AIBN in refluxing benzene,
according to reactions 1-3 in Scheme 6.6h The reactions were
followed by gas chromatography and the products were identi-
fied by comparison to authentic standards. Blank experiments
were done to make sure no reactions occurred in the injector
port of the gas chromatograph. The experiments were carried
out in the presence and absence of oxygen (air). The results of
these studies are shown in Tables 1 and 2.
f
f
2a
2b
2c
2d
2e
75
72
57
60
74
100
99
91
53
80
-
-
-
35
76
-
-
-
<1g
<1g
<1g
<1g
<1g
f
f
f
f
1
4
0.25 M Bu3SnH
f
f
2a
2b
2c
2d
2e
75
100
93
96
100
100
100
83
95
96
-
-
-
-
<1g
<1g
<1g
<1g
<1g
f
f
f
-
f
-
51
93
1
1
a Conversion of
2
determined by calibrated GC-FID. b Yield of
benzonitrile. c Yield of alcohol (4a-e) product. d Amount of aldehyde
(5a-e) product. e Amount of oxime ether (1a-e) product. f Products
could not be detected by gas chromatography due to volatility. g Amount
below the detection limit.
Reflux of an argon-purged solution of N-methoxybenziminoyl
chloride (2a, 0.015 M), tributyltin hydride (0.025 M) and AIBN
(0.005 M) in benzene for 1 h resulted in the formation of
benzonitrile as the only product (Table 1). The expected product
from the reduction pathway (O-methylbenzaldehyde oxime, 1a)
was not formed under these conditions (less than 1%). Attempts
to trap the intermediate N-methoximinoyl radical by employing
J. Org. Chem. Vol. 74, No. 4, 2009 1681

de Lijser et al.
SCHEME 7. Expected Products from Reactions of
N-Methoxybenziminoyl Radicals
It is unclear why N-alkoximinoyl radicals react differently
as compared to N-alkyliminoyl radicals. One possible scenario
would be that oxime ethers are formed but react on under the
conditions of the reaction to form the nitrile product (Scheme
9). To find out if these follow-up reactions were occurring,
oxime ether 1d was reacted with Bu3SnH and AIBN in benzene
under reflux. Although small amounts of benzonitrile were
detected, the conversion of the oxime ether was at most 5%;
therefore it can be concluded that this reaction is of no
significance and cannot be used to explain the absence of the
oxime ether in the product mixture. The most likely explanation
at this point is that the ꢀ-scission pathway that leads to the
formation of alkoxy radicals is energetically more favorable than
that of similar alkyl radicals. This may simply be a result of a
difference in bond dissociation energies; the N-O BDE in
higher concentrations of Bu3SnH (0.25 M) or by using toluene
as the solvent were unsuccessful, suggesting that the ꢀ-scission
pathway is a very efficient process. However, the other expected
product(s) from the ꢀ-scission pathway (alcohol 4a and aldehyde
5a; Scheme 7) could not be detected by gas chromatography
(due to volatility issues) and therefore it cannot be concluded
(at this point) that this pathway actually takes place.
acetaldoxime is 49.7 kcal mol-1 whereas the typical C-N BDE
11,12
is upward of 70 kcal mol-1
.
When the reactions were carried out in air-saturated benzene
the results were very similar to those in the argon-purged
solutions (Table 2). Again, all compounds give good (∼80%)
to excellent (∼100%) material balances with the exception of
2d. The reason for this behavior is unclear; the results are
different in the absence and in the presence of air, which
suggests that it may be due to follow up reactions with oxygen
although it is unclear why only one of these substrates would
be susceptible to this effect. At this point we have not further
investigated this behavior.
Estimation of the Rate Constants for ꢀ-Scission in
N-Alkoxybenziminoyl Radicals. On the basis of the results
listed in Tables 1 and 2, it can be concluded that N-alkoxyben-
ziminoyl radicals undergo a ꢀ-scission to yield benzonitrile and
an alkoxy radical. Since the product from the reduction pathway
(hydrogen atom transfer, HAT, from Bu3SnH) is not observed,
it seems reasonable to assume that the ꢀ-scission pathway is
significantly faster than the HAT pathway. Since there are no
reports on the rate constant for either the hydrogen atom transfer
or the ꢀ-scission reactions in iminoyl radicals, we have
attempted to use our data together with some literature sources
for an estimate of these numbers.
Similar results were obtained for N-ethoxybenziminoyl
chloride (2b) and N-t-butoxybenziminoyl chloride (2c). Other
than formation of benzonitrile, no direct evidence was found
for the ꢀ-scission pathway, since the expected products from
the radical fragment in these reactions (methanol, 4a; formal-
dehyde, 5a; ethanol, 4b; acetaldehyde, 5b; and t-butanol, 4c,
respectively) could not be identified with the available experi-
mental techniques. However, using N-benzyloxybenziminoyl
chloride (2d) under similar conditions led to the formation of
benzonitrile (3), benzyl alcohol (4d) and benzaldehyde (5d).
The latter two products confirm the suspected ꢀ-scission
pathway. Similarly, reacting N-octyloxybenziminoyl chloride
(2e) yielded benzonitrile (3), 1-octanol (4e) and octanal (5e) as
expected. In general, the material balances in these experiments
are acceptable. It is known that tin radicals can react with
carbon-nitrogen double bonds,9 which may explain the lower
material balances for compounds 2a-c. Analysis of the mixtures
by GC-MS suggested the formation of some products containing
tin (including tributyltin chloride and hexabutylditin), however
these were not isolated or quantified.
Comparing these results to those obtained by Wirth and
Ru¨chardt in their studies on N-alkyliminoyl radicals6h reveals
some significant differences. The reaction of N-benzylbenzimi-
noyl chloride in benzene resulted in the formation of benzonitrile
(76.5%), toluene (74.4%) and N-benzylbenzaldimine (10.1%).
Under similar conditions, N-octylbenziminoyl chloride reacted
to give only 2.4% (each) of benzonitrile and octane and 93.6%
of N-octylbenzaldimine. Other substrates (with the exception
of N-cinnamylbenziminoyl chloride) also reacted to yield the
imine product independent of the solvent (benzene, toluene,
xylene) or concentration of Bu3SnH, although the material
balance often was poor. In a separate study, Bringmann, Barton
and co-workers noted that reaction of an iminoyl chloride
derivative of a steroid with Bu3SnH resulted in the formation
of benzylamine (64%), suggesting that ꢀ-scission was not a
dominant pathway (Scheme 8).10
First, it must be noted that the product formation (products
and yields) is unaffected by the presence of oxygen. The
reactions of carbon-centered radicals with oxygen in solution
13,14
vary from 106 to 109 M-1 s-1
;
the “slow” reactions are
observed for stabilized radicals (e.g., benzylic) although other
resonance stabilized radicals have rate constants of 2 - 3 ×
13
108 M-1 s-1
.
A fast reaction of the N-alkoxybenziminoyl
radical with oxygen (kOx) would be competitive with the
ꢀ-scission pathway and it would likely lead to different products
or a diminished material balance. However, as seen from Tables
1 and 2, the material balances do not change significantly when
(11) Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic
Compounds; CRC Press: Boca Raton, FL, 2003.
(12) Although the BDE of the C-N bond in a typical imine is unknown, a
survey of different C-N BDE values suggest that most are in the range of 70-
11
100 kcal mol-1
.
(13) For a listing of rate constants for the reactions of carbon-centered radicals
with O2 see: (a) Neta, P.; Huie, R. E.; Ross, A. B. J. Phys. Chem. Ref. Data
1990, 19, 413. (b) Howard, J. A.; Scaiano, J. C. In Landolt-Barnstein Numerical
Data and Functional Relationships in Science and Technology. New Series,
Group ll; Atomic and Molecular Physics; Hellwege, K.-H., Madelung, O., Eds.;
Springer-Verlag: Berlin, 1984; Vol. 13, Part d.
(9) (a) McCarroll, A. J.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2 2000,
(14) (a) Sommeling, P. M.; Mulder, P.; Louw, R.; Avila, D. V.; Lusztyk, J.;
Ingold, K. U. J. Phys. Chem. 1993, 97, 8361. (b) Alfassi, Z. B.; Marguet, S.;
Neta, P. J. Phys. Chem. 1994, 98, 8019. (c) Mertens, R.; von Sonntag, C. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1262. (d) Brown, C. E.; Neville, A. G.; Rayner,
D. M.; Ingold, K. U.; Lusztyk, J. Aust. J. Chem. 1995, 48, 363.
1868. (b) McCarroll, A. J.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2 2000,
2399.
(10) Barton, D. H. R.; Bringmann, G.; Lamotte, G. Tetrahedron Lett. 1979,
24, 2291.
1682 J. Org. Chem. Vol. 74, No. 4, 2009

Efficient Formation of Nitriles and Alkoxy Radicals
SCHEME 8. Reduction by Tributyltin Hydride of the Steroid Derivative of a Benziminoyl Chloride10
SCHEME 9. Possible Alternative Pathway for Product Formation in the Reactions of N-Alkoxybenziminoyl Chlorides
TABLE 3. Summary of Literature Rate Constants for Solution-Phase Reactions of sp2-Hybridized Carbon-Centered Radicals with Oxygen
and Tributyltin Hydride
entry
reaction
rate constant (M-1 s-1
)
reference
14b
14c
14b
14d
14c
16d
16b,c
16a
•
1
2
3
4
5
6
7
8
C6H5 + O2 f C6H5OO•
7.1 × 108
4.6 × 109
1.6 × 109
1.8 × 109
4.6 × 109
7.8 × 108
3.9 × 105
3.5 × 108
•
C6H5 + O2 f C6H5OO•
•
-O2C-C6H5 + O2 f -O2C-C6H5OO•
C6H5C(O)• + O2 f C6H5C(O)OO•
H2C)CH• + O2 f H2C)CHOO•
•
C6H5 + Bu3SnH f C6H6 + Bu3Sn•
(CH3)3C(O)• + Bu3SnH f (CH3)3CHO + Bu3Sn•
(CH3)2C)CH• + Bu3SnH f (CH3)2C)CH2 + Bu3Sn•
SCHEME 10. Possible Follow-up Reactions for
N-Alkoxybenziminoyl Radicals
changing from an argon-purged solution to an air-saturated
solution. This suggests that the ꢀ-scission pathway is faster than
reaction of the N-alkoximinoyl radicals with oxygen. The rate
constant for the reaction of an sp2-hybridized carbon radical
with oxygen can be estimated from available literature values
(Table 3, entries 1-5). For example, the reaction of the phenyl
radical with oxygen (in water) has a reported rate constant of
14a
3.8 × 109 M-1 s-1
,
although it has been suggested that this
report used an incorrect O2 concentration.14b A value corrected
for the O2 concentration is 7.1 × 108 M-1 s-1. Mertens and
von Sonntag14c measured a value of 4.6 × 109 M-1 s-1 for the
same reaction and Neta and co-workers reported a value of 1.6
× 109 M-1 s-1 for the reaction of 4-carboxyphenyl radical with
oxygen.14b Other known solution-phase rate constants for the
reaction of sp2-carbon centered radicals with oxygen are also
on the order of 109 M-1 s-1 (e.g., benzoyl radical, 1.8 × 109
M-1 s-1;14c ethenyl radical, 6.4 × 109 M-1 s-1).14d On the basis
of these values, it seems reasonable to assume a similar rate
constant for the reaction of an iminoyl radical with oxygen.
Using a rate constant, kOx, of 1.0 × 109 M-1 s-1 for the reaction
of an sp2-hybridized carbon centered radical with oxygen and
assuming that the benzene solution is saturated with air (0.21
atm O2; [O2] ) 1.9 × 10-3 M),15 we can estimate the rate of
the reaction of N-alkoxybenziminoyl radicals with oxygen to
be approximately 1.9 × 106 s-1. Therefore, if the rate constant
of ꢀ-scission (kꢀ) is approximately 2 × 106 s-1 or slower, we
would expect to see a significant effect from the presence of
oxygen. Since no such effect is observed we can conclude that
nately, the rate constant for this pathway (kH) has not yet been
determined, and therefore we have to rely on the measured rate
constants for similar reactions. Several rate constants for the
reactions of different sp2-hybridized carbon-centered radicals
with Bu3SnH have been determined experimentally (Table 3,
entries 6 - 8). The rate constants vary from anywhere between
105 and 108 M-1 s-1, depending on the structure of the radical.16
For our purposes, we have chosen a rate constant of 1 × 106
M-1 s-1 as a lower limit for this process.
Now that we have established a lower limit for the HAT
process we can estimate a rate constant for the ꢀ-scission
pathways. Using the reaction of iminoyl chloride 2d (Scheme
10) as an example it can be seen that the two competing
pathways for the N-alkoxybenziminoyl radicals are hydrogen
atom transfer to yield the oxime ether 1 (kH) and ꢀ-scission to
yield benzonitrile 3 (kꢀ). Because both products are directly
formed directly from the same intermediate, we can use the
kꢀ must be significantly greater than 106 s-1
.
To determine the rate constant for the ꢀ-scission pathway
(kꢀ) of the intermediate N-alkoxybenziminoyl radicals we needed
a value for the hydrogen atom abstraction pathway. Unfortu-
(16) (a) Johnston, L. J.; Lusztyk, J.; Wayner, D. D. M.; Abeywickreyma,
A. N.; Beckwith, A. L. J.; Scaiano, J. C.; Ingold, K. U. J. Am. Chem. Soc. 1985,
107, 4594. (b) Chatgilialoglu, C.; Lucarini, M. Tetrahedron Lett. 1995, 36, 1299.
(c) Chatgilialoglu, C.; Ferreri, C.; Lucarini, M.; Pedrielli, P.; Pedulli, G. F.
Organometallics 1995, 14, 2672. (d) Garden, S. J.; Avila, D. V.; Beckwith,
A. L. J.; Bowry, V. W.; Ingold, K. U.; Lusztyk, J. J. Org. Chem. 1996, 61, 805.
(15) Murov, S. L.; Carmichael, I.; Hug, G. L. Handbook of Photochemistry,
2nd ed.; Dekker: New York, 1993.
J. Org. Chem. Vol. 74, No. 4, 2009 1683

de Lijser et al.
used without further purification. The aldoxime ethers were prepared
from benzaldehyde and commercially available O-alkylhydroxy-
lamine hydrochloride salts or from reaction of benzaldehyde oxime
with the appropriate alkyl halide in the presence of base (see below).
Benzene (spectrophotometric grade) was used as received.
Thermal Reactions. The desired N-alkoxybenziminoyl radicals
were generated via reaction of the corresponding N-alkoxybenz-
iminoyl chloride (2) with tributyltin hydride and AIBN in refluxing
benzene. In a typical experiment, a 25 mL round-bottom flask was
charged with the appropriate N-alkoxybenziminoyl chloride (2,
0.015 M), tributyltin hydride (0.025 or 0.25 M) and AIBN (0.005
M). Benzene (10 mL) was added and the mixture was refluxed for
1 h. Afterward, the reaction mixture was analyzed by gas chroma-
tography and the products were identified by comparison to
authentic standards. Blank experiments were done to make sure
no reactions occurred in the injector port of the gas chromatograph.
The experiments were carried out in the presence and absence of
oxygen (air).
Synthesis of O-Alkyl Benzaldehyde Oximes. The preparations
of oxime ethers 1a-d have been reported previously.5 In general,
the oxime ethers were prepared by the addition of the appropriate
O-alkyl hydroxylamine hydrochloride and a few drops of concen-
trated hydrochloric acid to benzaldehyde in 95% ethanol (50 mL).
The mixture was refluxed for 2-6 h after which the solvent was
removed under reduced pressure. The crude product (oil) was
purified by column chromatography using a hexane-ether gradient.
Synthesis of N-Alkoxybenziminoyl Chlorides (2a-e). The
synthesis of the N-alkoxylbenziminoyl chlorides was accomplished
using a modification of the procedure by Howe.7 A 10 mL round-
bottom flask was charged with the appropriate O-alkyl benzaldehyde
oxime (0.006 mol) and DMF (5.0 mL). While stirring the solution,
N-chlorosuccinimide (NCS, 0.006 mol) was slowly added. After
the addition was complete the mixture was stirred for 48 h.
Afterward the solution was poured into ice water (20 mL) and the
resulting mixture was extracted three times with dichloromethane.
The combined organic layers were dried over magnesium sulfate
and after filtration the solvent was removed under reduced pressure
yielding an oily residue. The iminoyl chlorides were further purified
by column chromatography on silica gel using a hexane-ethyl
acetate gradient.
product ratio to determine the approximate rate constants for
each pathway:
kH[Bu3SnH]
[1d]
)
[3]
kꢀ
which can be rewritten as:
kH[Bu3SnH][3]
[1d]
kꢀ )
Using kH ) 1 × 106 M-1 s-1 and [Bu3SnH] ) 0.25 M we
obtain a value of 2.5 × 105 s-1 for kꢀ if the product ratio {1d/
3} is equal to 1. Since the product from the hydrogen atom
abstraction pathway (oxime ether 1d) was not detected (less
than 1% yield, i.e., {3/1d} > 1 × 102), the lower limit for the
rate constant for the ꢀ-scission process in N-alkoxybenziminoyl
radicals is estimated to be greater than 2.5 × 107 s-1. This is in
agreement with the estimate presented above which suggests
that the rate of ꢀ-scission is significantly greater than 106 s-1
.
If kH is in the range of 108 M-1 s-1 (similar to the reactions of
phenyl radical and isobutenyl radical),16a,b the rate constant for
ꢀ-scission will be on the order of 2.5 × 109 s-1
.
Conclusions
Generation of N-alkoxybenziminoyl radicals from the cor-
responding N-alkoxybenziminoyl chlorides by means of the
tributyltin radicals results in a rapid and highly efficient
ꢀ-scission process, which yields the nitrile and the alkoxy
radical. The ꢀ-scission pathway is too fast for hydrogen atom
abstraction to compete. Using an estimated rate constant of 1
× 106 M-1s-1 for the hydrogen atom abstraction process (kH),
the lower limit for the rate constant for the ꢀ-scission process
(kꢀ) is estimated to be 2.5 × 107 s-1. The reactivity of
N-alkoximinoyl radicals is different than that of the similar
N-alkyliminoyl radicals, which react to give both products from
reduction and ꢀ-scission. The difference is thought to be a result
of different bond strengths (cleavage of the N-O bond versus
the N-C bond), although more evidence is expected to come
from theoretical studies on these intermediates. These results
seem to confirm the formation of alkoximinoyl radicals in the
photooxidation of aldoximes as shown by the formation of the
corresponding nitriles. In addition, the use of N-alkoxybenz-
iminoyl chlorides is a novel and highly efficient method for
the generation of alkoxyl radicals in solution. Further work is
underway to determine the exact rate constants for the ꢀ-scission
processes in iminoyl radicals.
Acknowledgment. We acknowledge the donors of the
Petroleum Research Fund, administered by the American
Chemical Society. Part of this work was supported by NSF
under grant nos. 0354159, 0521665, and 0649087. We thank
Ms. Diane Youker for her help with some of the experiments.
Supporting Information Available: Experimental proce-
dures and compound characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
Experimental Section
Materials. All chemicals other than the aldoxime ethers (1) and
the benziminoyl chlorides (2) were commercially available and were
JO8026142
1684 J. Org. Chem. Vol. 74, No. 4, 2009