Mechanistic aspects of the formation of aldehydes and nitriles in photosensitized reactions of aldoxime ethers

Article abstract of DOI:10.1021/jo0703707

(Chemical Equation Presented) The photooxidation of a series of aldoxime ethers was studied by laser flash photolysis and steady-state (product studies) methods. Nanosecond laser flash photolysis studies have shown that chloranu (CA)-sensitized reactions of the O-methyl (1), O-ethyl (2), O-benzyl (3), and O-tert-butyl (4) benzaldehyde oximes result in the formation of the corresponding radical cations. In polar non-nucleophilic solvents such as acetonitrile, there are several follow-up pathways available depending on the structure of the aldoxime ether and the energetics of the reaction pathway. When the free energy of electron transfer (ΔG_ET) becomes endothermic, syn-anti isomerization is the dominant pathway. This isomerization pathway is a result of triplet energy transfer from CA to the aldoxime ether. For substrates with α-protons (aldoxime ethers 1-3), the follow-up reactions involve deprotonation at the α-position followed by β-scission to form the benziminyl radical (and an aldehyde). The benziminyl radical reacts to give benzaldehyde, the major product under these conditions. A small amount of benzonitrile is also observed. In the absence of α-hydrogens (aldoxime ether 4), the major product is benzonitrile, which is thought to occur via reaction of the excited (triplet) sensitizer with the aldoxime ether. Abstraction of the iminyl hydrogen yields an imidoyl radical, which undergoes a β-scission to yield benzonitrile. An alternative pathway involving electron transfer followed by removal of the iminyl proton was not deemed viable based on charge densities obtained from DFT (B3LYP/6-31G*) calculations. Similarly, a rearrangement pathway involving an intramolecular hydrogen atom transfer process was ruled out through experiments with a deuterium-labeled benzaldehyde oxime ether. Studies involving nucleophilic solvents have shown that all aldoxime ethers reacted with MeOH by clean second-order kinetics with rate constants of 0.7 to 1.2 × 10⁷ M^-1 s^-1, which suggests that there is only a small steric effect in these reactions. The steady-state experiments demonstrated that under these conditions no nitrile is formed. This is explained by a mechanistic scheme involving nucleophilic attack on the nitrogen of the aldoxime ether radical cation, followed by solvent-assisted [1,3]-proton transfer and elimination of an alcohol, similar to the results obtained for a series of acetophenone oxime ethers.

Full text of DOI:10.1021/jo0703707

Mechanistic Aspects of the Formation of Aldehydes and Nitriles in
Photosensitized Reactions of Aldoxime Ethers
H. J. Peter de Lijser,* Natalie Ann Rangel, Michelle A. Tetalman, and Chao-Kuan Tsai
Department of Chemistry & Biochemistry, California State UniVersity, Fullerton, California 92834-6866
pdelijser@fullerton.edu
ReceiVed February 22, 2007
The photooxidation of a series of aldoxime ethers was studied by laser flash photolysis and steady-state
(product studies) methods. Nanosecond laser flash photolysis studies have shown that chloranil (CA)-
sensitized reactions of the O-methyl (1), O-ethyl (2), O-benzyl (3), and O-tert-butyl (4) benzaldehyde
oximes result in the formation of the corresponding radical cations. In polar non-nucleophilic solvents
such as acetonitrile, there are several follow-up pathways available depending on the structure of the
aldoxime ether and the energetics of the reaction pathway. When the free energy of electron transfer
(∆GET) becomes endothermic, syn-anti isomerization is the dominant pathway. This isomerization pathway
is a result of triplet energy transfer from CA to the aldoxime ether. For substrates with R-protons (aldoxime
ethers 1-3), the follow-up reactions involve deprotonation at the R-position followed by â-scission to
form the benziminyl radical (and an aldehyde). The benziminyl radical reacts to give benzaldehyde, the
major product under these conditions. A small amount of benzonitrile is also observed. In the absence of
R-hydrogens (aldoxime ether 4), the major product is benzonitrile, which is thought to occur via reaction
of the excited (triplet) sensitizer with the aldoxime ether. Abstraction of the iminyl hydrogen yields an
imidoyl radical, which undergoes a â-scission to yield benzonitrile. An alternative pathway involving
electron transfer followed by removal of the iminyl proton was not deemed viable based on charge densities
obtained from DFT (B3LYP/6-31G*) calculations. Similarly, a rearrangement pathway involving an
intramolecular hydrogen atom transfer process was ruled out through experiments with a deuterium-
labeled benzaldehyde oxime ether. Studies involving nucleophilic solvents have shown that all aldoxime
ethers reacted with MeOH by clean second-order kinetics with rate constants of 0.7 to 1.2 × 107 M-1
s-1, which suggests that there is only a small steric effect in these reactions. The steady-state experiments
demonstrated that under these conditions no nitrile is formed. This is explained by a mechanistic scheme
involving nucleophilic attack on the nitrogen of the aldoxime ether radical cation, followed by solvent-
assisted [1,3]-proton transfer and elimination of an alcohol, similar to the results obtained for a series of
acetophenone oxime ethers.
Introduction
lead to the formation of reactive intermediates by means of
enzymatic oxidation processes.5 The enzymes responsible for
oxidative degradation of xenobiotics are the cytochromes P450
(CYP). CYP3A4 is the most abundant human liver microsome
The use of oximes as drugs (antidotes for organophosphorus
poisoning, NO-donors),1,2 pesticides,3 and industrial chemicals
(e.g., cyclohexanone oxime in the synthesis of caprolactam)4
has dramatically increased in recent years. Their prevalence in
the environment can result in uptake by organisms, that could
(1) (a) Clement, J. G. Biochem. Pharmacol. 1982, 31, 1283. (b) Dunn,
M. A.; Siddell, F. R. JAMA, J. Am. Med. Assoc. 1989, 262, 649. (c) Maxwell,
D. M.; Lieske, C. N.; Brecht, K. M. Chem. Res. Toxicol. 1994, 7, 428. (d)
Kwong, T. C. Ther. Drug Monit. 2002, 24, 144. (e) Baigar, J. Acta Med.
1996, 39, 101.
* To whom correspondence should be addressed. Phone: (714) 278-3290,
Fax: (714) 278-5316.
10.1021/jo0703707 CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/04/2007
4126
J. Org. Chem. 2007, 72, 4126-4134

Photosensitized Reactions of Aldoxime Ethers
SCHEME 1
SCHEME 2
and has a broad substrate specificity. In fact, this isoform is
responsible for metabolizing more than 50% of the clinically
used drugs.6 The CYP enzymes are known to oxidize substrates
via hydrogen atom transfer (HAT) or single electron transfer
(SET) reactions.7 One-electron oxidation of oximes can result
in the formation of reactive intermediates such as radical
cations and iminoxyl radicals,8,9 which are harmful to organ-
isms.10 Oximes have also found use as NO-donors,2 and
iminoxyl radicals have been proposed as intermediates in this
process.2,11
We have previously used photooxidation as a tool to generate
these reactive intermediates and to study their behavior. Our
initial studies have shown that ketoximes react to give the
corresponding carbonyl compounds via the sequence given in
Scheme 1.9 The main intermediate in this reaction pathway is
the iminoxyl radical, Z.
Recently we have focused on the reactivity of aldoximes,
which under similar conditions react to give both aldehydes and
nitriles.9e The pathway for aldehyde formation is thought to be
via an iminoxyl radical in analogy to ketone formation above
(Scheme 1, R′ ) H). However, the nitrile formation was
proposed to result from a different intermediate, most likely an
imidoyl radical. We have also studied the photooxidation
reactions of oxime ethers derived from ketones.9c On the basis
of nanosecond laser flash photolysis and steady-state photolysis
(product) studies, we have proposed that these compounds react
via a pathway that does not involve the formation of iminoxyl
radicals. In non-nucleophilic solvents such as acetonitrile, the
reaction proceeds via deprotonation at the R-carbon followed
by â-scission and follow-up reactions (Scheme 2).
To further study the possible involvement of iminoxyl and
imidoyl radicals in the formation of nitriles in the photooxidation
of aldoximes, we have studied a series of aldoxime ethers. The
working hypothesis was that if nitriles are formed via iminoxyl
radical intermediates, no nitriles should be formed in the
photooxidation of oxime ethers, since oxime ethers do not react
to give iminoxyl radicals. The results of these studies and the
mechanistic implications are discussed.
(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) Koikov, L. N.; Alexeeva, N. V.;
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I. S.; Pyatakova, N. V.; Granik, V. G. MendeleeV Commun. 1998, 165. (d)
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B.; Fontecave, M.; Muller, J.-C.; Williams, P. H.; Loyaux, D. Bioorg. Med.
Chem. Lett. 1995, 5, 973. (g) Kita, Y.; Hirasawa, Y.; Maeda, K.; Nishio,
M.; Yoshida, K. Eur. J. Pharmacol. 1994, 257, 123. (h) Isono, T.; Koibuchi,
Y.; Sato, N.; Furuichi, A.; Nishii, M.; Yamamoto, T.; Mori, J.; Kohsaka,
M.; Ohtsuka, M. Eur. J. Pharmacol. 1993, 246, 205.
(3) Milne, G. W. A. CRC Handbook of Pesticides; CRC Press: Boca
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(4) Halford, B. Chem. Eng. News 2005, 83, 10.
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(7) Guengerich, F. P. In Cytochromes P450: Metabolic and Toxicological
Aspects; Ioannides, C., Ed., CRC Press: Boca Raton, 1996; p 55.
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Ford, E.; Mortensen, A.; Ferguson, A. C.; Vojnovic, B.; Wardman, P. J.
Chem. Soc., Perkin Trans. 2001, 1989. (b) Benchariff, L.; Tallec, A.;
Tardivel, R. Electrochim. Acta 1997, 42, 3509. (c) Rhodes, C. J.; Agirbas,
H. J. Chem. Soc. Faraday Trans. 1990, 86, 3303. (d) Horne, D. G.; Norrish,
R. G. W. Proc. Roy. Soc. Lond. A 1970, 315, 287. (e) Edge, D. J.; Norman,
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Ulloa, E. M. Can. J. Chem. 2003, 81, 575. (c) de Lijser, H. J. P.; Tsai,
C.-K. J. Org. Chem. 2004, 69, 3057. (d) Park, A.; Kim, J. S.; Kosareff, N.
M.; de Lijser, H. J. P. Photochem. Photobiol. 2006, 82, 110. (e) de Lijser,
H. J. P.; Hsu, S.; Marquez, B. V.; Park, A.; Sanguantrakun, N.; Sawyer, J.
R. J. Org. Chem. 2006, 71, 7785.
Results and Discussion
A. Laser Flash Photolysis Studies of Aldoxime Ethers in
the Presence of Chloranil. The benzaldehyde oximes used in
these photochemical studies are shown in Figure 1.
Previously we have used laser flash photolysis (LFP) to show
that both oximes and ketoxime ethers quench the triplet state
of chloranil (3CA) with rates close to the diffusion-controlled
limit.9 Similar results are obtained when using aldoxime ethers
1-4 as the quenchers (kq; Table 1). On the basis of the Weller
equation,12 SET is not favorable; however, it cannot be ruled
out as a pathway, although others must be considered as well.
Support for an initial SET step comes from the spectra
obtained from laser excitation (355 nm) of a solution containing
CA and aldoxime ether 1. The spectrum (Figure 2A) shows
absorption bands around 400 and 650 nm. The lifetime of the
intermediate formed in these reactions ((τ ) 200 ns) is
significantly shorter than the O-alkyl acetophenone oxime
radical cations (τ ) 500 ns).9c The band at 450 nm decays slower
than those at 400 and 650 nm and is most likely due to either
the chloranil radical anion or the semiquinone radical, which
are known to absorb in the region of 425-525 nm.13 Similar
spectra were obtained for aldoxime ethers 2-4 (Figures 2B-
(10) Halliwell, B.; Gutteridge, J. M. C. Free Radicals in Biology and
Medicine, 3rd ed.; Oxford University Press: Oxford, 1999.
(11) (a) Cai, T.; Xian, M.; Wang, P. G. Bioorg. Med. Chem. Lett. 2002,
12, 1507. (b) Sanakis, Y.; Goussias, C.; Mason, R. P.; Petrouleas, V.
Biochemistry 1997, 36, 1411.
(12) Rehm, D.; Weller, A. Isr. J. Chem. 1970, 8, 259.
(13) (a) Bockman, T. M.; Kochi, J. K. J. Chem. Soc., Perkin Trans. 2
1996, 1633. (b) Jones, G., II; Mouli, N.; Haney, W. A.; Bergmark, W. R.
J. Am. Chem. Soc. 1997, 119, 8788.
J. Org. Chem, Vol. 72, No. 11, 2007 4127

de Lijser et al.
FIGURE 1. Benzaldehyde oximes used in the chloranil-sensitized
reactions.
TABLE 1. Summary of Kinetic Data Obtained from Nanosecond
Laser Flash Photolysis Experiments of Aldoxime Ethers 1-4
aldoxime
ether
Ep
∆GET
kq
kMeOH
b
(V)a
(kcal mol-1
)
(M-1 s-1
)
(M-1 s-1
)
1
2
3
4
2.48
2.42
2.44
2.32
+7.6
+6.2
+6.7
+3.9
3.22 × 109
4.74 × 109
3.44 × 109
5.18 × 109
1.15 × 107
1.00 × 107
1.21 × 107
7.13 × 106
a Oxidation potentials measured by cyclic voltammetry (0.1 M tetraethyl
ammonium perchlorate in CH3CN, Ag/AgCl electrode); each value was
corrected by +0.29 V in order to convert the reference to SCE. b calculated
using the Weller equation (ref 12): ∆GET ) 23.06[Eox - Ered - ET] kcal/
mol; ET is the triplet energy of CA (2.13 eV) and Ered is the reduction
potential of CA (+0.02 V vs SCE).
D). These spectra are very similar to those obtained for ketoxime
ether radical cations.9c
Similar spectra were obtained when N-ethylquinolinium
tetrafluoroborate (NEQ) was used as the sensitizer (Figure 3).
3
When the signals from CA, the CA radical anion, and the
semiquinone radical are absent, it becomes obvious that the band
between 390 and 410 nm belongs indeed to the aldoxime ether
(1) radical cation. As noted before,9c the spectra of oxime radical
cations cannot be observed under these conditions. This is most
likely because the aldoxime radical cation is a strongly acidic
species14 and will readily give up a proton to any available base.
To obtain further evidence for the formation of the aldoxime
ether radical cation under these conditions, the addition of
variable concentrations of the electron donor (4,4′-dimethox-
ystilbene; DMS) was studied. Monitoring the spectrum upon
addition of DMS revealed a decay of the signal at 665 nm as a
function of the concentration of added DMS and the appearance
of a new signal at 530 nm. The latter signal is assigned to the
DMS radical cation, consistent with literature data.15 The slope
of the plot of the rate constant for the growth of the signal at
530 nm against the DMS concentration gave a bimolecular rate
constant of ∼2 × 1010 M-1 s-1. As expected for an electron-
transfer process, this rate constant is close to the diffusion-
controlled limit. These experiments confirm that under the
conditions of the reactions, SET occurs and the aldoxime ether
radical cations species are formed. The bands appearing between
390-410 nm and 550-750 nm in the spectra shown in Figure
2 are assigned to the aldoxime ether radical cations.
The reactions of the aldoxime ether radical cations with
MeOH as a nucleophile (kMeOH) were studied separately (in
MeCN), and the rate constants for these reactions are listed in
Table 1. There is little difference between the rate constants of
the reactions of aldoxime ethers 1-3 with MeOH, but aldoxime
ether 4 reacts somewhat slower. On the basis of the previously
(14) (a) Bordwell, F. G.; Ji, G.-Z. J. Org. Chem. 1992, 57, 3019. (b)
Bordwell, F. G.; Zhang, X.-M.; Satish, A. V.; Cheng, J.-P. J. Am. Chem.
Soc. 1994, 116, 6605. (c) Bordwell, F. G.; Zhang, S. J. Am. Chem. Soc.
1995, 117, 4858. (d) Bordwell, F. G.; Zhao, Y.; Cheng, J.-P. J. Phys. Org.
Chem. 1998, 11, 10.
(15) Gould, I. R.; Ege, D.; Moser, J. E.; Farid, S. J. Am. Chem. Soc.
1990, 112, 4290.
FIGURE 2. Spectra obtained from CA-sensitized laser photolysis (355
nm) of (A) aldoxime ether 1 in MeCN, (B) compound 2 in MeCN, (C)
compound 3 in MeCN, and (D) compound 4 in MeCN. The spectra
were taken 65 ns (O), 200 ns (0), 450 ns (]), and 1 µs (4) after the
laser pulse.
4128 J. Org. Chem., Vol. 72, No. 11, 2007

Photosensitized Reactions of Aldoxime Ethers
TABLE 2. Summary of the Results from the Photosensitized
Reactions of Aldoxime Ethers 1-4 with CA in MeCN
product yieldsb
aldoxime
ether
%Ca
6
7
%Ic
6:7
1
2
3
4
41
45
20
15
17
28
37
4
7
5
4
74
66
64
-
2.4
5.6
9.3
0.04
96
a Conversion was calculated on the basis of the GC-FID peak area of
the aldoxime ether before and after photolysis. b Product yields determined
by calibrated GC-FID. c Syn-anti isomerization.
of the aldoxime ether without any CA present is irradiated. Both
syn and anti isomers of the aldoxime ethers can be detected
and quantified by GC-FID.
The results of the steady-state photolysis experiments of
aldoxime ethers 1-4 are summarized in Table 2. Irradiation of
an argon purged MeCN solution containing chloranil and
O-methyl benzaldehyde oxime (1) resulted in the formation of
benzaldehyde (6) and benzonitrile (7) in moderate yield. The
aldehyde-nitrile ratio (6:7) is approximately 2. The main
product, however, is a result of syn-anti isomerization of the
starting material. Isomerization of oxime ethers upon triplet
sensitization is a well-known phenomenon and is a result of
energy transfer.17 If SET becomes endothermic and unfavorable,
the energy transfer pathway can be followed provided the triplet
energy of the aldoxime ether is low enough for triplet-triplet
energy transfer to take place, although nonvertical energy
transfer could also be responsible.17i,j From Table 1 it can be
seen that the free energy for SET (∆GET) is endothermic (+7.6
kcal/mol), suggesting that energy transfer is likely competitive
with SET, and therefore syn-anti isomerization is a dominant
reaction pathway.
FIGURE 3. Spectra obtained from NEQ-sensitized laser photolysis
(355 nm) of aldoxime ether 1 in MeCN. The spectra were taken 65 ns
(O), 200 ns (0), 450 ns (]), and 1 µs (4) after the laser pulse.
SCHEME 3
postulated mechanism for nucleophilic attack on the nitrogen
of the ketoxime ether radical cation,9c the lifetime differences
are best explained by a small steric effect. Similar results
were observed in a series of ketoxime ethers derived from
acetophenone,9c as well as in the reactions of other radical cation
species with nucleophiles.16 The results of these LFP studies
show that upon laser photolysis of a mixture containing CA
and an aldoxime ether, SET occurs resulting in the formation
of the aldoxime ether radical cation. In the presence of a
nucleophilic solvent, the radical ions are short-lived because of
follow-up reactions.
Similar results were obtained for the irradiation of O-ethyl
benzaldehyde oxime (2). Both benzaldehyde and benzonitrile
are formed; the aldehyde-nitrile ratio is higher than for
aldoxime ether 1. Again, a significant amount of isomerization
was observed, which is in agreement with the calculated free
energy of electron transfer.
The CA-sensitized photolysis of O-benzyl benzaldehyde
oxime (3) in MeCN results in the formation of benzaldehyde
(6) and benzonitrile (7) as the major products (Table 2). The
ratio of aldehyde-nitrile is higher than in the case of aldoxime
ethers 1 and 2. Isomerization of the starting material remains
the major pathway, in agreement with the calculated energetics.
The irradiation of O-tert-butyl benzaldehyde oxime (4) gave
different results (Table 2). The reaction is slower compared to
those of aldoxime ethers 1-3; however, no isomerization is
observed. On the basis of the energetics, this reaction is the
most favorable of all four aldoxime ethers, which may (in part)
explain the absence of syn-anti isomerization. The major
B. Steady-State Photolysis of Aldoxime Ethers in the
Presence of Chloranil. In general, irradiations were carried out
for 2 h on argon-purged (15 min) acetonitrile or methanol
solutions (5 mL) containing the aldoxime ether (0.015 M) and
chloranil (CA; 0.015 M) in Pyrex tubes using a Rayonet
photochemical reactor equipped with 16 RPR-3500A bulbs.
UV-vis analysis of the mixtures with and without CA showed
that under the conditions of the reactions only CA absorbs the
incident light. The reactions were followed by gas chromatog-
raphy with flame ionization detection (GC-FID) or with mass
spectrometry (GC-MS). The major products formed in these
reactions are benzaldehyde (6) and benzonitrile (7) (Scheme
3). The reactions typically proceed cleanly although some
secondary products were detected by GC-FID or GC-MS. No
conversion of the starting material is observed when a solution
(17) (a) Padwa, A.; Albrecht, F. J. Am. Chem. Soc. 1972, 94, 1000. (b)
Padwa, A.; Albrecht, F. J. Am. Chem. Soc. 1974, 96, 4849. (c) Padwa, A.;
Albrecht, F. J. Org. Chem. 1974, 39, 2361. (d) Padwa, A. Chem. ReV. 1977,
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Tetrahedron 1980, 36, 1779. (f) Takeda, Y.; Misawa, H.; Sakuragi, H.;
Tokumaru, K. Bull. Chem. Soc. Jpn. 1989, 62, 2213. (g) Furuuchi, H.; Arai,
T.; Sakuragi, H.; Tokumaru, K. J. Phys. Chem. 1991, 95, 10322. (h) Arai,
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597. (i) Laleve´e, J.; Allonas, X.; Loue¨rat, F.; Fouassier, J. P.; Tachi, H.;
Izumitani, A.; Shirai, M.; Tsunooka, M. Phys. Chem. Chem. Phys. 2001,
3, 2721. (j) Laleve´e, J.; Allonas, X.; Loue¨rat, F.; Fouassier, J. P. J. Phys.
Chem. A 2002, 106, 6702.
(16) (a) Dinnocenzo, J. P.; Todd, W. P.; Simpson, T. R.; Gould, I. R. J.
Am. Chem. Soc. 1990, 112, 2462. (b) Dinnocenzo, J. P.; Lieberman, D. R.;
Simpson, T. R. J. Am. Chem. Soc. 1993, 115, 366. (c) Dinnocenzo, J. P.;
Simpson, T. R.; Zuilhof, H.; Todd, W. P.; Heinrich, T. J. Am. Chem. Soc.
1997, 119, 987. (d) Dockery, K. P.; Dinnocenzo, J. P.; Farid, S.; Goodman,
J. L.; Gould, I. R.; Todd, W. P. J. Am. Chem. Soc. 1997, 119, 1876. (e) de
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2001, 123, 9698.
J. Org. Chem, Vol. 72, No. 11, 2007 4129

de Lijser et al.
SCHEME 4
TABLE 3. Summary of the Results from the Photosensitized
these products is shown in Scheme 5A. Nucleophilic attack on
the oxime radical cation proceeds via addition of MeOH to
nitrogen followed by a nucleophile (MeOH)-assisted1,3-proton
transfer and elimination of an alcohol.9c An alternative mech-
anism involving hydrogen atom abstraction (by 3CA) followed
by â-scission (Scheme 5B) can be ruled out because it would
also yield benzonitrile (7), which is not observed under these
conditions.
Reactions of Aldoxime Ethers 1-4 with CA in MeOH
product yieldsb
aldoxime
ether
%Ca
6
7
8
9
1
2
3
4
11
25
38
4
6
3
5
6
-
-
-
-
94
97
98
93
-
-
97
-
a Conversion was calculated on the basis of the GC-FID peak area of
the aldoxime ether before and after photolysis. b Product yields determined
by calibrated GC-FID.
The reactivity of aldoxime ether 4 in MeCN does not follow
that of aldoxime ethers 1-3 because it does not have R-protons.
Although aldoxime ether 4 reacts slower than aldoxime ethers
1-3, it is not much slower than 3, suggesting that an alternative
pathway is available. Together with the observation that
formation of the nitrile is now the dominant pathway suggests
that these two facts are related. Previously it was observed that
O-tert-butyl acetophenone oxime reacted sluggishly upon pho-
tolysis in MeCN with CA as the sensitizer.9c It was concluded
that because of the lack of R-hydrogens no viable reaction
pathway was available and therefore no reaction was observed.
The only difference between aldoxime ether 4 and O-tert-butyl
acetophenone oxime is the availability of the iminyl hydrogen
in 4. We have recently suggested that abstraction of the iminyl
hydrogen in benzaldehyde oximes may be responsible for the
formation of nitriles.9e The results presented here seem to
support that hypothesis. It must be noted that aldoxime ethers
1, 2, and 3 also produce a small amount of nitrile, suggesting
that a similar pathway is available in these aldoxime ethers.
However, benzonitrile (7) is only a minor product in those
reactions, and therefore the pathway to the nitrile is clearly not
favored. Nevertheless, in the following discussion we will
include all possible pathways for aldoxime ethers, including
those with available R-hydrogens.
product from the reaction is benzonitrile (7). A small amount
of benzaldehyde is formed as well but the aldehyde-nitrile ratio
is now only 0.04.
The presence of a nucleophile on the reaction was tested by
carrying out the photolysis of 1-4 in methanol as the solvent
(Scheme 4).
The results are listed in Table 3. Irradiation of 1 and CA in
MeOH for 2 h results in the formation of benzaldehyde dimethyl
acetal (8) as the major product and a small amount of
benzaldehyde (6). No benzonitrile (7) was detected under these
conditions and no syn-anti isomerization is observed. We have
reported earlier on the photosensitized acetalization of aldehydes
and ketones; under the conditions of the reaction, aldehydes
(and ketones) react to form the dimethyl acetals in almost
quantitative yield.18 Hence, it is fair to assume that the initial
(and major) product in these reactions is benzaldehyde.
Similar results were obtained for aldoxime ethers 2 and 4.
The reaction of 3 in MeOH yields equal amounts of benzalde-
hyde (in the form of the acetal) and benzyl alcohol (9). Separate
experiments have shown that irradiation of a solution of CA
and benzaldehyde in methanol does not yield any benzyl alcohol.
The formation of benzyl alcohol is best explained by a
nucleophilic attack-proton transfer-elimination sequence simi-
lar to that proposed for O-alkyl acetophenone oximes.9c Similar
reactions are proposed to occur for aldoxime ethers 1, 2, and 4;
however, the corresponding alcohols (MeOH, EtOH, and
t-BuOH) cannot be detected due to their volatility.
In principle there are three different pathways that can lead
to the imidoyl radical. Following the proposed mechanism as
shown in Scheme 2, electron transfer and deprotonation at the
R-carbon yields the R-radical. Intramolecular hydrogen atom
transfer (HAT) would yield the imidoyl radical, which can react
to give the observed nitrile and benzyloxy radical (Scheme 6;
path A). In addition it would be possible to form the imidoyl
3
radical via a direct HAT mechanism using CA (path B). The
third possibility would involve removal of the iminyl proton
from the aldoxime ether radical cation (path C).
C. Mechanistic Interpretation of the Steady-State and
Laser Flash Photolysis Data. The laser flash photolysis data
shown for aldoxime ethers 1-4 is consistent with an initial SET
step. On the basis of the similarities between the previously
studied reactions of O-alkyl acetophenone oximes and those of
O-alkyl benzaldehyde oximes 1-4 in acetonitrile, the formation
of benzaldehyde is concluded to be a result of an electron
transfer-deprotonation-â-scission mechanism (Scheme 2; R′
) H). This mechanism is the main pathway for aldoxime ethers
1, 2, and 3 (ignoring the isomerization pathway). In MeOH the
mechanism changes; the main products are now benzaldehyde
dimethyl acetal (formed from benzaldehyde) and benzyl alcohol
(in the case of 3). The proposed mechanism for formation of
Of the three potential pathways, path C seems the least likely
despite the fact that the spectrum of the radical cation was
observed in the LFP experiments discussed above. Previously
we have also observed the spectrum of the radical cation of
O-tert-butylacetophenone oxime; however, steady-state experi-
ments did not show any significant conversion or product
formation over time. This suggests that electron-transfer may
be favorable (energetically); however, if there is no convenient
reaction pathway available, no reaction (other than return
electron-transfer) will occur. There are several other observations
that support this conclusion. First, the change in product
distribution in a series of substituted benzaldoximes was directly
related to the substituent on the aromatic ring.9e An increase in
(18) de Lijser, H. J. P.; Rangel, N. A. J. Org. Chem. 2004, 69, 8315.
4130 J. Org. Chem., Vol. 72, No. 11, 2007

Photosensitized Reactions of Aldoxime Ethers
SCHEME 5
SCHEME 6
nitrile was observed for aldoximes bearing electron-withdrawing
substituents. It was suggested that the presence of the electron-
withdrawing group increased the oxidation potential of the
aldoxime and therefore made SET less favorable. Under those
conditions, the mechanism is believed to switch from SET to
HAT. Second, calculations on the aldoximes and aldoxime
ethers have shown that there is no significant charge develop-
ment on the iminyl hydrogen. In the aldoximes, the most acidic
proton is the hydroxyl proton, whereas in aldoxime ethers the
charges on most hydrogens in the entire molecule are very
similar. A summary of the calculated (B3LYP/6-31G*) charge
densities in aldoxime ethers 3 and 4 is listed in Table 4. At this
point we conclude that the data are not consistent with pathway
C.
The fact that aldoxime ether 4 does not have R-hydrogens
available rules out pathway A. However, that same pathway
cannot be ruled out a priori for aldoxime ethers 1-3. To
distinguish between pathways A and B, we have prepared and
studied the reactivity of O-benzyl p-methoxybenzaldehyde-d
oxime (10). In the case of pathway A (Scheme 7; clockwise
starting from 10), intramolecular HAT should eventually yield
both benzaldehyde-d (6-d) and benzaldehyde-h (6), whereas
pathway B (Scheme 7; counterclockwise starting from 10)
should only yield benzaldehyde-h (6) (Scheme 7).
A solution of aldoxime ether 10 and CA in MeCN was
irradiated, and the reaction mixture was analyzed by GC-MS.
Because 6 and 6-d are eluted simultaneously, the data were
analyzed in terms of relative abundance of specific ions observed
in the mass spectrum. To interpret the results, a number of
standard solutions containing varying amounts of 6 and 6-d were
prepared and analyzed, and the ion abundances of the ions of
interest were determined. The relative abundance data obtained
from the reaction mixture was then compared to the data
obtained from the standard solutions (Table 5). It can be seen
TABLE 4. Calculated (B3LYP/6-31G*) Charge Densities on
Hydrogen Atoms in Aldoxime Ethers 3 and 4. Both Mulliken and
Natural Population Charges Are Listed
3
4
atom
Mulliken
natural
Mulliken
natural
H1
H2
H3
H4
H5
H6
H7
H8
0.215519
0.194302
0.202221
0.200590
0.208103
0.206895
0.206577
0.206554
0.151936
0.168279
0.169945
0.168207
0.151884
-
0.249024
0.263480
0.273752
0.273299
0.268694
0.273467
0.255450
0.255404
0.243995
0.255332
0.256348
0.255342
0.243926
-
0.214745
0.196442
0.204431
0.210363
0.202140
0.205603
0.181026
0.181024
0.190785
0.192886
0.178111
0.179496
0.179506
0.192890
0.178102
0.248742
0.264305
0.275015
0.269727
0.274127
0.272287
0.255813
0.255811
0.265622
0.268011
0.253194
0.254203
0.254208
0.268009
0.253186
H9
H10
H11
H12
H13
H14
H15
-
-
that the data from the reaction mixture most closely resembles
that of the standard solution containing only 6, suggesting that
under these conditions, 6-d is not formed. This, in turn,
implicates that the intramolecular HAT pathway is negligible.
The formation of benzonitrile from aldoxime ethers most likely
proceeds via an imidoyl radical, which is formed via a direct
hydrogen atom abstraction process by 3CA. It must be reiterated
that loss of an iminyl proton from the radical cation would give
J. Org. Chem, Vol. 72, No. 11, 2007 4131

de Lijser et al.
SCHEME 7
TABLE 5. Results from Experiments with Deuterated Aldoxime Ether 10
mass
ratios
%D
105
106
107
108
105:106
105:107
0
249.2
41.9
32.3
25.6
33.3
39.0
11.9
265.7
33.2
22.4
15.1
23.6
30.6
1.2
20.4
13.7
13.0
12.6
13.7
14.3
12.4
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.9
1.3
1.4
1.7
1.4
1.3
9.8
12.2
3.1
2.5
2.0
2.4
2.7
1.0
20
33
50
66
80
100
reaction 1
reaction 2
318.6
328.1
342.1
357.4
25.4
27.2
1.0
1.0
0.9
0.9
12.5
12.1
a The mass spectra of solutions with varying amounts of benzaldehyde (6) and benzaldehyde-d (6-d) were analyzed. Masses 105 and 106 occur predominantly
in 6 whereas masses 107 and 108 are associated with 6-d. All data is relative to mass 108. For simplicity, the data was also analyzed in terms of the ratios
105:106 and 105:107. The data from the irradiated sample (listed at the Bottom) was compared to that of the stock solutions. The reaction was carried out
twice.
SCHEME 8
a similar result; however, based on our earlier discussion, we
do not favor that particular pathway.
are available) is the aldehyde. On the basis of available BDE
values, this is not an expected outcome. Previously we have
suggested that the BDE for the iminyl C-H bond is ap-
proximately the same as the C-H bond in benzaldehyde
(88 kcal mol-1).9e Bordwell has suggested a BDE of 94.9 kcal
mol-1 for the R-C-H bond in benzamidoxime O-methyl
ether.14a On the basis of these numbers, we would expect
hydrogen abstraction from the iminyl carbon to be the dominant
pathway and the major product should be the nitrile. However,
it must be pointed out that the accuracy of Bordwell’s methods
for determining BDE values has recently been disputed,19 and
the actual number may be different.20 On the basis of the results
obtained so far, we currently favor the SET mechanism for the
Finally, it must be noted that a HAT pathway could also
3
explain the formation of the aldehyde. Reaction of CA at the
R-C-H position with aldoxime ether 1, 2, or 3 would produce
the R-radical species, which can undergo a â-scission to
eventually yield benzaldehyde (Scheme 8).
An argument in favor of this mechanism would be the
observation that the major pathway for most aldoxime ethers
under these conditions is syn-anti isomerization, which suggests
that energy transfer rather than SET is dominant. On the other
hand, two arguments can be made against this mechanism. The
first argument would be the observation of the spectra of the
aldoxime ether radical cations suggesting an initial SET step.
The second argument would involve bond dissociation energies
(BDE). The major product in each case (provided R-hydrogens
(19) Pratt, D. A.; Blake, J. A.; Mulder, P.; Walton, J. C.; Korth, H.-G.;
Ingold, K. U. J. Am. Chem. Soc. 2004, 126, 10667.
4132 J. Org. Chem., Vol. 72, No. 11, 2007

Photosensitized Reactions of Aldoxime Ethers
1H NMR (CDCl3): δ 8.06 (1 H, s), 7.57 (2 H, m), 7.36 (3 H, m),
formation of the aldehyde product and the HAT pathway for
the formation of the nitrile. However, we continue to explore
the â-scission pathways of these and other reactive intermedi-
ates.
3.97 (3 H, s).
O-Ethyl Benzaldehyde Oxime (2). Prepared according to the
method described above using O-ethylhydroxyl amine hydrochloride
(2.02 g, 21 mmol) and benzaldehyde (2.00 g, 19 mmol). Yield:
1
1.60 g, 57% (colorless oil). H NMR (CDCl3): δ 8.07 (1 H, s),
Conclusions
7.58 (2 H, m), 7.35 (3 H, m), 4.24 (2 H, q, J ) 7.1 Hz), 1.34 (3 H,
t, J ) 7.1 Hz).
Chloranil-sensitized photooxidation of aldoxime ethers in
acetonitrile results in the formation of aldoxime ether radical
cations (and chloranil radical anion). Follow-up reactions may
involve deprotonation at the R-position, yielding a radical
species that undergoes â-scission. The major product under these
conditions is benzaldehyde (6), but a small amount of benzoni-
trile (7) is also formed. In the absence of R-hydrogens (i.e.,
aldoxime ether 4), the major product is benzonitrile (7), which
is produced via a different pathway. Although SET is favorable,
it does not lead to products. Instead, the triplet sensitizer
abstracts the iminyl hydrogen to yield an imidoyl radical, which
undergoes a â-scission to yield a nitrile. A similar pathway is
most likely responsible for the formation of benzonitrile from
aldoxime ethers that do have R-hydrogens; however, for those
substrates it is only a minor pathway. A third pathway that was
observed involves energy transfer, which leads to syn-anti
isomerization. This pathway is observed when the free energy
for electron transfer (∆GET) becomes endothermic but usually
competes with ET (as seen by the presence of both isomerization
and oxidation products). In nucleophilic solvents such as
methanol, the major photooxidation product is benzaldehyde.
No nitrile is observed, which is explained by a mechanistic
scheme involving nucleophilic attack on the nitrogen of the
aldoxime ether radical cation, followed by proton-transfer and
elimination as was observed for a series of acetophenone oxime
ethers.
O-Benzyl Benzaldehyde Oxime (3). Prepared according to the
method described above using O-benzylhydroxylamine hydrochlo-
ride (2.22 g, 14 mmol) and benzaldehyde (2.21 g, 21 mmol).
Yield: 1.11 g, 58% (colorless oil). H NMR (CDCl3): δ 8.15
(1 H, s), 7.59-7.25 (10 H, m), 5.20 (2 H, s).
1
O-tert-Butyl Benzaldehyde Oxime (4). Prepared according to
the method described above using O-tert-butylhydroxylamine
hydrochloride (1.01 g, 9 mmol) and benzaldehyde (1.01 g, 9 mmol).
1
Yield: 1.58 g, 91% (colorless oil). H NMR (CDCl3): δ 8.04
(1 H, s), 7.61-7.55 (2 H, m), 7.36-7.31 (3 H, m), 1.36 (9H, s).
O-Benzyl 4-Methoxybenzaldehyde-R-d Oxime (10). Prepared
according to the method described above using O-benzylhydroxy-
lamine hydrochloride (1.00 g, 14 mmol) and 4-methoxybenzalde-
hyde-R-d (0.51 g, 21 mmol). Yield: 0.45 g, 50% (white powder),
mp ) 42-44 °C. 1H NMR (CDCl3): δ 7.56 (2 H, d, J ) 8.8 Hz),
7.47-7.32 (5 H, m), 6.92 (2 H, d, J ) 8.8 Hz), 5.22 (2 H, s), 3.85
(3 H, s).
Steady-State Photolysis Experiments. Appropriate amounts of
the O-alkyl benzaldehyde oxime (0.015 M) and chloranil
(0.015 M) were weighed out and dissolved in 5 mL of solvent. For
experiments where oxygen was to be excluded, and the solution
was purged with argon for 15 min prior to photolysis. The solution
was placed in a Pyrex tube and irradiated in a Rayonet RPR-100
photochemical reactor, equipped with 16 RPR-3500A (black light
phosphor) bulbs (λ ) 350 nm) for 2 h. The progress of the reactions
was followed by GC-FID, and the products were identified by GC-
MS. Conversion of the starting material and product yields were
determined by calibrated GC-FID. The products were confirmed
by comparison with authentic (commercially available) samples.
Experimental Section
Electrochemistry. The oxidation potentials of the aldoxime
ethers were determined by cyclic voltammetry at a scan rate of
100 mV/s in MeCN with tetraethyl ammonium perchlorate
(0.1 M) as the electrolyte using a Ag/AgCl reference electrode.
The reported potentials were referenced to SCE by adding 0.29 V
to the measured values. All measurements were carried out under
an argon atmosphere.
Materials. All chemicals other than the aldoxime ethers were
commercially available. The aldoxime ethers were prepared from
benzaldehyde and commercially available O-alkylhydroxylamine
hydrochloride salts (see below). Acetonitrile and methanol (spec-
trophotometric grade) were used as received.
Synthesis of O-Alkyl Benzaldehyde Oximes. All benzaldehyde
oxime ethers were prepared according to literature procedures with
minor modifications.21 The aldoxime ethers were chromatographed
on silica gel and were analyzed for purity by gas chromatography
with flame ionization detection (GC-FID; >99% peak area); their
Laser Flash Photolysis. The apparatus used for the laser flash
photolysis (LFP) experiments was of standard design,22 and the
details have been described elsewhere.23 The quenching rates were
obtained as follows. An MeCN (spectrophotometric grade) solution
containing chloranil (CA; OD ∼ 0.5-1) in a glass cuvette was
purged with argon for about 5 min. The sample was subjected to
the laser pulse (355 nm, 10 Hz, 0.5-2 mJ/pulse; 4 ns pulse width),
1
identity was verified by mass spectrometry and H NMR.
O-Methyl Benzaldehyde Oxime (1). To a mixture containing
methoxylamine hydrochloride (1.01 g, 12 mmol) and benzaldehyde
(1.01 g, 10 mmol) in 50 mL of 95% ethanol was added several
drops of concentrated hydrochloric acid after which it was refluxed
for 2-6 h. Evaporation of the solvent under reduced pressure
produced an oily yellow residue. Purification by column chroma-
tography (hexane-ether gradient) gave a colorless oil (0.91 g, 71%).
3
and the decay of CA at 510 nm was observed. Small amounts
(10-25 uL) of the quencher (∼0.015 M aldoxime ether standard
solutions in MeCN) were added to the solution after which the decay
was measured. The quenching rate was obtained from a plot of the
measured decay rates against the quencher concentration. A similar
methodology was used to obtain the rates for the reaction of MeOH
with the aldoxime ether radical cations. A solution containing the
aldoxime ether (10 mM) and chloranil (OD ∼ 0.5-1) was subjected
to the laser pulse, and the decay of the radical cation at 650 nm
was observed. Small amounts (25-100 µL) of MeOH were added
to the solution after which the decay was measured. The quenching
(20) Recent experiments in our laboratory suggest that the iminyl C-H
bond is indeed weaker than the R-C-H bond. Chlorination of O-alkyl
benzaldehyde oximes with N-chlorosuccinimide proceeds selectively and
results in the formation of the corresponding N-alkoxy iminoyl chlorides;
no chlorination at the R-carbon is observed.
(21) (a) Corey, E. J.; Petrzilka, M.; Ueda, Y. HelV. Chim. Acta 1977,
60, 2294. (b) Ensley, H. E.; Lohr, R. Tetrahedron Lett. 1978, 19, 1415. (c)
Keck, G. E.; Wager, T. T.; McHardy, S. F. Tetrahedron 1999, 55, 11755.
(d) Geno, M. J. K.; Dawson, J. H. Inorg. Chem. 1984, 23, 509. (e)
McCarroll, A. J.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2 2000, 1868.
(f) Di Gioia, M. L.; Leggio, A.; Le Pera, A.; Liguori, A.; Siciliano, C. J.
Org. Chem. 2005, 70, 10494.
(22) Herkstroeter, W. G.; Gould, I. R. in: Physical Methods of Chemistry
Series, 2nd ed.; Rossiter, B.; Baetzold, R. Eds.; Wiley: New York, 1993;
Vol. 8, p 225.
(23) Lorance, E. D.; Kramer, W. H.; Gould, I. R. J. Am. Chem. Soc.
2002, 124, 15225.
J. Org. Chem, Vol. 72, No. 11, 2007 4133

de Lijser et al.
rate was obtained from a plot of the measured decay rates against
the MeOH concentration.
Acknowledgment. Acknowledgment is made to the donors
of the Petroleum Research Fund, administered by the American
Chemical Society, for support of this work. Part of this work
was supported by the National Science Foundation under Grant
Nos. 0354159 and 0521665. We are grateful to Professor I. R.
Gould (Arizona State University) for the generous use of his
laser flash photolysis equipment and for stimulating discussions.
We thank Ms. Jennie Kittipha and Ms. Jennifer Cuvin (Cali-
fornia State University, Fullerton) for their help with the
preparation and reactivity studies of the deuterated aldoxime
ether, and Ms. Zofia Wosinska (Arizona State University) for
her help with the laser flash photolysis experiments using NEQ.
Spectra were obtained by flash photolysis (355 nm, 10 Hz, 0.5-2
mJ/pulse; 4 ns pulse width) of argon-saturated solutions (3 mL) in
a glass cuvette containing the aldoxime (10 mM) and chloranil
(OD ∼ 0.5-1).
Computational Methods. Semiempirical (AM1)24 and DFT
(B3LYP)25 calculations were performed with Spartan 2004,26
installed on a PowerMac G4. For the DFT calculations, the 6-31G*
basis set27 implemented within the program was used.
(24) Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J.
Am. Chem. Soc. 1985, 107, 3902.
(25) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Stephens, P.
J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994,
98, 11623.
(26) Spartan ‘04, Wavefunction, Inc., Irvine CA.
(27) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; John Wiley and Sons: New York, 1986.
Supporting Information Available: Total energies and Car-
tesian coordinates for the optimized structures of the radical cations
of compounds 3 and 4. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0703707
4134 J. Org. Chem., Vol. 72, No. 11, 2007