Dissociation or cyclization: Options for a triad of radicals released from oxime carbamates

Article abstract of DOI:10.1021/ja402833w

A set of oxime carbamates having N-alkyl and N,N-dialkyl substituents were prepared via carbonyldiimidazole intermediates. It was shown by EPR spectroscopy that they underwent clean homolysis of their N-O bonds upon UV photolysis. During photolysis of acetophenone O-allylcarbamoyl oxime, the corresponding oxazolidin-2-onylmethyl radical was detected by EPR spectroscopy, providing the first evidence that N-monosubstituted carbamoyloxyl radicals can hold their structural integrity. N,N-Disubstituted carbamoyloxyl radicals dissociated rapidly at the lowest accessible temperatures. Above room temperature, both types of oxime carbamate acted as selective new precursors for aminyl and iminyl radicals. Rate parameters were measured for 5-exo cyclization of N-benzyl-N-pent-4-enylaminyl radicals; the rate constant was smaller than for C-centered and O-centered analogues. Oxime carbamates derived from the volatile diethylamine afforded aryliminyl radicals that proved convenient for phenanthridine preparations.

Full text of DOI:10.1021/ja402833w

Article
pubs.acs.org/JACS
Dissociation or Cyclization: Options for a Triad of Radicals Released
from Oxime Carbamates
Roy T. McBurney*,† and John C. Walton*
EaStCHEM School of Chemistry, University of St. Andrews, St. Andrews, Fife KY16 9ST, U.K.
S
* Supporting Information
ABSTRACT: A set of oxime carbamates having N-alkyl and N,N-
dialkyl substituents were prepared via carbonyldiimidazole intermedi-
ates. It was shown by EPR spectroscopy that they underwent clean
homolysis of their N−O bonds upon UV photolysis. During
photolysis of acetophenone O-allylcarbamoyl oxime, the correspond-
ing oxazolidin-2-onylmethyl radical was detected by EPR spectrosco-
py, providing the first evidence that N-monosubstituted carbamoyloxyl
radicals can hold their structural integrity. N,N-Disubstituted
carbamoyloxyl radicals dissociated rapidly at the lowest accessible
temperatures. Above room temperature, both types of oxime
carbamate acted as selective new precursors for aminyl and iminyl radicals. Rate parameters were measured for 5-exo
cyclization of N-benzyl-N-pent-4-enylaminyl radicals; the rate constant was smaller than for C-centered and O-centered
analogues. Oxime carbamates derived from the volatile diethylamine afforded aryliminyl radicals that proved convenient for
phenanthridine preparations.
prototypical carbamoyloxyls. We also prepared a set of model
oxime carbamates (see Scheme 1) and investigated the radicals
released by each upon photolysis. In this article, we show that
by an appropriate choice of substituents the rare carbamoyloxyl
radicals could indeed be generated. They were cleanly
transformed to aminyl radicals at higher temperatures, thus
providing a new and promising source of these intermediates.
Information about the cyclization behavior of both carbamoy-
loxyl and aminyl radicals was obtained. Furthermore, with a
different substitution pattern, oxime carbamates could be
adapted for release of iminyl radicals and hence for subsequent
preparations of N-heterocycles.
INTRODUCTION
■
Oxime carbamates (O-carbamoyl oximes) have been known for
a considerable time for their antimicrobial activity1 and as
inhibitors of various enzymes.2 End-product analyses of
complex mixtures obtained from photolyses of a few carbamate
pesticides were reported,3 but the notion of oxime carbamates
as selective radical precursors had not been tested. We recently
discovered that oxime carbonates efficiently dissociate upon
photolysis to generate iminyl and alkoxycarbonyloxyl radicals.
These oxime derivatives proved to be valuable precursors for
clean syntheses of several types of heterocycles.4 In view of the
structural similarity of oxime carbamates [ArC(R1)N−
OC(O)NR2R3], we conjectured that their N−O bonds would
also break upon photolysis. In this way, access to iminyl radicals
and the much more exotic carbamoyloxyl radicals might be
gained. The latter radicals were essentially unknown. Ingold
and co-workers’ attempts to observe them by laser flash
photolysis of tert-butyl percarbamates [RR′NC(O)OOBu-t]
disclosed only aminyls (RR′N•),5 as did Newcomb’s study of
N-hydroxypyridine-2-thione carbamates.6 No other reports of
carbamoyloxyl radicals have appeared. They were expected to
dissociate rapidly to CO2 and aminyl radicals, so there were
question marks concerning their structural integrity.
RESULTS AND DISCUSSION
■
DFT Computations on Carbamoyloxyl and Related
Radicals. Would carbamoyloxyl radicals be too fragile to take
part in chemical reactions or to be observed spectroscopically?
To obtain theoretical insight into how the rate of CO2 loss
responded to carbamoyloxyl structure, we carried out DFT
computations7 on the model radicals shown in Table 1.
Previous calculations on the structurally related alkoxycarbo-
nyloxyl radicals4c had shown that for these species the B3PW91
functional8 and the M06-2X hybrid metafunctional9 gave
energies seriously at odds with experiment. Similarly, second-
order Møller−Plesset perturbation theory (MP2) with the 6-
311+G(2d,p) basis set delivered activation energies that greatly
exceeded experiment. The best results were obtained using the
B3LYP functional. For our study of carbamoyloxyls, we
Suitable tuning of the oxime carbamate structure might
enable individual members of this triad of radicals (iminyl,
carbamoyloxyl, aminyl) to be highlighted and examined. A
distinct advantage of oxime carbamate precursors would be the
opportunity to search for evidence of carbamoyloxyl radicals at
much lower temperatures using electron paramagnetic
resonance (EPR) spectroscopy. We carried out an exploratory
density functional theory (DFT) study of the reactivity of
Received: March 20, 2013
Published: April 21, 2013
© 2013 American Chemical Society
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Table 1. DFT-Computed Activation Energies (ΔE⧧298),
Reaction Enthalpies (ΔH298), and Reaction Free Energies
To put these conclusions to the test, we prepared a set of
model oxime carbamates (Scheme 1).
a
•
Preparation of Oxime Carbamates. Previous prepara-
tions of oxime carbamates have involved treatment of oximes
with either phosgene and then an amine or with an
isocyanate.13,14 Some organic carbamates have been made via
carbonyldiimidazole (CDI) derivatives of alcohols.5,15 We used
this reagent successfully in preparations of oxime carbonates.4
Laboratory use of phosgene can be avoided by using CDI, so
we tried the analogous route to oxime carbamates 2 via
intermediates 1 (Scheme 1). Although the method succeeded
(ΔG298) for CO2 Loss from Z−CO2 Radicals at 298 K
b
radical
method
ΔE⧧298
ΔH298
ΔG298
E⧧expt
•
Et2N−CO2
A
B
A
B
A
B
A
B
A
B
1.3
0.7
−8.8
−5.5
−5.5
−4.7
−1.2
−3.5
−7.8
−3.9
−16.5
−14.6
−20.2
−16.8
−15.6
−14.7
−9.5
−12.1
−18.9
−13.8
−28.6
−24.8
−
•
EtNH−CO2
6.5
−
−
7.4
•
NH2−CO2
11.6
11.8
11.5
16.1
c
•
EtO−CO2
∼13
Scheme 1. CDI-Mediated Preparations of Oxime
Carbamates
d
e
•
Et−CO2
[0.4]
∼1.7
d
−
a
b
Energies in kcal mol−1 are reported. Method A: UB3LYP/cc-pvtz
level including corrections to 298 K. Method B: CBS-QB3 level.
c
d
Value for primary RCH2OC(O)O• radicals (see ref 4b). A well-
defined transition state was not found with the cc-pvtz basis set or at
the CBS-QB3 level. A ΔE⧧298 value of 0.44 kcal mol−1 was obtained for
e
a transition state located with the 6-31G(d) basis set. See ref 12.
therefore employed the standard UB3LYP functional with the
correlation-consistent polarized triple-ζ cc-pvtz basis set
(method A),10 and we also employed the CBS-QB3 level of
theory (method B).11
Although the magnitudes of the values differ somewhat
depending on the computational level, two remarkable trends
can be clearly discerned. First, for the carbamoyloxyl radicals,
the ΔE⧧298 barriers increased strongly and the reactions became
less exothermic as the number of H atoms attached to nitrogen
with both primary and secondary amines, the unoptimized
yields were rather variable. The carbamates from primary
amines were difficult to purify and degraded comparatively
quickly.
EPR Spectroscopic Study of Oxime Carbamate
Photolysis. The photolytic reactions of oxime carbamates
2a−g were first investigated in solution by 9 GHz EPR
spectroscopy. Deaerated samples of each oxime carbamate, plus
1 equiv of 4-methoxyacetophenone (MAP) as a photo-
sensitizer, in t-BuPh or cyclopropane solvent were irradiated
with unfiltered UV light from a medium-pressure Hg lamp
directly in the spectrometer resonant cavity. The spectrum
obtained with diallyl precursor 2f (Figure 2a) revealed the
iminyl radical PhCMeN• (Im) together with a second radical
•
increased. Second, for the series Z−CO2 , the barriers increased
significantly as the leading atom of Z moved across the first row
of the periodic table from Z = Et to EtHN to EtO. The
computed structures and singly occupied molecular orbitals
•
(SOMOs) (Figure 1) showed that the SOMO of EtCO2 is
•
Figure 1. DFT-computed SOMOs of Z−CO2 radicals.
•
confined mainly to the CO2 unit, whereas the EtNHCO2 and
EtOCO2• radicals are alike in that their SOMOs are delocalized
to the adjacent heteroatoms and to the alkyl substituents. This
•
was a hint that monoalkyl EtNHCO2 radicals might behave
•
like EtOCO2 radicals in losing CO2 comparatively slowly,
•
rather than extruding CO2 essentially instantly as RCH2CO2
radicals do.
12
•
•
For RCO2 and ROCO2 , the computed barriers were in
reasonable agreement with the experimental activation energies
(E⧧expt) (Table 1). This lent credibility to the predicted trends.
•
The computed intermediate properties of EtNHCO2 and its
substantial ΔE⧧298 suggested that monoalkyl-substituted carba-
moyloxyls would have finite lifetimes. This implied that adducts
or cycloadducts might be detectible at the low temperatures
accessible in EPR spectroscopy. On the other hand, the very
low ΔE⧧298, high exothemicity, and strongly negative ΔG298 for
Figure 2. EPR spectra from sensitized photolyses of oxime carbamates
(experimental spectra are shown in black and simulations in red): (a)
diallyl precursor 2f in t-BuPh at 210 K; (b) monoallyl precursor 2e in
cyclopropane at 155 K. [im = iminyl radical, io = iminoxyl radical, c =
cyclized radical 4e].
•
Et2NCO2 implied that photolyses of N,N-dialkyl oxime
carbamates would directly release dialkylaminyls (with iminyls)
in the temperature/time zone accessible to EPR spectroscopy.
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displaying a pentet of 1:1:1 triplets structure. These EPR
parameters were similar to literature data for (allyl)2N• radicals
(6f).16 The measured [6f]/[Im] concentration ratio was 0.92
0.1 at 210 K (see Figure 3a). The fact that this was close to 1.0
indicated that decarboxylation of 3f to give 6f (Scheme 2) must
be fast at 210 K.
The dibenzyl precursor 2d yielded EPR spectra of Bn2N•
(6d) and Im. Cyclohexadienyl radical 5d, which would have
resulted from spiro cyclization of 3d onto the phenyl ring, was
not detected. The [6d]/[Im] ratio was close to 1.0 over the
accessible temperature range (Figure 3a). It was therefore
evident that 3d dissociates very rapidly. We conclude that all of
the N,N-dialkyl precursors act as clean sources of aminyl and
iminyl radicals.
Scheme 2. Reaction Channels for Carbamoyloxyl Radicals
●
,
Figure 3. (a) Temperature dependence of [6]/[Im] ratios: blue
•
•
PeBnN• (6g); red , Bn2N (6d); green , (allyl)2N (6f). (b)
□
◇
Arrhenius plot of kc for 6g.
Precursor 2g with a pentenyl (Pe) chain was prepared for use
in examining aminyl radical cyclization. Upon photolysis at
temperatures in the range 210−260 K, the EPR spectrum
revealed a mixture of Im and a second radical having the
following EPR parameters: g = 2.0048, a(N) = 14.2 G, a(2H) =
35.4 G, and a(2H) = 36.9 G at 230 K. By comparison with data
for other dialkylaminyl radicals, this species was easily identified
as the disubstituted aminyl 6g (Scheme 3; also see the SI).
By analogy with alkoxycarbonyloxyl radicals, the carbamoy-
loxyl radical 3f derived from 2f was expected to undergo rapid
ring closure to give oxazolidin-2-onyl-methyl radical 4f.
However, 4f was not observed over the temperature range
160−270 K, which supports the conclusion that N,N-diallyl
radical 3f loses CO2 rapidly. The EPR spectra observed upon
photolysis of N,N-diethyl precursor 2c revealed that it too
yielded Im and Et2N• radicals throughout the accessible
temperature range [see the Supporting Information (SI)].
Thus, N,N-diethylcarbamoyloxyl radical 3c also dissociates
extremely rapidly.
Scheme 3. Ring Closure of Pentenyl-Substituted Aminyl 6g
The best spectrum obtained upon photolysis of the
monoallyl precursor 2e at 155 K (Figure 2b) showed Im and
some iminoxyl (io) impurity.17 At higher temperatures, only the
Im (and io) were visible (see the SI). Monoalkylaminyl radicals
RHN• are EPR-silent in solution,16 and therefore, the CO2 loss
reaction of 3e could not be monitored by observation of
(allyl)HN•. However, Figure 2b shows weak signals (c) that
were simulated with a radical having g = 2.0023, a(2Hα) = 22.0
G, and a(Hβ) = 8.5 G. These EPR parameters are close to those
of structurally similar 1,3-dioxolan-2-onylmethyl radicals,4 and
we attribute them to oxazolidin-2-onylmethyl radical 4e.
If this identification is correct, it is evidence that N-
monoalkyl-substituted carbamoyloxyls retain their structural
integrity at 155 K. Radical 4e was not observed in spectra at
higher temperatures, so dissociation evidently sets in at T ≳
170 K. An estimate of the activation energy for CO2 loss from
3e (E⧧d) was obtained from the empirical relationship for the
activation energies of β-scission reactions and EPR temperature
data.18 A midpoint temperature of 170 K yielded E⧧d ≈ 8 kcal
mol−1. This compares favorably with the DFT-computed ΔE⧧298
The ring-closed pyrrolidinylmethyl radical 7g was not
observed over the accessible temperature range up to 300 K.
However, as the temperature was increased, the [6g]/[Im]
ratio steadily decreased (Figure 3a), in contrast to the
essentially invariant [R2N•]/[Im] ratios obtained with the
dibenzyl (2d) and diallyl (2f) precursors, where the R2N•
products were not capable of cyclization. We interpret the
decreasing [6g]/[Im] ratio to result from the onset of 5-exo
ring closure of 6g.20 An estimate of the cyclization rate constant
(kc) for 6g could still be obtained because the Im radical acted
as a reference. Equimolar quantities of Im and 6g are formed
upon homolysis of 2g, and hence, [Im] = [6g] + [7g]. The
mechanism is shown in Scheme 3, including termination
processes for Im, 6g, and 7g radicals. With the steady-state
approximation, it can easily be shown that21
2[Im]2
[6g]
kc
2kt
=
− 2[Im]
(1)
•
values of 6.5 and 7.4 kcal mol−1 for EtNHCO2 (Table 1),
particularly when the known propensity of the B3LYP
functional to underestimate barrier heights19 is taken into
account. The other monoalkyl precursor 2b was poorly soluble
in cyclopropane, so only broad, ill-defined signals were
observed in this solvent. At T > 210 K in t-BuPh solvent,
only Im (and impurity io) could be detected.
under the assumption that all of the termination reactions are
diffusion-controlled (because all of the radicals are small) and
have the same rate constant, 2kt. Values of kc were derived from
eq 1 using radical concentrations determined from the EPR
spectra in the T > 210 K region. Under the assumption that the
termination reactions are diffusion-controlled, the well-
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established 2kt Arrhenius parameters for t-Bu• radicals derived
by Fischer22 [log At = 11.63 M−1 s−1, Et = 2.25 kcal mol−1],
corrected for solvent viscosity as described previously,23 could
be used for 2kt without introducing serious errors. A good
Arrhenius plot of kc was obtained (Figure 3b). The temperature
range was narrow and the data were scattered, so the log(Ac/
Scheme 4. Reactions of Biphenyl Oxime-Derived
Carbamates
s−1) value of 9.0
1.5 derived by linear regression is not
reliable. Most radical cyclizations have log(Ac/s−1) ≈ 10.5.24
For consistency in comparing our data with related kinetic
parameters, this value was assumed, leading to the following
expression for kc:
9.6 0.4
log(kc/s−1) = [10.5] −
(2)
θ
θ = 2.303RT/1000. This gives kc = 3 × 103 s−1 for 6g at 300 K,
which compares well25 with the values of 5 × 104 and 1 × 104
s−1 for 5-exo ring closures of N-butyl-N-pentenylaminyl and N-
butyl-N-(2-phenylcyclopropyl)pentenylaminyl, respectively, at
50 °C as reported by Newcomb and co-workers.26 Clearly,
N,N-dialkylaminyl radicals cyclize nearly 2 orders of magnitude
more slowly at 300 K than archetypal C-centered hex-5-enyl
radicals, for which kc = 2.5 × 105 s−1.27
a
b
Isolated yield. 1H NMR yield calculated using CH2Br2 as an internal
Preparative-scale photolyses of 2g in PhCF3 and PhMe
showed complex product mixtures. GC−MS analysis pointed to
the termination products Im2 and Im−NBnPe along with the
ring-closure products 1-benzyl-2-methylpyrrolidine and 1-
benzyl-2-methylenepyrrolidine; attempts to isolate these for
confirmation were not successful. The mechanism in Scheme 3
was supported, but as might be expected under the nonchain
conditions, cyclization competed poorly with terminations.
Iminyl Radical Cyclization and Phenanthridine Prep-
aration. Making the aminyl moiety small and volatile might
allow oxime carbamates to be adapted for selective production
of N-heterocycles derived from their iminyl portions. To test
this possibility, diethylaminyl carbamate 8a was prepared.
Indeed we found that 3-methoxy-6-methylphenanthridine (10)
was obtained in 60% yield from photolysis of 8a at room
temperature in benzotrifluoride with MAP as a photosensitizer.
The reaction also worked well (61%) in the absence of MAP,
which is a significant advance because the photosensitizer can
be difficult to remove during product purification. The
mechanism probably involves generation of iminyl radical
8Im, which cyclizes onto the adjacent aromatic ring to produce
cyclohexadienyl radical 9 (Scheme 4). Radical 9 readily
rearomatizes to 10 either by H-atom transfer to another radical
or by electron transfer with production of the corresponding
cyclohexadienyl cation and subsequent proton loss.28 In
support of this, iminyl radical 8Im was observed when 8a
was UV-irradiated in the EPR spectrometer. Not surprisingly,
the ring-closed radical 9 was not detected because cyclization
occurs at T > 300 K, where the spectra are weak.
standard.
Spectroscopic evidence was obtained for the formation of
oxazolidin-2-onylmethyl radical 4e at 155 K by cyclization of N-
allylcarbamoyloxyl radical 3e. N,N-Dialkylcarbamoyl radicals,
on the other hand, dissociated rapidly even at 155 K, yielding
dialkylaminyls. These observations confirmed our theoretical
prediction that the rates of decarboxylation of carbamoyloxyls
would increase as the number of N-alkyl substituents increased.
The experimental and computed activation energies for
dissociation of carbamoyloxyls, alkoxycarbonyloxyls,4,30 and
acyl radicals12 are compared in Figure 4.
Figure 4 shows a considerable degree of consonance between
theory and experiment. Also in agreement with theory, the rates
of CO2 loss from Z−C(O)O• radicals decrease as the leading
atom of Z changes from C to N to O. Of the ROC(O)O series,
the member having R = Ph dissociates most rapidly because of
the resonance stabilization of the phenoxyl radical. Of course,
An intriguing process took place during attempts to prepare
the analogous oxime carbamate 13 from N-benzylpent-4-en-1-
amine. When the CDI precursor 12 and oxime 11 were treated
with NaH in the standard way, instead of the expected 13,
phenanthridine 10 was isolated in 44% yield. The mechanism
probably does not involve radical intermediates. A sequence of
electrocyclic rearrangements of 13 can readily be envisaged.29
CONCLUSIONS
■
Oxime carbamates were shown reliably to dissociate photolyti-
cally by scission of their N−O bonds. The resulting iminyl
radicals were directly monitored by EPR spectroscopy.
Figure 4. Comparison of activation energies for CO2 loss from Z−
CO2• radicals. Horizontal dashed lines point to DFT-computed values;
hashed areas represent experimental data.
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•
the corresponding N-arylcarbamoyloxyl radicals (Ph2NCO2
complete ref 7 (as SI ref 3). This material is available free of
charge via the Internet at http://pubs.acs.org.
•
and PhHNCO2 ) are also expected to dissociate with great
rapidity, if they have any finite lifetime at all. The parent
carbamic acid radical (H2NCO2 ) was projected to lose CO2
•
AUTHOR INFORMATION
Corresponding Author
roy.mcburney@glasgow.ac.uk; jcw@st-and.ac.uk
■
comparatively slowly. Figure 4 indicates that this would occur at
about the same rate as for RCH2OC(O)O• radicals, which
•
dissociate slowly at room temperature. H2NCO2 dissociation
Present Address
would be rapid at higher temperatures. The literature contains
virtually no information about this radical apart from a study of
some protonated forms.31 However, carbamic acid itself is well-
known to be unstable above room temperature and to
†R.T.M.: University of Glasgow, Glasgow G12 8QQ, U.K.
Notes
The authors declare no competing financial interest.
•
dissociate to carbon dioxide and ammonia. H2NCO2 was not
ACKNOWLEDGMENTS
accessible via our oxime carbamate route to assess these points.
At T > 200 K, both N-alkyl- and N,N-dialkyloxime
carbamates were found to be new and effective precursors for
aminyl radicals. By this means we determined that pent-4-
enylaminyl radical 6g undergoes 5-exo cyclization compara-
tively slowly. The rate constants for 5-exo cyclization
[k5c‑exo(300 K)] for a set of model hex-5-enyl-type radicals
having N, C, and O centers, including 6g, 3e, hex-5-enyl,27 hex-
5-enoyl,32 allyloxycarbonyloxyl,4b and pent-4-enyloxyl,33 are
ranked in Figure 5. The rate constants span 5 orders of
■
We thank the EPSRC (Grant EP/I003479/1) and EaStCHEM
for funding, the EPSRC U.K. National Electron Paramagnetic
Resonance Service at the University of Manchester, and the
EPSRC National Mass Spectrometry Service in Swansea. We
are grateful to Dr. Herbert Fruchtl for help with the computing
and Annika Eisenschmidt for data collection.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, full spectroscopic data for new
compounds, sample EPR spectra and kinetic data, DFT-
computed ground-state and transition-state structures, and
■
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