Interconversion of nitrenes, azirenes, and diradicals: Rearrangement of 3-isoquinolylnitrene to o-cyanophenylketenimine and 1-cyanoisoindole

Article abstract of DOI:10.1021/jo802273y

Photolysis of tetrazolo[1,5-b]isoquinoline/3-azidoisoquinoline 22T/22A generates 3-isoquinolylnitrene 23, which has been characterized together with a diradical species (25) by Ar matrix ESR spectroscopy. Photolysis at λ > 300 nm generates azirene 24, characterized by IR spectroscopy, whereas further broadband UV photolysis destroys the azirene to produce o-cyanophenylketenimine 17. The use of ¹⁵N-labeled tetrazole/azide 22T′/22A′ demonstrates rapid equilibration of two regioisomeric ¹⁵N-labeled azirenes 24′ and 24″ prior to formation of 17. Flash vacuum thermolysis (FVT) of 22T/22A affords 1-cyano-2H-isoindole 27 in quantitative yield. FVT of ¹⁵N-labeled tetrazole/azide 22T′/22A′ causes scrambling of ¹⁵N label in the 1-cyano-2H-isoindole product. It is concluded that the interconversion of azirenes 24 takes place via the unobserved diazacycloheptatetraene/ diazacycloheptatrienylidene 32/33, and that the rearrangement of azirene to ketenimine 17 and 1-cyanoisoindole 27 takes place via reversion to nitrene 23 followed by ring opening to diradical 25.

Full text of DOI:10.1021/jo802273y

Interconversion of Nitrenes, Azirenes, and Diradicals:
Rearrangement of 3-Isoquinolylnitrene to o-Cyanophenylketenimine
and 1-Cyanoisoindole
Michael Vosswinkel, Holger Lu¨erssen, David Kvaskoff, and Curt Wentrup*
School of Chemistry and Molecular Biosciences, The UniVersity of Queensland,
Brisbane, Qld 4072, Australia
wentrup@uq.edu.au
ReceiVed October 10, 2008
Photolysis of tetrazolo[1,5-b]isoquinoline/3-azidoisoquinoline 22T/22A generates 3-isoquinolylnitrene
23, which has been characterized together with a diradical species (25) by Ar matrix ESR spectroscopy.
Photolysis at λ > 300 nm generates azirene 24, characterized by IR spectroscopy, whereas further broad-
band UV photolysis destroys the azirene to produce o-cyanophenylketenimine 17. The use of 15N-labeled
tetrazole/azide 22T′/22A′ demonstrates rapid equilibration of two regioisomeric 15N-labeled azirenes 24′
and 24′′ prior to formation of 17. Flash vacuum thermolysis (FVT) of 22T/22A affords 1-cyano-2H-
isoindole 27 in quantitative yield. FVT of 15N-labeled tetrazole/azide 22T′/22A′ causes scrambling of
15N label in the 1-cyano-2H-isoindole product. It is concluded that the interconversion of azirenes 24
takes place via the unobserved diazacycloheptatetraene/diazacycloheptatrienylidene 32/33, and that the
rearrangement of azirene to ketenimine 17 and 1-cyanoisoindole 27 takes place via reversion to nitrene
23 followed by ring opening to diradical 25.
Introduction
tetrazolopyridines.5,6 Nevertheless, this ring expansion reaction
is often accompanied by a minor ring opening reaction, leading
to ketenimines 9, presumably via the unobserved dienylnitrene/
diradical 5, termed a type II ring opening.7 Small amounts of
ketenimines 9 have been observed in matrix photolysis
reactions,5,6 whereas tautomeric glutacononitriles 10 are obtained
in yields on the order of 10% in flash vacuum thermolysis (FVT)
reactions.2 FVT affords mixtures of 2- and 3-cyanopyrroles 7
and 8 as major products;2 they are believed to be formed via
the unobserved 2-cyano-2H-pyrrole 6, and they interconvert by
means of a series of thermal 1,5-H and 1,5-CN shifts (Scheme
1).
Thermal and photochemical rearrangements of pyridylnitrenes
have been described in recent papers.1,2 Thus, 2-pyridylnitrene
2, generated from tetrazolo[1,5-a]pyridine 1T and/or 2-azidopy-
ridine 1A, undergoes ring expansion to 1,3-diazacyclohepta-
1,2,4,6-tetraene 4. This reaction is assumed to take place via
transient azirene 3, which has not, however, been observed
directly. The corresponding azirenes have been observed in the
photochemical rearrangements of the naphthylnitrenes3 in Ar
matrixes and in the photolyses of fluorinated4 phenyl azides.
The formation of diazacycloheptatetraenes 4 is a preparatively
useful process, which can be applied in the synthesis of a variety
of 1,3-diazepines, usually in high yields, from substituted
In 2-quinolyl- and 1-isoquinolylnitrenes 11 and 13, which
interconvert via observable diazacycloheptatetraene 12, photo-
(5) (a) Reisinger, A.; Bernhardt, P. V.; Wentrup, C. Org. Biomol. Chem.
2004, 2, 246. (b) Reisinger, A.; Koch, R.; Bernhardt, P. V.; Wentrup, C. Org.
Biomol. Chem. 2004, 2, 1227.
(6) Addicott, C.; Wentrup, C. Aust. J. Chem. 2008, 61, 592.
(7) Kvaskoff, D.; Bednarek, P.; George, L.; Waich, K.; Wentrup, C. J. Org.
Chem. 2006, 71, 4049.
(1) Bednarek, P.; Wentrup, C. J. Am. Chem. Soc. 2003, 125, 9083.
(2) McCluskey, A.; Wentrup, C. J. Org. Chem. 2008, 73, 6265.
(3) Maltsev, A.; Bally, T.; Tsao, M.-L.; Platz, M. S.; Kuhn, A.; Vosswinkel,
M.; Wentrup, C. J. Am. Chem. Soc. 2004, 126, 237.
(4) Morawitz, J.; Sander, W. J. Org. Chem. 1996, 61, 4351.
10.1021/jo802273y CCC: $40.75
Published on Web 12/10/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1171–1178 1171

Vosswinkel et al.
SCHEME 1. Pyridylnitrene Rearrangements
SCHEME 3. Synthesis of 22T/22A
SCHEME 2. 2-Quinolylnitrene and 1-Isoquinolylnitrene
Rearrangements
of 20 with o-mesitylsulfonylhydroxylamine (MSH)10 followed
by diazotization of salt 21 afforded tetrazole 22T/azide 22A.
The use of ammonia-15N (98 atom %) in the first step afforded
N1-labeled tetrazole/azide 22T′/22A′. In the following, unlabeled
compounds have numbers 19-22, etc.; 15N-labeled compounds
have numbers 19′-22′, etc.
Compound 22 exists as a mixture of tetrazole 22T and
3-azidoisoquinoline 22A already in the solid state at rt;9 the IR
spectrum of the solid in KBr features a medium-intensity azide
band at 2120 cm-1. Varying proportions of azide 22A have been
described for solutions.9 We measured the equilibrium concen-
trations in DMSO-d6 at temperatures between 301 and 373 K
by 1H NMR spectroscopy and determined ∆S° ) 52.4 ( 1.5 J
K-1 mol-1, ∆H° ) 17.7 ( 0.6 kJ/mol, and ∆G° ) 2.05 ( 1
kJ/mol for the isomerization 22T f 22A at 25 °C, i.e., the
tetrazole and the azide are nearly isoergic. The values are in
line with those determined for several tetrazolopyridines.11 In
general, DMSO favors the tetrazole, whereas chloroform favors
the azide in the tetrazole/azide equilibrium.12 The azide/tetrazole
ratio for 22 was 0.36 in DMSO-d6 and 4.1 in CDCl3 at 19 °C.
The compound exists exclusively as azide 22A in the gas phase.
Gentle evaporation of the compound at 45-55 °C (3.3 × 10-6
mbar) and condensation of the material with Ar to form a matrix
at 7 K results in pure azide with strong absorptions at 2139
and 2122 cm-1 (Figure 1A). Comparison of the solid in KBr
with the IR spectrum reveals that no tetrazole is present in the
matrix. Moreover, on subsequent photolysis of this matrix, all
IR bands decrease with the same rate. This is strong evidence
that only one species is present, viz. azide 22A, because we
have observed in many cases that azides photolyze much faster
than the valence isomeric tetrazoles.
chemical ring opening to 2-o-cyanophenylketenimine 17 is a
major process, whereas FVT leads to nitriles 15 and 16 (Scheme
2).8 Again, ring opening to vinylnitrene 14 is assumed. The
azirenes corresponding to 11 and 13 were not observed, and
they are calculated to be transition states, not energy minima.
We have now investigated 3-isoquinolylnitrene 23 and present
direct ESR spectroscopic evidence for the nitrene, IR evidence
for azirene 24, 15N-labeling evidence for rapid interconversion
of regioisomeric azirenes via the unobserved diazacyclohep-
tatetraene, and type II ring opening of the nitrene to form 2-o-
cyanophenylketenimine 17.
Results and Discussion
2. Photolysis. Photolysis of an Ar matrix of azide 22A in a
cryostat for ESR spectroscopy at λ ) 254 nm or λ > 300 nm
afforded intense X2Y2 ESR transitions around 6600-6850 G
characteristic of a heteroaromatic nitrene (D ) 0.943; E ) 0.005
cm-1) (Figure 2A). The spectrum is ascribed to 3-isoquinolylni-
trene 23 in its triplet ground state (T0). The open shell (S1) and
closed shell (S2) nitrenes are calculated to lie 60.7 and 146.9
kJ/mol above the triplet, respectively, at the B3LYP/6-31G*
1. Tetrazolo[1,5-b]isoquinoline 22T/3-Azidoisoquinoline
22A. Three different syntheses of this material have been
described.9 In order to investigate the reaction mechanisms by
15N labeling, we modified the third method9c to permit the late
and reliable introduction of the 15N label using only a small
amount of ammonia (Scheme 3). 3-Aminoisoquinoline 20 is
accessible by amidation of methyl isoquinoline-3-carboxylate
18 followed by a Hofmann degradation of amide 19. Amination
(10) Krause, J. G. Synthesis 1972, 140.
(8) Addicott, C.; Reisinger, A.; Wentrup, C. J. Org. Chem. 2003, 68, 1470.
(9) (a) Hajos, G.; Messmer, A. J. Heterocycl. Chem. 1976, 13, 881. (b) Hajos,
G.; Messmer, A. J. Heterocycl. Chem. 1978, 15, 453. (c) Hajos, G.; Messmer,
A. J. Org. Chem. 1981, 46, 843.
(11) Evans, R. A.; Wong, M. W.; Wentrup, C. J. Am. Chem. Soc. 1996,
118, 4009.
(12) (a) Tisler, M. Synthesis 1973, 123. (b) Wentrup, C. Tetrahedron 1970,
26, 4969.
1172 J. Org. Chem. Vol. 74, No. 3, 2009

Nitrenes, Azirenes, and Diradicals
FIGURE 1. IR spectra of (A) 3-azidoisoquinoline 22A deposited in
Ar matrix at 7 K, (B) azirene 24 formed by photolysis at λ > 300 nm
for 6.5 min, and (C) ketenimine 17 formed by further photolysis without
a filter for 10 h (abscissa in cm-1, w ) water).
computational level, whereby the Cramer-Ziegler method13 was
used to estimate the S1 energy (see Table S2, Supporting
Information, for a summary of computational data).
The strong ESR signals ascribed to triplet 23 were obtained
in many experiments under a variety of UV photolysis condi-
tions. However, depending on wavelength and time, further
signals ascribed to diradical 25 appeared in the 1600 and
2500-4000 G range, and in the 5000-5500 G range ascribed
to carbene 21, as is seen in Figure 2B-D (see also Figure S1,
Supporting Information, for larger-scale spectra). They will be
discussed later in this section.
A similar photolysis of an Ar matrix of 22A using λ > 300
nm and IR spectroscopic detection caused complete depletion
of azide (Figure 1A) within about 6 min with simultaneous
formation of a new compound absorbing at 1733 and 1726 cm-1
(Figure 1B). The IR spectrum is ascribed to azirene 24 because
of an excellent correlation with the calculated spectrum at the
B3LYP/6-31+G* level (Figure 3). It is normal for azirenes of
this type to show split bands of medium intensity for the CdN
stretching vibration in the 1700 cm-1 region.3,14 A strong band
at 1529 cm-1 is due to the CdN group of the isoquinoline ring.
Azide 22A was also deposited as a neat solid and photolyzed
at 7 K to produce azirene 24 as a virtually pure substance, now
absorbing at 1723 and 1523 cm-1 (Figure S2, Supporting
Information). The azirene was remarkably stable, surviving to
110 K on warm-up, and then disappearing on further warming
between 110 and 140 K.
FIGURE 2. ESR spectra obtained by photolysis of 22A in Ar matrixes.
(A) Photolysis of 22A at about 11 K using light of λ ) 332 nm for
1 h. Nitrene 23 appears at X2 ) 6625 G, Y2 ) 6860 G; D ) 0.9444
cm-1, E ) 0.0049 cm-1; a monoradical appears at g ) 2, and very
weak ∆ms ) 2 signals are ascribed to diradicals at 1625-1665 G,
assigned to geometrical isomers of 25; H0 ) 3374.0 G, ν ) 9.4544
GHz. (B) Photolysis of 22A at 13 K, λ ) 332 nm for 2 h. Besides
nitrene 23, signals for two diradicals and two carbenes [assigned as
two conformers of 31, most likely the EZE and EEE conformers (see
below)] are seen. First carbene: Z1 ) 1258 G, X2 ) 4950 G, Y2 )
5443 G; D ) 0.4336 cm-1, E ) 0.0123 cm-1. Second carbene: X2 )
5069 G, Y2 ) 5547 G; D ) 0.4664 cm-1, E ) 0.0115 cm-1. First
diradical (assigned to a geometrical isomer of 25): X1 ) 3126, X2 )
3611, Y1 ) 3033, Y2 ) 3750, Z1 ) 2841, Z2 ) 3907 (∆ms ) 2) 1645
G; D ) 0.0518, E ) 0.0036 cm-1; H0 ) 3372.5 G, ν ) 9.45141 GHz.
(C) Photolysis of 22A at about 13 K, λ ) 254 nm for 2 h. Stronger
signals for diradicals are seen. H0 ) 3372.5 G, ν ) 9.45131 GHz. (D)
Photolysis of 22A at 12 K, λ ) 364 nm for 1.5 h. Nitrene 23, strong
signals for two diradicals, assigned to geometrical isomers of 25, and
weak signals for the two carbenes 31 are seen. Second diradical
(assigned to a geometrical isomer of 25): X1 ) 2935 G, X2 ) 3720 G,
Y1 ) 2830 G, Y2 ) 3850 G, Z1 ) 2436 G, Z2 ) 4344 G (∆ms ) 2)
1582 G; D ) 0.0874 cm-1, E ) 0.0037 cm-1; H0 ) 3372.4 G, ν )
945101 GHz. Signs of D and E were not determined.
The azirene in the Ar matrix (Figures 1B and 3) changed
very slowly on further irradiation at λ > 300 nm, but irradiation
using either the unfiltered light of a high-pressure Hg/Xe lamp
or the 254 nm line of a low-pressure Hg lamp caused the
development of a new, strong, and complex band with maxima
at 2049 and 2022 cm-1 (Figure 1C). The azirene was fully
converted after 10 h of irradiation. The compound formed is
unambiguously identified as the open-chain ketenimine 17
(Scheme 4), which has been obtained previously from iso-
(13) Johnson, W. T. G.; Sullivan, M. B.; Cramer, C. J. Int. J. Quantum Chem.
2001, 85, 492.
(14) Dunkin, I. R.; Thomson, P. C. P. Chem. Commun. 1980, 499.
J. Org. Chem. Vol. 74, No. 3, 2009 1173

Vosswinkel et al.
S3, Supporting Information). The formation of compounds 17
and 26 is a logical consequence of a ring opening of 3-iso-
quinolylnitrene 23 to the diradical 25, i.e., a type II ring opening
of nitrene 23. As described below, the more stable 2H-isomer
27 is formed by FVT, but not in the matrix photolysis. It is
assumed that intersystem crossing between the singlet and triplet
states of nitrene 23 can take place easily during photolysis. The
reaction mechanism is summarized in Scheme 4.
We can now assign the diradical-type ESR signals in Figure
2B-D to diradical 25 (Scheme 4), which is analogous to the
dienylnitrene/diradical 5 postulated to be formed from 2-py-
ridylnitrene (Scheme 1) and styrylnitrene 14 postulated in
Scheme 2. In the pyridine case, this species will have a high
degree of nitrene character. In the isoquinoline case, species
25 will have a high degree of diradical character because the
nitrene canonical structure is o-quinoid. The strong and sharp
half-field signals (∆ms ) 2) at 1588-1645 G in Figure 2B-D
are characteristic of diradicals and are never seen with such
intensity for hetaryl-nitrenes or -carbenes. The relative intensities
of the two sets of signals change depending on the photolysis
wavelength and time, thereby making it clear that there are two
closely related diradical species. Only tiny amounts of the
diradicals are seen in Figure 2A. Increasing amounts are seen
in Figures 2B-D. The signals are assigned to s-Z and s-E
conformational isomers of 25. The lines in the range 2200-4200
G are typical Z1, Y1, and X1 and X2, Y2, and Z2 transitions of a
triplet diradical.15 The D values (0.0518 and 0.0874 cm-1) are
smaller than that determined for 29 (0.119 cm-1, see eq 3), as
would be expected for a diradical with one less nitrogen center.
The D values of 25 and 29 are higher than those determined
for several other organic 1,5-diradicals (∼0.02 cm-1).15 This
can be ascribed to the partial nitrene-type canonical structure
(see formula 25, Scheme 4), which puts a high electron spin
density on N (see calculated spin densities in the Supporting
Information).
FIGURE 3. Experimental (A) and calculated (B) IR spectra of azirene
24 (B3LYP/6-31+G*, wavenumbers scaled by 0.9613). Abscissa in
cm-1, w ) water.
SCHEME 4. 3-Isoquinolylnitrene Rearrangements
The chemistry described here is analogous to that of
2-quinazolylnitrene 28, where ring opening affords a diradical
29 as well as a secondary minor nitrene to which structure 30
was assigned (eq 3).7
Analogous ring opening in 3-isoquinolylnitrene 23 will
generate diradical 25 (eq 2) and arylcarbene 31 (eq 3). Thus, a
likely candidate for the weak carbene signals seen in Figure
2B-D around 5000-5500 G is the arylcarbene 31, which can
exist in several geometrically isomeric forms (eq 3) (further
possible conformers are shown in the Supporting Information).
An excellent linear correlation exists between experimental D
values and calculated natural spin densities F on the carbene
center of monosubstituted carbenes of the type RCH.16 The D-F
correlation fits the equation D ) 0.78446F - 0.78316 cm-1
with a standard deviation of D ( 0.015 cm-1; R2 ) 0.990 at
the UB3LYP/EPR-III level of theory.
quinolylnitrene 11 (Scheme 2)8 (see Table S1 and Figure S3,
Supporting Information). It is common for ketenes and keten-
imines to feature multiple absorption maxima in the cumulene
stretching region around 2000 cm-1. This can be due to the
existence of two conformers, s-Z and s-E, as well as several
nonplanar conformers that may be populated in the Ar matrix.
The integrated intensities of the IR bands due to azide 22A,
azirene 24, and ketenimine 17 were monitored as a function of
photolysis time (Figure S4, Supporting Information). This
allowed a clear-cut attribution of IR bands to the individual
compounds and also revealed a subset of bands in the IR
spectrum in Figure 1C, which does not belong to 17. These
bands are at 2264, 1590, 1554, 1286, 1265, 1209, 884, 736,
720, and 600 cm-1. The weak CN absorption at 2264 cm-1 is
indicative of an unconjugated nitrile. This set of bands match
the calculated IR spectrum of 1-cyano-1H-isoindole 26 (Figure
The data for the EZE and EEE isomers of carbene 31 (eq 3)
fit extremely well with this correlation (31-EZE: D ) 0.4336,
(15) Berson, J. M. In Diradicals; Borden, W. T., Ed.; Wiley: New York,
1982.
(16) Kvaskoff, D.; Bednarek, P.; George, L.; Pankajakshan, S.; Wentrup, C.
J. Org. Chem. 2005, 70,7947, footnote 13.
1174 J. Org. Chem. Vol. 74, No. 3, 2009

Nitrenes, Azirenes, and Diradicals
E ) 0.0123 cm-1, F ) 1.5245; 31-EEE: D ) 0.4664, E )
0.0118 cm-1, F ) 1.5939), but other conformations are not
excluded. The correlation is illustrated in Figure S5 of the
Supporting Information.
76-80 kJ/mol above ground state nitrene 23 (T0), i.e., about
20 kJ/mol above the open-shell singlet nitrene (S1) (vide
supra).17 Azirene 24 was found to be about 40 kJ/mol more
stable than 32 or 33.17
While compound 32 is a twisted o-quinoid carbodiimide
benefiting from some Mo¨bius-aromatic stabilization, 33 is best
described as a resonance hybrid of a carbene 33a and an ylidic
zwitterion 33b.17 Bond-localized cyclic nitrile ylide 34 was not
located as an energy minimum.17 Comparison of the experi-
mental IR spectra with the calculated data17 for 32 and 33 makes
it clear that these compounds were not present in any of our
experiments. This is in stark contrast to the situation with
2-pyridylnitrene 2 (Scheme 1), where the diazacycloheptatet-
raene 4 is the major and easily detected reaction product under
both thermal and photochemical conditions, azirene 3 is not
observable, and ring opening to 9/10 is a minor process.
The use of 15N-labeled tetrazole/azide 22T′/22A′ (98 atom
The intensities as well as the ratios of geometrical isomers
of the carbene varied as a function of photolysis wavelength
and time (Figure 2 and Figure S1, Supporting Information).
The activation barriers for conversion of triplet nitrene 23 to
triplet diradical 25 and triplet carbene 31 were calculated at the
UB3LYP/6-31 G* level of theory as 110.9 and 199.6 kJ/mol,
respectively, i.e., the formation of the diradical is less costly
energetically, in accord with the observed relative intensities
in the ESR spectra (Figure 2). Moreover, the barrier for
%
15N, see Scheme 3) proved that azirenes 24′ and 24′′
interconvert rapidly as they are being formed by photolysis. This
interconversion is complete before the ring-opened ketenimines
17′/17′′ are formed. 1-Cyanoisoindole 27 formed by FVT also
has complete scrambling of the 15N label. We postulate that
the 15N scrambling takes place, both photochemically and
thermally, via facile interconversion of azirene with the
7-membered ring species 32 or 33 (eq 4). The activation barrier
for this process is calculated to be only 55 kJ/mol at the B3LYP/
6-31G* level.
1
conversion of the open-shell singlet nitrene A′′ to the open-
1
shell singlet diradical A′′ (139.7 kJ/mol) was higher than for
the triplet-triplet reaction.
It must be noted that ESR spectroscopy is far more sensitive
than IR spectroscopy. Comparison with the calculated vibra-
tional frequencies of nitrene 23 and diradicals 25 (Supporting
Information) clearly shows that these are not the species being
observed in the IR spectra, where azirene formation is observed
very rapidly and quantitatively (Figures 1B and 3). We have
observed several other related nitrenes, e.g., 28, by IR and
UV-vis spectroscopy,7 but this would not be possible under
these reaction conditions (λ > 300 nm) because the nitrenes
themselves undergo rapid photolysis at visible wavelengths.
3. FVT. Preparative FVT of 22A at 550 °C afforded 1-cyano-
2H-isoindole 27 in quantitative yield. FVT with Ar matrix
isolation and IR spectroscopy of the product at 7 K demonstrated
that 27 starts forming at about 350 °C, and its formation is
complete at 500-550 °C. No other product or intermediate was
discernible. It is logical to assume that 27 is formed by
tautomerization of 26 (Scheme 4). This tautomerization reaction
is calculated to have a barrier of about 160 kJ/mol at the B3LYP/
6-31G* level. 27 is calculated to lie 37 kJ/mol below 26 (see
computational data in the Supporting Information). Therefore,
the tautomerization 26 f 27 will take place easily under FVT
conditions but not in low-temperature matrixes.
It is also conceivable that the two azirenes 24′ and 24′′ could
interconvert directly in a concerted pericyclic reaction, but we
were unable to locate a TS for such a process at either the HF
or B3LYP computational level.
Photolysis of 15N-labeled azide 22A′ at λ > 300 nm led
initially (within 30 s) to labeled azirene 24′, as seen in a red
shift of the complex azirene CdN band from 1733 to 1711 cm-1
(Figure 4). However, within a few minutes of photolysis, the
unshifted band at 1733 cm-1 started growing, and the red-shifted
band at 1711 cm-1 decreased, eventually reaching about a 1:1
ratio of the two azirenes 24′ and 24′′ (Figure S6 of the
Supporting Information). At the same time, the CdN band of
the isoquinoline moiety, which appeared at first in the unshifted
position of 1529 cm-1, decreased, and a red-shifted band at 1521
cm-1 grew in intensity, indicating that isoquinoline-N was
becoming labeled (Figure S6 of the Supporting Information).
The isotopic shifts of about 20 and 8 cm-1 for azirene and
isoquinoline CdN moieties are in excellent agreement with
calculations (19 and 8 cm-1, respectively).17 There were no other
significant differences between labeled and unlabeled spectra.
It is postulated that ring opening to diradical 25 is a key step
in both photolysis and thermolysis reactions. The mechanism
is summarized in Scheme 4.
4. 15N Labeling. In none of the experiments described so
far was there any evidence for the existence of diazacyclohep-
tatetraene 32. This molecule is calculated to absorb strongly at
about 1930 cm-1 in the IR.17 Calculations also indicate that
molecule 33 is virtually isoergic with 32, both of them lying
(17) Kuhn, A.; Vosswinkel, M.; Wentrup, C. J. Org. Chem. 2002, 67, 9023.
J. Org. Chem. Vol. 74, No. 3, 2009 1175

Vosswinkel et al.
This is the first direct observation of a fused azirene in the
hetarylnitrene series. Azirenes have been postulated but never
observed as intermediates in the ring expansion of 2-pyridylni-
trenes, 2-quinolylnitrene, 2-pyrazinylnitrene, and 4-pyrimidylni-
trene to cyclic carbodiimides. Ring opening of 2-pyridylnitrenes
to dienylnitrenes/diradicals analogous to 25 has long been
postulated as a mechanism of formation of open-chain keten-
imines and glutacononitriles but not previously observed.
Computational Method. Standard DFT calculations were
performed using the Gaussian 98 suite of programs.18 Geometry
optimizations and frequency calculations were computed at the
B3LYP/6-31G* and in some cases the B3LYP/6-31+G* level
of theory. A scaling factor of 0.9613 was used for wavenum-
bers.19 The nature of transition states was established by intrinsic
reaction coordinate (IRC) calculations. The energy of open-
shell singlet nitrene 23 (S1, 1A′′) was estimated using the
Cramer-Ziegler method.13 An overview of calculated relative
energies is given in Table S2 of the Supporting Information.
FIGURE 4. IR spectra of unlabeled and 15N-labeled azirenes 24 (A)
and 24′/24′′ (B) (Ar matrix, 7 K).
Experimental Section
General. Apparatus for matrix isolation, photolysis, ESR and
IR spectroscopy, and FVT have been described.7,20
Further broad-band photolysis of labeled azirene afforded
labeled ketenimine 17′/17′′, showing red shifts of the complex
CdCdN absorption band at 2049-2016 cm-1 (unlabeled) to
2050-2006 cm-1 (labeled); the band maxima at 2040/2022 cm-1
shifted to 2032/2013 cm-1 in agreement with a calculated
isotopic shift of 13 cm-1 (Figure S7 of the Supporting
Information). The absorption of the CN group was split into
two with a shift of 26 cm-1. Unlike the situation for the azirenes,
there was no dynamic evolution pattern for the labeling of the
ketenimines; the ratio of labeled and unlabeled substances
remained constant throughout the photolysis and is assumed to
be 1:1.
Labeled azide 22A′ was also subjected to FVT at 550 °C.
Examination of the isolated 1-cyano-2H-indole 27′ by 13C and
15N NMR spectroscopy demonstrated complete scrambling of
the 15N label. In particular, the IR spectrum featured two peaks
of equal intensity for the CN group, viz. 2200 (C14N) and 2180
cm-1 (C15N).
Isoquinoline-3-carboxamide-15N 19′. The efficient synthesis of
amide 19, using only small amounts of ammonia, was achieved by
means of a vacuum line. Ammonia-15N (98 atom % 15N, 400 mg,
22.22 mmol) was condensed into a degassed and frozen solution
of 700 mg (3.74 mmol) of isoquinoline-3-methylcarboxylate in 10
mL of dry methanol in a 50 mL flask cooled in liquid N2 and
containing a magnetic stirring bar. The flask was closed, and the
stopcock and the attachment of the flask were secured with springs.
The content was allowed to warm to rt and then stirred magnetically
for 12 h at rt, after which time a white precipitate had formed.
Excess ammonia was condensed from the reaction flask into another
container for reuse. The white product was isolated by filtration,
yielding 503 mg (2.91 mmol, 77.7%) of 19′: mp 206-208 °C; mp
of unlabeled material 206-208 °C; lit.21 mp 206-207 °C.
3-Aminoisoquinoline-15N 20′. Bromine (0.13 mL, 2.7 mmol)
was added to a stirred solution of 2.13 g (41.4 mmol) of KOH in
5 mL of H2O at -5 to -3 °C. Another 5 mL of water was then
added, and stirring was continued for 10 min. Labeled 3-aminoiso-
quinoline (500 mg, 2.89 mmol) was now added in portions with 5
mL of H2O with vigorous stirring at -5 to 0 °C over 1 h. The
thick, white suspension was warmed to rt, heated at 80 °C for 1 h,
and then heated at 100-110 °C for 10 min. A clear yellow solution
formed for a short time, followed by a yellow precipitate. The
mixture was cooled to rt. Another 2.70 g of KOH was added, and
the mixture was allowed to stand for 12 h. A yellow solid was
filtered off, and the solution was concentrated and filtered. The
combined precipitates were extracted with boiling toluene and
filtered hot. Evaporation of the filtrate afforded 0.236 g (56.4%) of
yellow plates of 20′: mp 176-178 °C; mp of unlabeled material
174-180 °C; lit.21 mp 178 °C.
Conclusion
Photolysis of 3-azidoisoquinoline 22A causes rapid formation
of 3-isoquinolylnitrene 23 (observed by ESR) and ring closure
to azirene 24 (observed by IR spectroscopy). 15N labeling reveals
that the azirene undergoes photochemical automerization (24′
h 24′′), and it is concluded that this takes place via a
symmetrical intermediate, viz. the 7-membered ring carbodi-
imide or carbene/ylide 32/33 (eq 4). The azirene is obtained
virtually pure and is stable to temperatures above 110 K. UV
photolysis of the azirene causes rearrangement to o-cyanophe-
nylketenimine 17.
In addition to the ESR signal for the triplet nitrene, signals
due to triplet diradicals also develop rapidly upon UV photolysis.
These diradicals are assigned structure 25, which can form by
ring opening of the nitrene (eq 2). Thus, azirene 24 can rearrange
to ketenimine 17 via reversion to nitrene 23, followed by ring
opening to diradical 25 (Scheme 4). Diradical 25 can undergo
a 1,6-H shift to give ketenimine 17 or cyclize to 1H-1-
cyanoisoindole 26. Finally, a 1,5-H shift in 26 affords 2H-1-
cyanoisoindole 27, which is obtained in quantitative yield on
FVT, with complete nitrogen scrambling when labeled azide
22A′ is used.
(18) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.; Strathmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.;
Strain, M. C.; Farkas, O.; Tomasi, J.; Baroni, V.; Cossi, M.; Cammi, R.;
Mennucci, B.; Pommelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson,
G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts,
R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.; Johnson, B.; Chen,
W.; Wong, M. W.; Andres, J. L.; Head-Gordon, M.; Replogle, E. S.; Pople,
J. A. Gaussian 98; Gaussian, Inc.: Pittsburgh, PA, 1998.
(19) Wong, M. W. Chem. Phys. Lett. 1996, 256, 391.
(20) Wentrup, C.; Blanch, R.; Briehl, H.; Gross, G. J. Am. Chem. Soc. 1988,
110, 1874.
(21) Teague, C. E.; Roe, A. J. Am. Chem. Soc. 1951, 73, 688–689.
1176 J. Org. Chem. Vol. 74, No. 3, 2009

Nitrenes, Azirenes, and Diradicals
Tetrazolo[1,5-b]isoquinoline-15N/3-Azidoisoquinoline-15N 22T′/
22A′. Labeled 3-aminoisoquinoline (0.171 g, 1.18 mmol) was
dissolved in 7 mL of DCM and cooled to 5-7 °C, affording a
yellow suspension. A suspension of MSH (0.280 g, 1.30 mmol) in
7 mL of DCM was cooled to 5 °C and added to the above
suspension at 5 °C with stirring. The DCM was previously freed
of acid by passing it through a column of basic alumina. When a
clear lemon solution had formed, stirring was stopped, and the
solution was allowed to stand for 1 h, after which time a precipitate
had formed. After addition of 2 mL of diethyl ether, the mixture
was allowed to stand at 5 °C for 12 h. The product was filtered,
washed thoroughly with diethyl ether, and dried in vacuo to afford
319 mg (0.88 mmol, 75.0%) of a yellow solid: mp 170-172 °C.
This material was dissolved in 6 mL of acetic acid (50%), and a
cold solution of 97 mg (1.41 mmol) of sodium nitrite in 2 mL of
water was added dropwise at 0-5 °C. After the mixture had been
stirred in ice in the dark for 2 h, the crude product (48 mg, 32%)
was filtered and purified by vacuum sublimation to yield 13 mg
(9%) of 22T′/22A′: mp 126-128 °C. Unlabeled tetrazole 22T/22A
was obtained in the same manner: mp 126-128 °C; lit.9b mp 122
°C.
1603 w, 1523 s, 1448 w, 1359 vw, 1219 m, 917 w, 848 vw, 793
vw, 768 w, 757 w, 744 w, 630 w, 615 w, and 586 w cm-1. On
subsequent warming, the bands of azirene disappeared between 110
and 140 K.
Argon Matrix Photolysis of 3-Azidoisoquinoline-15N 22A′. The
tetrazole/azide mixture was sublimed at 46-49 °C (2 × 10-6 mbar)
over 2 h and 15 min and codeposited in argon (flow rate about 4
mbar/min): IR (Ar matrix, 7 K) ν 3069, 2330, 2293, 2207, 2182,
2175, 2154 (all vw), 2143 w, 2133 vs, 2116 w, 2111 w, 2105 vw,
1636 m, 1595 m, 1588 vw, 1585 w, 1498 vw, 1496 vw, 1450 vw,
1444 sh, 1443 m, 1438 vw, 1349 m, 1345 sh, 1344 sh, 1340
vw, 1294 vw, 1288 w, 1286 m, 1279 vw, 1274 w, 1270 w, 1236
vw, 1232 w, 1228 m, 1225 vw, 1222 vw, 1193 vw, 1191 w, 1145,
1136, 1107, 1103, 1016, 958, 952, 890, 875, 873, 845, 791, 777,
748, 681, 606, 526, and 468 (all vw) cm-1
.
The azide was then photolyzed with light of λ > 300 nm. The
progress of the photolysis was followed in discrete intervals. After
10.5 min, the azide had almost disappeared, and only a negligible
amount of final photolysis product 17 was present. The bands of
15N-labeled azirines 24′ and 24′′ were observed: IR (Ar matrix, 7
K) ν 1731 vw, 1724 vw, 1717 vw, 1711 w, 1574 vw, 1529 s,
1521 w, 1465 vw, 1448 w, 1446 w, 1356 vw, 1349 vw, 1291 vw,
1216 sh, 1213 m, 1203 br w, 1170 vw, 966 vw, 964 vw, 914 w,
913 w, 910 vw, 908 sh, 844 vw, 842 vw, 836 vw, 834 sh, 792 vw,
790 vw, 766 vw, 762 w, 756 w, 741 vw, 636 vw, 633 vw, 614 vw,
596 vw, 593 w, 591, 589, 587, 555, and 553 (all vw) cm-1 (Figure
4).
Argon Matrix Photolysis of 3-Azidoisoquinoline 22A. The
tetrazole/azide mixture 22T/22A was sublimed at 45-55 °C (3.3
× 10-6 mbar) and codeposited in argon (flow rate about 3 mbar/
min). The condensate consisted only of 3-azidoisoquinoline 22A,
as evidenced by comparison with the IR spectrum of the solid
tetrazole/azide mixture: IR (Ar matrix, 7 K) ν 3069, 3048, 2345,
2301, 2244, 2215 (all vw), 2191 w, 2185 w, 2147 w (N3), 2139 vs
(N3), 2122 s (N3), 2091 w, 1636 s, 1627 m, 1598 m, 1593 s, 1584 m,
1578 w, 1573 vw, 1495 w, 1457 vw, 1450 m, 1444 s, 1440 m,
1400 vw, 1351 s, 1345 sh, 1340 vw, 1302 w, 1299 m, 1293 s,
1291 m, 1282 w, 1280 w, 1275 m, 1270 m, 1245 w, 1243, 1241,
1239, 1237 (all m), 1197 sh, 1194 w, 1150 sh, 1147 w, 1142 sh,
1138 sh, 1136 vw, 1109 w, 1107 w, 1080 vw, 1016 vw, 961 br w,
958 w, 953 w, 931 vw, 892 w, 889, 886, 883, 880, 877 (all vw),
875 w, 873 w, 848, 845, 801, 796, 780, 753 (all vw), 749 m, 682
After 42 min, the filter was removed, and the sample was exposed
to broad-band UV light. After 5 h and 15 min, only minor amounts
of azirines were visible. The dominant bands in the spectrum are
assigned to two 15N-labeled o-cyanophenylketenimines 17′ and 17′′:
IR (Ar matrix, 7 K) ν 3316 vw, 3313 w, 3300 w, 3290 vw, 2235
vw, 2231 vw, 2208 vw, 2201 vw, 2068 vw, 2050 m, 2040 s, 2032 s,
2025 s, 2013 s, 2006 s, 1573 vw, 1495 w, 1491 m, 1465 vw, 1462
vw, 1460 vw, 1344 br w, 1303 vw, 1080 vw, 956 w, 948 s, 939 s,
937 s, 934 s, 933 s, 930 s, 928 s, 926 s, 916 m, 914 m, 884 w, 850
vw, 841 vw, 832 vw, 827 w, 765 w, 760 m, 757 m, 755 m, 598
vw, 606 w, 526 vw, 472 vw, and 468 w cm-1
.
For quantitative, time-dependent IR measurements, 22A was
irradiated in discrete intervals. Initially, the condensate was
photolyzed with light of λ > 300 nm. After 6.5 min photolysis,
the starting material was fully converted, leading to a spectrum
that presented only negligible amounts of secondary photolysis
product 17. The dominating bands originate from 7bH-azireno[3,2-
c]isoquinoline 24: IR (Ar matrix, about 7 K) ν 1733 w, 1726 m,
1723 m (all CdN), 1574 w, 1529 s (CdN), 1466 w, 1449 m,
1356 w, 1292 w, 1290 w, 1214 m, 1203 br w, 1172 vw, 969 vw,
967 vw, 914 w, 846 vw, 839 br vw, 792 w, 791 sh, 766 vw, 763 w,
756 w, 742 br w, 637 vw, 635 w, 632 sh, 615 w, 596 w, 593 vw,
591 vw, 588 vw, 586 vw, 584 vw, 556 sh, and 554 vw cm-1 (Figure
1B).
After removal of the filter, the sample was subjected to broad-
band photolysis for 605 min (high-pressure Hg/Xe lamp). This
resulted in a slow decay of the bands of azirene and a gradual
increase of the bands of o-cyanophenylketenimine 17, to which
the major bands in the final spectrum are ascribed: IR (Ar matrix,
7 K) ν 3316 sh, 3313 w, 3307 w, 3297 vw (all NH), 2236 w, 2232 w
(all CdN), 2055 w, 2049 m, 2040 s, 2031 m, 2022 s, 2016 m (all
CdCdN), 1573 vw, 1492 m, 1465 w, 1464 w, 1460 m, 1418 w,
1411 w, 1346 w, 1341 br w, 1303 vw, 1085 br vw, 1083 vw, 955 w,
951 m, 949 m, 942 m, 937 m, 935 m, 933 s, 928 m, 916 w, 851
vw, 828 w, 765 w, 761 m, 758 m, 755 m, 607 vw, 464 vw, 420 w
cm-1 (Figure 1C). A set of weak bands at 2264, 1590, 1554, 1286,
1265, 1209, 884, 736, 720, and 600 cm-1 is ascribed to 1-cyano-
1H-isoindole 26 (Figure S3 in the Supporting Information).
Photolysis of Neat 3-Azidoisoquinoline 22A. Azide was
sublimed at 46-48 °C (2 × 10-6 mbar) over a 2.5 h period and
deposited neat, without Ar. Azide was then photolyzed (λ > 300
nm) for 8 min, which yielded the IR spectrum of neat azirene 24
(Figure S2 in the Supporting Information): IR (neat, 7 K) ν 1723 w,
vw, 464 vw, 457 vw, and 420 w cm-1
.
Preparative FVT of 3-Azidoisoquinoline 22A: FVT/Argon
Matrix Isolation of 3-Azidoisoquinoline 22A. The tetrazole/azide
mixture was sublimed at 70-75 °C (5 × 10-5 mbar) over a period
of 2 h and 20 min, and the vapor was passed through a FVT tube
at 500-550 °C. The thermolysate was codeposited in Ar (flow rate
about 3 mbar/min) and consisted entirely of 2H-1-cyanoisoindole
27 as evidenced by comparison with a pure, isolated sample: IR
(Ar matrix, 15 K) ν 3480 vs, 2224 vw, 2219 s, 2209 vw, 1660 br
vw, 1590 w, 1453 m, 1410 m, 1386 m, 1311 m, 1304 w, 1240 m,
1137 m, 1110 m, 1105 m, 1045 w, 995 w, 769 m, 750 m, 632 w,
595 w, 589 m, 553 m, 529 w, 476 w, and 427 w cm-1
.
Preparative FVT of 3-Azidoisoquinoline-15N 22A′. Over 2 h,
a sample of 200 mg of 22T′/22A′ was sublimed at 40-50 °C (10-2
mbar) into the quartz tube of the FVT apparatus held at 550 °C.
The product of FVT was isolated on a coldfinger cooled in liquid
N2. At the end of the thermolysis, the isolated substance was
dissolved in acetone and purified by thick layer chromatography
on silica gel, eluting with diethyl ether. Only one band eluted with
isolable quantities of a substance. This material dissolved in acetone
to give a green solution. Evaporation of the solvent and sublimation
at 80 °C (10-2 mbar) afforded 160 mg (96%) of white crystals: mp
130-132 °C dec; mp for unlabeled material 130-132 °C; lit.22
mp 132-134 °C; MS m/z 143 (100%), 144 (10%); IR (KBr) ν
3260 s, 2930 w, 2200 s (C14N), 2180 s (C15N, same intensity as
2200 cm-1 band), 1450 m, 1410 m, 1400, s, 1285 m, 1315 m,
1240 s, 1135 s, 1110 s, 765 s, 755 s, 730 s cm-1 13C NMR (acetone-
;
d6) δ 90.3 (m), 115.5 (m), 117.5 (d, JNC ) 14 Hz), 117.5 (s), 125.2
(s), 118.4, 122.3, 122.9, 125.9, 131.5 (d, JNC ) 4 Hz); 15N NMR
(22) Brown, R. F. C.; Smith, R. J. Aust. J. Chem. 1972, 25, 607.
J. Org. Chem. Vol. 74, No. 3, 2009 1177

Vosswinkel et al.
(acetone-d6 referenced to saturated 15NH4Cl in H2O, δN ) 27.34
ppm) δ 272.2 (tertiary N), 174.5 (secondary N, d, JNH ) 97 Hz).
and tables of computational data (Cartesian coordinates, absolute
and relative energies, and vibrational frequencies for all
calculated structures). This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. This research was supported by the
Australian Research Council. We thank Dr. Jens Morawitz for
some preliminary experiments.
Supporting Information Available: ESR and IR spectral
Figures S1-S6, tables of IR spectral data for ketenimine 17,
JO802273Y
1178 J. Org. Chem. Vol. 74, No. 3, 2009