Imidazo[1,5-a]pyridinium salts from phenylchlorocarbene and 2-pyridyl Schiff bases: Synthesis, reaction mechanism and effect of rotamerism

Article abstract of DOI:10.1002/ejoc.200600397

3-Phenylimidazo[1,5-a]pyridinium salts are easily prepared in excellent yield by thermolysis of phenylchlorodiazirine in the presence of 2-pyridyl Schiff bases (2-Pyr-CH=NR, where R is an aromatic or alkyl group). When the reaction is conducted in an alkane solvent, the salts precipitate and are easily obtained with a high level of purity after filtration and repeated washing of the precipitate with a nonpolar solvent. A laser-flash photolysis study of the reaction mechanism reveals that the phenylchlorocarbene produced by decomposition of the diazirine reacts with the Schiff base to give two different ylides. The intramolecular cyclization of these two ylides yields the same intermediate product, which rapidly eliminates a chlorine anion. Neither semi-empirical calculations of the energy barriers for the formation and cyclization of the various possible ylides, nor comparison of their calculated and experimental absorption spectra, allow us to determine whether the two ylides are rotamers of a pyridinium ylide or a pyridinium ylide and an iminium ylide. Only the comparison of systems where R is a cyclohexyl or a tert-butyl group indicates that the two ylides are rotamers of a pyridinium ylide. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600397

FULL PAPER
DOI: 10.1002/ejoc.200600397
Imidazo[1,5-a]pyridinium Salts from Phenylchlorocarbene and 2-Pyridyl Schiff
Bases: Synthesis, Reaction Mechanism and Effect of Rotamerism
Roland Bonneau*[a] and Philippe Guionneau[b]
Keywords: Carbenes / Ylides / Cyclization / Intermediates / Time-resolved spectroscopy
3-Phenylimidazo[1,5-a]pyridinium salts are easily prepared
in excellent yield by thermolysis of phenylchlorodiazirine in
the presence of 2-pyridyl Schiff bases (2-Pyr-CH=NR, where
R is an aromatic or alkyl group). When the reaction is con-
ducted in an alkane solvent, the salts precipitate and are eas-
ily obtained with a high level of purity after filtration and
repeated washing of the precipitate with a nonpolar solvent.
eliminates a chlorine anion. Neither semi-empirical calcula-
tions of the energy barriers for the formation and cyclization
of the various possible ylides, nor comparison of their calcu-
lated and experimental absorption spectra, allow us to deter-
mine whether the two ylides are rotamers of a pyridinium
ylide or a pyridinium ylide and an iminium ylide. Only the
comparison of systems where R is a cyclohexyl or a tert-butyl
A laser-flash photolysis study of the reaction mechanism re- group indicates that the two ylides are rotamers of a pyridi-
veals that the phenylchlorocarbene produced by decomposi-
tion of the diazirine reacts with the Schiff base to give two
different ylides. The intramolecular cyclization of these two
ylides yields the same intermediate product, which rapidly
nium ylide.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
products are orally effective hypoglycemic agents that are
used as antidiabetics.[5]
Introduction
According to semi-empirical calculations,[6] the two most
stable geometries of the 2-pyridylimines have a trans imine
double bond and the anti rotamer is slightly more stable
than the syn rotamer. It should therefore be largely pre-
dominant in photolysis experiments at 20 °C as well as in
thermolysis experiments at 80 °C. Considering only the anti
rotamer, it may react with PCC to give either anti-PyY, a
pyridinium ylide, or anti-ImY, an iminium ylide. The syn
rotamers of both of these ylides may give CP1 and then III
after elimination of Cl–, whereas only the anti rotamer of
ImY can cyclize to CP2, which would then yield the prod-
uct(s) IV and/or V.
Carbenes and metal carbenoids are useful intermediates
in the synthesis of nitrogen-containing heterocyclic com-
pounds as they react with azomethines to give oxazolidines,
aziridines, pyrrolidines, and β-lactams.[1] They also react
with 1-azabuta-1,3-dienes to give pyrroles by intramolecu-
lar cyclization of an intermediate ylide and elimination of
HCl.[2] The same mechanism accounts for the formation of
phenylindolizine from phenylchlorocarbene (PCC) and 2-
vinylpyridine (VP).[3] In the latter case, the pyridinium ylide
was shown to be a mixture of two rotamers that give a
single product after cyclization and HCl elimination. There
are also two rotamers for the ylide resulting from the attack
of 2,2Ј-bis(pyridyl) (BiPy) on PCC.[4] They give a dipyr-
ido[1,2-c;2Ј,1Ј-e]imidazolium salt as a single product in
nonpolar solvents but two products in polar solvents, the
second being a pyrido[2,3-a]indolizinium salt.
Here we report a study of this system: the nature of the
products was determined and the mechanism of their for-
mation investigated, with special attention being paid to the
nature of the intermediate ylide species.
In light of these results, the reaction of PCC with 2-pyr-
idylimines (2-Pyr-CH=NR) is expected to give the imid-
azo[1,5-a]pyridinium salt III and/or the pyrrolo[3,4-b]pyr-
idine derivatives IV and V, as shown in Scheme 1. These
Results
Synthesis of the Imidazopyridinium Salts by Thermolysis
[a] Laboratoire de Physico-Chimie Moléculaire, UMR 5803
CNRS & Université Bordeaux 1,
With R = Cyclohexyl (Schiff Base 1)
33405 Talence Cedex, France
Fax: +33-540-006-645
This compound was synthesized as described in the Exp.
Sect. Its UV spectrum in water is shown in Figure 1. Slow
evaporation of a solution of this product in 1,2-dichloro-
ethane gave colorless crystals which were submitted to X-
ray diffraction analysis.[7] The results indicated unambigu-
E-mail: r.bonneau@lpcm.u-bordeaux1.fr
[b] Institut de Chimie de la Matière Condensée de Bordeaux,
ICMCB-CNRS, Université Bordeaux 1,
33608 Pessac Cedex, France
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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R. Bonneau, P. Guionneau
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Scheme 1.
ously that the product is 2-cyclohexyl-3-phenylimidazo-
[1,5-a]pyridin-2-ium chloride (III-1). Details of the molecu-
lar structure reveal alternatively short and long C–C bonds
from C1 to C6 [1.343(2) and 1.431(2) Å], in agreement with
the three mesomeric structures that can be drawn for this
compound. The length of both the C7–N1 and C7–N2 bonds
is around 1.35 Å, which indicates a strong double bond
character. The former is slightly shorter [1.344(2) Å] than
the latter [1.354(2) Å], thus indicating a predominance of
structure 1 over structure 2. This was confirmed by the fact
that the chloride anion is located closer to N1 [3.08(1) Å]
than to N2 [3.46(1) Å], in the crystal (Figure 2).
Figure 2. Atom numbering and mesomeric structures of III-1.
ride of III-2 did not give single crystals, contrary to the
perchlorate of III-2. However, X-ray diffraction experi-
ments performed with the latter were not completely suc-
cessful in solving the crystal structure (see Exp. Sect.).
However, preliminary results are clearly in line with the
crystallization of III-2 together with perchlorate moieties.
Photolysis under Continuous Irradiation
Figure 1. Absorption spectrum of the products obtained by ther-
molysis of chlorophenyldiazirine in isooctane in the presence of 2-
pyridyl Schiff bases 1 (Ϫ) and 2 (----).
Continuous irradiation experiments were performed in
CH2Cl2 to avoid the spectroscopic problems arising from
the precipitation of the product and with the Schiff base 1
because the absorption of 2 extends up to 400 nm and pre-
vents both the irradiation of the diazirine and spectroscopic
With R = Phenyl (Schiff Base 2)
A similar procedure was used for the thermolysis of chlo- measurements below 360 nm.
rophenyldiazirine in the presence of 2. The light-brown pre-
Figure 3 (graph 1) shows a set of UV absorption spectra
cipitate formed during the photolysis was filtered, washed recorded during irradiation of a solution of phenylchlorodi-
with hexane, and dried under vacuum. As in the case of 1, azirine alone and with 5 m of 1 at 366 nm. In the absence
the mother isooctane solution did not contain any nonionic of 1, one can see an isosbestic point at 345 nm where the
cycloaddition product. Assuming that the precipitate is the absorbance increase due to the formation of azine compen-
chloride of III-2, as suggested by its UV absorption spec- sates the absorbance decrease due to the loss of diazirine.
trum, which is very similar to that of III-1 (see Figure 1), In the presence of 1, at concentrations of 2.5, 5, or 10 m,
the chemical yield is greater than 80% with respect to the the evolution of the spectra is different, thus indicating the
1
initial amount of diazirine. The H NMR spectrum is con- formation of a reaction product in addition to azine. The
sistent with the structure III-2 as a single product. The chlo- increase of the absorbance at 345 nm reflects the formation
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Imidazo[1,5-a]pyridinium Salts from Phenylchlorocarbene and Schiff Bases
FULL PAPER
Figure 3. Graph (1) shows the evolution of the absorption spectrum of an isooctane solution of chlorophenyldiazirine with 0 and 5 m
of the Schiff base 1 as a function of irradiation time (0, 30, 60, and 120 seconds). The slope of the linear plot of the increase of the
absorbance at 345 nm as a function of the time of irradiation, graph (2), is proportional to the yield of the reaction for [1] = 5 m.
Similar experiments conducted with [1] = 2.5 and 10 m gave two other slope values. The slope/intercept ratio of the line in graph (3),
which is a plot of [1/slope of graphs (2)] vs. [1]–1, gives the value of the product kq τ0 (see text).
of the product. For each of the concentrations of 1, a plot solvent decreases) and the difference in diazirine concentra-
of ∆A345 as a function of time is linear [see Figure 3 (graph tions (due to the reaction between carbene and diazirine,
2)]. The slope of these lines, ∆A345 per second, is pro- the lower concentration used in continuous irradiation ex-
portional to the rate of formation of the product. This rate periments results in a larger value of τ0).
is itself proportional to the yield of conversion of the car-
bene into the intermediate ylide, φ = kr [1]/(kr [1] + 1/τ0) so
that (∆A345 per second) = Pkr τ0 [1]/(kr τ0 [1] + 1), where P
is a proportionality factor.
A Stern–Volmer plot of 1/(∆A345 per second) as a func-
tion of 1/[1] is linear and the slope/intercept ratio gives kr τ0
≈ 380 [Figure 3 (graph 3)]. The lifetime of the PCC carbene
in the absence of 1 is limited by reactions with the diazirine,
oxygen, and solvent,[8] and in our experimental conditions
τ0 ≈ 1 µs. The rate constant for the reaction between PCC
and 1, kr, should thus be around 4ϫ108 –1 s–1, which me-
ans that the reaction of PCC with 1 would be faster than
with BiPy or 2-VP. This was confirmed by laser flash pho-
tolysis measurements (see below).
Laser Flash Photolysis Measurements
Figure 4. Rate of growth of the ylide absorption vs. the concentra-
tion of 2-Pyr-CH=Nc-hexyl (monitored at 500 nm in isooctane).
After excitation of an isooctane solution containing the
diazirine (0.7 m) and 1 (10 to 60 m) by a laser pulse at
355 nm, a transient absorption appears in the 400–700-nm
In isooctane, the absorption spectrum of the ylide spe-
wavelength range. This absorption is assigned to an ylide cies, shown in Figure 5, is time-dependent: unusually broad
species and grows according to first-order kinetics. The plot when it is recorded 1 µs after excitation, it becomes notice-
of 1/τgrowth vs. [1], shown in Figure 4, follows the linear rela- ably narrower after 25 µs. When monitored at 500 nm, the
tionship 1/τgrowth = 1/τ0 + kyl [1]. The intercept of the decay of the ylide follows first-order kinetics with a decay
straight line yields the lifetime of the carbene in the absence time of around 450 µs at room temperature, whereas in the
of 1 (τ0 = 0.9 µs) and its slope gives the rate constant for red part of the transient absorption spectrum (600–
ylide formation (kyl = 3.23ϫ108 –1 s–1). The product kyl τ0 700 nm), the decay is complex, as shown in Figure 6. The
= 300 is in good agreement with the value (ca. 380) ob- absorption appears to be the sum of two components: the
tained from the Stern–Volmer plot of the continuous irradi- first one decays with a lifetime of 7.5 µs (at 23 °C) and the
ation data. The small difference is easily explained by the second with a lifetime of 450 µs, identical to the value mea-
difference in solvents (kr increases as the viscosity of the sured in the 450–550-nm region.
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Figure 7. Arrhenius plot for the decay of the long-lived ylide 2-Pyr-
CH=Nc-hexylǞPCC (monitored at 500 nm in isooctane).
Figure 5. Transient absorption spectra recorded 1 (trace A) and
25 µs (trace B) after excitation of an isooctane solution of chloro-
phenyldiazirine in the presence of 1 (50 m). Trace C, the difference
between smoothed traces A and B, represents the absorption spec-
trum of the short-lived ylide species.
However, the lifetime of this iminium ylide depends little
on the temperature, changing from 290 µs at 13 °C to 200 µs
at 47 °C. Its decay is sensitive to oxygen even though the
rate constant for reaction with O2, around 2ϫ105 –1 s–1, is
small,[9] and it is not strictly first order: the fit between the
experimental and calculated decay curves is improved when
a second-order process with k2 ≈ (1.5ϫ104 ϫε) –1 s–1 at
500 nm[10] is added to the analysis.
Figure 6. Kinetic behavior of the transient absorption produced by
excitation of an isooctane solution of chlorophenyldiazirine in the
presence of 1 (50 m; monitored at 650 nm).
The lifetime of the second component, monitored at
500 nm, depends strongly on temperature, and an Arrhen-
ius plot, Ln(1/τdecay) = f(1/T), shown in Figure 7, yields an
activation energy, ∆Ea, of 12.94 kcalmol–1 and a frequency
factor, A, of 6.8ϫ1012 s–1. As the ylide lifetime is most
Figure 8. Absorption spectra of the ylides 2-Pyr-CH=Nc-
hexylǞPCC in CH2Cl2 (trace A) and PhCH=NMeǞPCC in iso-
octane (trace B). Both spectra were recorded 1 µs after excitation,
in a single-shot experiment for trace B and an averaged four-shot
probably limited by its rate of cyclization, these kinetic pa- experiment for trace A.
rameters would be those of the cyclization reaction. How-
ever, as stated by one of the referees, the value of the fre-
quency factor seems awfully large for a cyclization reaction.
As an alternative, the lifetime of the long-lived ylide might
Discussion
be limited by its conversion into the short-lived ylide, which
then undergoes a rapid cyclization.
The nature of the main product III has been well defined,
as has the mechanism for its formation, which is the same
In CH2Cl2, the absorption spectrum of the ylide(s) as the mechanism described for the system PCC + BiPy.
(PCCǟ1) shows only one component that resembles the However, from the reported flash photolysis measurements,
spectrum of the long-lived component observed in isooc- it is not clear whether the formation of III results from the
tane and also more or less resembles the absorption spec- cyclization of either an iminium ylide or a pyridinium ylide,
trum of the iminium ylide observed when PCC is produced or both. The very broad transient absorption spectrum ob-
in the presence of PhCH=NMe, as shown in Figure 8. served in isooctane is clearly due to two ylide species, which
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Imidazo[1,5-a]pyridinium Salts from Phenylchlorocarbene and Schiff Bases
FULL PAPER
may be either the iminium and pyridinium ylides, or two idinium ylide moiety are calculated to be around 2 or
rotamers of the pyridinium ylide.
3 kcalmol–1 higher, with the more stable geometries being
those with the imine in an anti position (out of plane by
Ϯ60°). A complete description of the energetics of this rota-
tion is given as Supporting Information.
Absorption Spectra
Thus, from the study of the spectroscopic properties, the
species absorbing in the red must be a pyridinium ylide,
although the species with a maximum absorption at 500 nm
could be either an iminium ylide or a pyridinium ylide. The
question therefore remains as to whether it is possible to
determine the nature of this second ylide from the study of
its kinetic properties, rates of formation, and cyclization?
The absorption spectra of the iminium ylide
PCCǟPhCH=NMe and of the long-lived transient are sim-
ilar. This suggests that the latter could be an iminium ylide
whereas the short-lived transient could be a pyridinium
ylide. Alternatively, the two transient species could be rota-
mers of the pyridinium ylide resulting from rotation around
the ϾC––N+Ͻ ylide bond (rotamers PyY-1 and PyY-2 in
Scheme 1) similar to the two rotamers of the PCCǟVP
ylide, characterized by λmax at 500 and 620 nm and lifetimes
equal to 20 and 0.5 µs, respectively. The interconversion be-
tween rotamers of this type is slow (or non-existent) be-
cause the ϾC––N+Ͻ ylide bond has some double bond
character. Its calculated length, in the range 1.36–1.38 Å, is
closer to that of a C=N double bond (1.29 Å) than to that
of a C–N single bond (1.49 Å). As shown in Figure 9, the
λmax of the calculated absorption spectrum of a pyridinium
ylide depends greatly on the tilt angle between the carbenic
phenyl group and the pyridyl moiety, whereas the enthalpy
of formation is nearly unaffected by such a change. In con-
trast, the calculated absorption spectrum of the iminium
ylide is less sensitive to the planarity of the system. The
most stable conformations, with a tilt angle of the phenyl of
around 60°, have a maximum absorption in the 430–440 nm
range and, even with a tilt angle equal to 5°, the calculated
value of λmax does not exceed 490 nm.
Rate of Formation
The value of the rate constant for the formation of the
(PCCǟ1) ylides (3.2ϫ108 –1 s–1) is similar to those pre-
viously measured for the formation of the pyridinium ylides
PCCǟpyridine
(3.3ϫ108 –1 s–1)
and
PCCǟVP
(7ϫ107 –1 s–1), but it is also similar to that measured in
this work for the formation of the iminium ylide
PCCǟPhCH=NMe (kr = 1.06ϫ108 –1 s–1). The reaction
pathways leading to the formation of the pyridinium and
iminium ylides were therefore calculated by semi-empirical
methods. As shown in Figure 10, the formation of both
ylides is exothermic by 50 kcalmol–1 and is hindered by a
small activation energy of around 4 kcalmol–1 in both cases,
in agreement with rate constants that are two or three or-
ders of magnitude lower than the rate of diffusion-con-
trolled reactions.
Figure 10. Calculated reaction paths for the formation of a pyridi-
nium ylide (open circles) or an iminium ylide (closed circles). Start-
ing from the optimized geometries of these ylides, the enthalpy of
formation of the system is calculated as a function of the distance
between the carbene center and the related N atom. For each point,
this distance is imposed and locked but all the other geometrical
parameters of the structure are recalculated to minimize the value
of ∆Hf.
Figure 9. Calculated absorption spectrum for the pyridinium ylide
anti-α for several values of θ, which is the tilt angle between the
phenyl and pyridyl groups. As θ decreases from 63° to 26° and then
to 5°, λmax increases from 440 to 520 and then to 580 nm but the
calculated enthalpy of formation, ∆Hf, remains nearly constant (70,
71, and 73 kcalmol–1).
A third possibility — rotamerism around the C–C pyr-
idyl–imine bond (rotamerism anti ↔ syn) similar to that
observed in the case of the PCCǟBiPy ylide — may be dis-
carded because rotamers of this type are in fast equilibrium
Rate of Decay
The lifetime of the (PCCǟ1) ylide that absorbs in the
so their lifetimes should be the same. The energy barriers blue–green part of the spectrum is strongly temperature-
for the rotation of the imine group with respect to the pyr- dependent, with kinetic parameters A ≈ 6.8ϫ1012 s–1 and
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Ea = 12.9 kcalmol–1, very similar to those measured for the group this C–H is changed to a C–CH3, which, due to steric
(PCCǟVP) ylide (around 1013 s–1 and 12 kcalmol–1).[11] In hindrance, should destabilize the iminium ylide and in-
contrast,
the
lifetime
of
the
iminium
ylide crease the activation energy barrier for its formation, Ea(f).
(PCCǟPhCH=NMe) depends very little on the tempera- This is confirmed by the results of calculations, as shown
ture. However, this does not prove that the long-lived in Figure 12. With the Schiff base 3, the calculated value of
(PCCǟ1) ylide is
a
pyridinium ylide. The ylide the enthalpy barrier for the formation of the iminium ylide
(PCCǟPhCH=NMe) does not decay by cyclization as this is 4 kcalmol–1 larger than for the formation of the pyridi-
would require the attack of a phenyl ring, whereas the cycli- nium ylide, whereas these values are the same for the cyclo-
zation of a (PCCǟ1) iminium ylide, involving the attack of hexyl-substituted Schiff base 1. Consequently, if the two
a pyridyl ring on its N atom, may be much easier.
transient species observed with the system (PCC + 1) were
According to calculations (see Figure 11), the enthalpy a pyridinium ylide, with a short lifetime and absorbing in
barrier, ∆Ha, for the cyclization of the pyridinium and imin- the red, and an iminium ylide absorbing in the blue, then
ium ylides to give CP1 is around 20 kcalmol–1 in both cases, the relative importance of the second one should be largely
i.e., similar to that calculated for the cyclization of the decreased or even completely suppressed[13] for the system
PCCǟVP ylide (25 kcalmol–1).[12] The calculated value of (PCC + 3). In fact, the characteristics of the transient spe-
∆Ha is substantially larger than the experimental value of cies observed for the systems (PCC + 3) and (PCC + 1) are
Ea but this is a well-known characteristic of semi-empirical the same, as can be seen when comparing Figures 13 and 5.
methods due to the fact they use parameters (PM3 or AM1)
designed for stable species and not for transition states.
More important than the absolute values of ∆Ha is the sig-
nificant result that the cyclization of the pyridinium and
iminium ylides may occur at nearly the same rate, assuming
that the entropy and frequency factors are similar for both
systems. With ∆Ha values of around 20 kcalmol–1 for the
cyclization of the pyridinium ylide and 30 kcalmol–1 for the
cyclization of the iminium ylide we could discard the latter,
but this is not the case. Therefore, neither the shape of the
absorption spectra of the ylide species nor the values of the
rate constants for their formation and cyclization allow us
to distinguish unambiguously between the two types of
ylide. Therefore, we used a different approach to tackle the
problem.
Figure 12. Calculated reaction pathways for the formation of the
pyridinium and iminium ylides (PCCǟ3).
Figure 11. Calculated reaction paths for the cyclization of a pyrid-
inium ylide (open circles) or an iminium ylide (closed circles).
The cyclohexyl group of 1 was changed to a tert-butyl
group to give 2-Pyr-CH=NtBu (3). In the most stable geo-
metries calculated for the iminium ylide, the cyclohexyl
group is nearly orthogonal to the two aromatic rings such
that the C–H α to the imino N atom is pointing towards
Figure 13. Absorption spectra of the transient species formed by
photolysis of an isooctane solution of chlorophenyldiazirine + 2-
Py-CH=NtBu. The spectra were recorded 1 µs (trace A) and 25 µs
(trace B) after excitation by a 20-ns laser pulse at 355 nm. The
latter is the spectrum of the long-lived ylide. Trace C, which is the
difference between the two former, corresponds to a short-lived
one of these rings (see inset in Figure 10). With a tert-butyl ylide.
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Imidazo[1,5-a]pyridinium Salts from Phenylchlorocarbene and Schiff Bases
FULL PAPER
In both cases, there are two ylide species. One absorbs in
Experimental Section
the red (λmax = 650 nm for 1 and 620 nm for 3) and has a
short lifetime; the second absorbs in the blue-green region
(λmax = 500 nm for 1 and 490 nm with 3) and has a much
longer lifetime. The small blue shift from 650 to 620 nm
observed when going from 1 to 3 can be explained by a
decrease of the planarity of the pyridinium ylide that ab-
General: Isooctane and dichloromethane (SDS or Aldrich) were
“UV spectroscopy” or “HPLC” grades. Isooctane was kept over
molecular sieves in order to minimize its water content. A medium
pressure Hg lamp (Philips HPK 125) and a set of filters (UG, 5
and WG 360 Schott glasses) to isolate the 366-nm line were used
for continuous irradiations. The evolution of the UV/Vis spectrum
sorbs in the red due to the steric effect of the additional of the solutions after these irradiations was recorded with a diode-
array spectrophotometer (HP, 8452A).
CH3.
The ratio of the absorbance values measured at λmax
The flash photolysis system used for kinetics measurements in the
10 ns–1 ms range uses a frequency-tripled mode-locked Nd-YAG
laser (Quantel), providing 200-ps single pulses with 30 mJ energy
at 355 nm for the excitation and the analytical light beam is pro-
vided by a pulsed 75-W Xe arc. The excitation and analytical light
beams cross at right angles in a 10ϫ10 mm2 spectroscopic cell held
between diaphragms that restrict the analysis to a small volume
(2ϫ3ϫ10 mm3) of the solution located close to the cell window
receiving the excitation. The optical paths are thus equal to 10 mm
for the analysis and 2 mm for the excitation, which allows a homo-
geneous excitation of the analyzed volume. The detection system
has a 3-ns response time. We collected the data on a digital oscillo-
scope (Tektronix TDS 620B, 500 MHz, 2.5 GS/s) operating in
oversampling mode to improve the signal/noise ratio.
(A490/A620 = 1.8 for 3 and A500/A650 = 1.2 for 1) indicate a
relative population of the ylide absorbing in the blue larger
with 3 than with 1 if one assumes that the absorption coeffi-
cients are unaffected (or only slightly affected) by the
change of the Schiff base.[14] If the ylide absorbing in the
blue were an iminium ylide, one would get the opposite, i.e.,
a strong decrease of the relative population of this ylide, the
formation of which is impeded by the steric effect of the
CH3. We therefore conclude that the two ylide species are
rotamers of a pyridinium ylide.
With this assignment, the hypothesis according to which
the lifetime of the long-lived ylide is determined by its rate
of conversion into the short-lived ylide, and not by its rate
of cyclization, as already stated above, becomes quite plaus-
ible. The calculated value of the energy barrier for rotation
around the ylide bond is about 14 kcalmol–1 (see Support-
ing Information), which is close to the experimental value
of 13 kcalmol–1, a very large frequency factor is expected
for an intramolecular rotation, and the geometry factors
determining the rate of cyclization (distance C7···N1 and
orbital orientations) may be such that the cyclization reac-
tion is fast for one rotamer and very slow for the other one.
We measured the transient absorption spectra by using a CCD
camera coupled to a gated MCP image intensifier (Andor Instaspec
V) attached to a spectrograph (Oriel Multispec). Some time (adjust-
able from –10 ns to several milliseconds) after the excitation of the
sample by an 8-ns pulse of 355-nm light provided by a frequency-
tripled Q-switched Nd-YAG laser (BMI), a delay/pulse generator
(Stanford Research Systems, DG535) activated the MCP during a
given time window (adjustable from 5 ns to several microseconds).
The absorption spectrum of the ylide species was obtained with a
100- or 200-ns time window, much shorter than their lifetime.
We used a package of molecular mechanics and semi-empirical
methods (CAChe 3.2 for Windows) to calculate the geometries, the
enthalpies of formation (MOPAC with PM3 parameters), and the
UV/Vis absorption spectra (ZINDO) of various species involved in
this study.
Conclusions
Thermolysis of chlorophenyldiazirine in the presence of
a large excess of the 2-pyridyl Schiff bases (2-Pyr-CH=NR,
R is an aromatic or alkyl) gives (almost) quantitatively the
corresponding 2-substituted-3-phenylimidazo[1,5-a]pyridi-
nium salt. When the reaction is conducted in an alkane sol-
vent, this salt precipitates and is easily obtained with a high
level of purity after filtration and repeated washing of the
precipitate with a non-polar solvent.
Phenylchlorocarbene was generated by photolysis of chlorophenyl-
diazirine in isooctane by laser pulses at 355 nm. We prepared chlo-
rophenyldiazirine from benzamidine by oxidation with NaOCl, ac-
cording to the procedure by Graham,[15] and purified it by
chromatography on a silica column with hexane as eluent.
The 2-pyridyl Schiff bases 2-Pyr-CH=NR [R = cyclohexyl (1) or
phenyl (2)] were obtained by mixing equimolar amounts of 2-pyr-
idinecarboxaldehyde and cyclohexylamine or aniline in the pres-
ence of catalytic amounts of p-toluenesulfonic acid. The water re-
leased by the reaction was removed from the organic mixture by
A laser flash photolysis study of the reaction mechanism
reveals that the chlorophenylcarbene produced by decom-
position of the diazirine reacts with the Schiff base to give
two different ylides. These two ylides give, upon intramolec- CaCl2. The products were purified by recrystallization from a solu-
tion in hexane. Their purity was checked by IR spectroscopy, where
the CO stretching band of the aldehyde and some bands of the
amine were easily detected.
2-Pyr-CH=NC6H11 (1): UV (in isooctane): λmax (εϫ10–4) = 236
ular cyclization, the same intermediate product, which
rapidly eliminates a chloride anion. Neither a comparison
of the calculated and experimental absorption spectra nor
the semi-empirical calculations of the activation energies for
the formation and cyclization of the various possible ylides
allows us to determine the nature of the two ylides — either
rotamers of a pyridinium ylide or a pyridinium ylide and
an iminium ylide. However, a comparison of systems where
R is a cyclohexyl or a tert-butyl group indicates that the
two ylide species involved in the mechanism are rotamers
of a pyridinium ylide.
nm (1.16), 266 (0.446, sh), 272 (0.454), 280 (0.31, sh). IR: ν = 1437,
˜
1450, 1469, 1568, 1588, 1648, 2855, 2929 cm–1
2-Pyr-CH=NC6H5 (2): UV (in isooctane): λmax (εϫ10–4) = 228 nm
(1.12), 234 (1.12), 260 (1.12, sh), 278 (1.17), 326 (0.6, sh)
Synthesis of III-1: 10 mL of an isooctane solution of chlorophenyl-
diazirine (0.1 ) was added portionwise (2 mL portions added ev-
ery 30 min) to 15 mL of boiling isooctane containing 1.05 g of 1.
Eur. J. Org. Chem. 2006, 5459–5466
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5465

R. Bonneau, P. Guionneau
FULL PAPER
The mixture was then refluxed for 2 h. The yellow precipitate
formed during the reaction was filtered, washed with hexane, and
dissolved in EtOH. The UV absorption spectra of the filtered iso-
octane and of the hexane used to wash the precipitate showed only
the presence of 1 in excess and did not indicate the formation of
the non-ionic product V. Evaporation of the EtOH solution gave
230 mg (isolated yield: 75%) of a product which shows the follow-
ing characteristics: UV (in water): λmax = 292 nm (see Figure 1). IR
[1] A. Padwa, M. D. Weingarten, Chem. Rev. 1996, 96, 223–270;
A. Padwa, S. F. Hornbruckle, Chem. Rev. 1991, 91, 263–309;
A. F. Khlebnikov, R. R. Kostikov, Russ. Chem. Bull. 1993, 42,
653; M. P. Doyle, D. C. Forbes, Chem. Rev. 1998, 98, 911; L. S.
Hegedus, J. Montgomery, Y. Narukawa, D. S. Snustad, J. Am.
Chem. Soc. 1991, 113, 5784–5791; E. Vedejs, J. W. Grissom, J.
Am. Chem. Soc. 1988, 110, 3238–3246.
[2] R. R. Kostikov, A. F. Khlebnikov, V. Y. Bespalov, J. Phys. Org.
Chem. 1993, 6, 83; T. N. Danks, D. Velo-Rego, Tetrahedron
Lett. 1994, 35, 9443; Y. N. Romashin, M. T. H. Liu, R.
Bonneau, Chem. Commun. 1999, 447–448.
(KBr): ν = 710 cm–1, 757, 781, 1167, 1343, 1448, 1470,1526, 1654,
˜
2856, 2940, 3010, 3042, 3073, 3433 (very broad).
Synthesis of III-2: This compound was synthesized analogously to
III-1 but with 2 instead of 1. 1H NMR (250 MHz, CDCl3): δ =
7.08 (t, JH,H = 7 Hz, 1 H, H3 or H4), 7.23 (t, JH,H = 8 Hz, 1 H, H3
or H4; this triplet is mixed with the CHCl3 signal but is clearly
resolved in deuterated acetone), 7.44–7.60 (m, 10 H, phenyls), 7.86
and 7.89 (d, JH,H = 9 Hz,1 H, H2), 8.04 and 8.07 (d, JH,H = 6 Hz,
1 H, H7), 8.13 (s, 1 H, H1) ppm.
[3] R. Bonneau, D. Collado, M. Dalibart, M. T. H. Liu, J. Phys.
Chem. A 2004, 108, 1312–1318.
[4] R. Bonneau, M. T. H. Liu, Eur. J. Org. Chem. 2005, 1532–1540.
[5] US Patent 4,044,015; Donald E. Kulha (Pfizer Inc., USA). Ger.
Offen. 2634910 (1977).
[6] CAChe 3.2, from Oxford Molecular Ltd., UK.
[7] a) Programs for Crystal Structure Analysis (release 97-2).
G. M. Sheldrick, Institüt für Anorganische Chemie der Uni-
versität, Tammanstrasse 4, 3400 Göttingen, Germany, 1998; b)
L. J. Farrugia, J. Appl. Crystallogr. 1999, 32, 837.
Crystallographic Data for III-1: Prismatic, transparent, light-brown
single crystals of approximate dimensions 1.20ϫ0.08ϫ0.08 mm
were selected under a polarizing microscope and mounted on a
Bruker-Nonius κ-CCD diffractometer (Mo-Kα radiation, λ =
0.71073 Å). Data collection was performed at 150 K using mixed
φ and ω scans, 45 s per frame and a crystal–detector distance of
45 mm. Structural determination was performed by direct methods
and the atomic parameters refined by full-matrix least-squares on
F2 using the SHELX-97[7a] programs within the WINGX pack-
age.[7b] C19H23ClN2O, [C19H21N2]·Cl·H2O, orthorhombic, space
group Pbca, a = 10.997(5), b = 11.396(5), c = 27.830(5) Å, V =
3488(2) Å3, ρcalcd. = 1.260 gcm–3, 97.9% completeness to theta
[8] PCC reacts with O2 with kq ≈ 107 –1 s–1 (M. T. H. Liu, R.
Bonneau, C. W. Jefford, J. Chem. Soc., Chem. Commun. 1990,
1482) and with the diazirine with kq ≈ 106 –1 s–1 (R. Bonneau,
M. T. H. Liu, J. Phys. Chem. A 2000, 104, 4115).
[9] Deduced from the values of k1 measured in N2-flushed and O2-
saturated solutions: 1.25ϫ103 and 3.5ϫ103 s–1, respectively.
[10] The order of magnitude of ε at 500 nm is 104 –1 cm–1. This
value is deduced from the absorption spectrum of the iminium
ylide calculated with ZINDO and from the amplitude of the
transient absorptions obtained under the same conditions for
the ylide (PCCǟPhCH=NMe) and for the triplet state of
benzophenone in benzene (see: R. Bonneau, I. Carmichael,
G. L. Hug, Pure Appl. Chem. 1991, 63, 2289). This gives a value
for k2 of around 108 –1 s–1, two orders of magnitude lower
than the rate of diffusion-controlled reactions.
26.37°, 24143 collected data, 3486 independent reflections (Rint
=
0.023) for 216 refined parameters, Robs = 0.033, wR2obs = 0.086,
(∆/σ)max = 0.001, largest difference peak and hole 0.25/–0.26 eA–3.
The crystal packing is based on an asymmetric unit that contains
one formula unit. Chloride and water entities are linked through
hydrogen bonds.
[11] M. T. H. Liu, Y. N. Romashin, R. Bonneau, Int. J. Chem. Ki-
net. 1994, 26, 1179–1184; the values given are Ea
=
12.1Ϯ0.3 kcalmol–1 and logA = 13.4Ϯ0.2. The A factor seems
too large: discarding the point corresponding to the lowest
temperature, a new analysis of the data plotted in Figure 2 of
this reference gives Ea = 11.1 kcalmol–1 and logA = 12.7, i.e.
A = 5ϫ1012 s–1.
The perchlorate of III-2 crystallizes as large, well-shaped, trans-
parent, light-brown single crystals of approximate dimensions
0.5ϫ0.25ϫ0.25 mm. Despite many attempts, the crystal structure
could not be solved in a reliable way. The presence of a strong
statistic disorder affecting both the III-2 entity and the perchlorate
prevents any accurate description of the molecular structures. This
compound crystallizes in the triclinic system with unit cell dimen-
sions a = 9.398(5), b = 12.799(5), c = 14.636(5) Å, α = 89.15(2)°, β =
88.17(2)°, γ = 77.30(2)°, V = 1716(2) Å3. The final classical quality
criterion are acceptable (Robs = 0.074, wR2obs = 0.080) but as al-
most all the atoms occupy two statistical positions no reliable quan-
titative detailed analysis could be performed with this data set.
However, the nature of the sample is clear.
[12] See Figure 14 in ref.[4]
.
[13] At T = 300 K and with a 4 kcalmol–1 difference between the
energy barriers, the kinetic term exp(4000/RT) = 800 so that
the selectivity should be complete.
[14] One may also assume that the absorption coefficients of the
ylides absorbing in the red and in the blue are affected in the
same manner when the Schiff base 1 is changed to 3. If these
two species are rotameric pyridinium ylides, the oscillator
strength of their absorption bands should not depend on the
nature of the Schiff base. Therefore, the values of ε500 and ε650
(in case of 1) should be smaller than ε490 and ε620 (in case of
3), respectively, because both the red and blue absorption
bands are larger in the first case than in the second.
[15] W. H. Graham, J. Am. Chem. Soc. 1965, 87, 4396.
Received: May 4, 2006
CCDC-603236 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/
data_request/cif.
Published Online: August 11, 2006
Acknowledgments
R. B. gratefully acknowledges Professor J. L. Pozzo for his help
with the NMR analysis.
5466
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 5459–5466