Absolute reactivity of halo(pyridyl)carbenes

Article abstract of DOI:10.1021/jo802132z

A comprehensive series of halo(pyridyl)carbenes was generated by laser flash photolysis of the appropriate diazirines. Only the chloro-and bromo(2-pyridyl)carbenes and the chloro-and bromo(3-pyridyl)carbenes could be directly observed, but the reactivity

Full text of DOI:10.1021/jo802132z

Absolute Reactivity of Halo(pyridyl)carbenes
Reinaldo Moya-Barrios, Frances L. Cozens,* and Norman P. Schepp
Department of Chemistry, Dalhousie UniVersity, Halifax, NoVa Scotia B3H 4J3
fcozens@dal.ca
ReceiVed October 8, 2008
A comprehensive series of halo(pyridyl)carbenes was generated by laser flash photolysis of the appropriate
diazirines. Only the chloro- and bromo(2-pyridyl)carbenes and the chloro- and bromo(3-pyridyl)carbenes
could be directly observed, but the reactivity of all nine halo(pyridyl)carbenes could be directly studied
using the standard and a modified pyridine-ylide approach. The carbenes were all ambiphilic, being
highly reactive toward both electron-rich and election-deficient alkenes. Second-order rate constants for
these reactions ranged from 2.9 × 106 to 3.5 × 109 M-1 s-1 and depended on both the position of the
nitrogen atom within the pyridine ring and the nature of the halogen group, as well as the electrophilicity
or nucleophilicity of the alkene. A reactivity trend with respect to the location of the nitrogen within the
pyridine ring was observed, with the 4-pyridyl carbenes being the most reactive followed by the
2-pyridylcarbenes and then the 3-pyridylcarbenes being the least reactive. This observed reactivity trend
is consistent with the pyridyl ring acting as an overall electron-withdrawing group. The results also show
that resonance delocalization of electron density into the nitrogen atom of the 4-pyridyl- and
2-pyridylcarbenes in the transition state significantly reduces the effect of the adjacent halogen (F, Cl, or
Br) on the reactivity of the pyridyl carbenes with a series of alkenes.
Introduction
1, that are of pharmaceutical interest due to their antispasmic,6,7
analgesic,8 anti-inflammatory,8 and kinase inhibitor activities.9,10
There has been continuing interest in the use of carbenes
containing aryl and heterocyclic groups to prepare novel
heterocyclic compounds such as indolizines and heteroarylcy-
clopropanes.1-4 Of the wide variety of different carbenes that
have been used in these reactions, halo(pyridyl)carbenes are
distinctive in that they provide for the synthesis of pyridine-
containing products, such as pyridyl-substituted pyrroles,5 eq
(1) Bonneau, R.; Liu, M. T. H.; Lapouyade, R. J. Chem. Soc., Perkin Trans.
1 1989, 1547–1548.
(2) Baird, M. S.; Bruce, I. J. Chem. Res., Synop. 1989, 374–375.
(3) Moss, R. A.; Jang, E. G.; Kim, H.-R.; Ho, G.-J.; Baird, M. S. Tetrahedron
Lett. 1992, 33, 1427–1430.
(4) Moss, R. A.; Fu, X.; Ma, Y.; Sauers, R. R. Tetrahedron Lett. 2003, 44,
773–776.
(5) Romashin, Y. N.; Liu, M. T. H.; Ma, W.; Moss, R. A. Tetrahedron Lett.
1999, 7163–7165.
(6) Rips, R.; Derappe, C.; Buu-Hoi, N. P. J. Org. Chem. 1960, 25, 390–392.
(7) Buu-Hoi, N. P.; Rips, R.; Cavier, R. J. Med. Pharm. Chem. 1960, 2,
335–337.
At present, the chemistry of only a small number of
halo(pyridyl)carbenes, such as R-chloro-1-3,5 and R-fluoro-
substituted3 2-pyridyl- and 3-pyridylcarbenes, has been inves-
tigated. The generation of these carbenes by thermal or
photochemical decomposition of appropriate diazirines has been
demonstrated,1-3,5 as has their ability to undergo classical
reactions of carbenes, such as addition to alkenes to give pyridyl-
(8) Gillet, C.; Dehoux, E.; Kestens, J.; Roba, J.; Lambelin, G. Eur. J. Med.
Chem., Chim. Ther. 1976, 11, 173–181.
(9) Vanotti, E.; D’Alessio, R.; Tibolla, M.; Varasi, M.; Montagnoli, A.;
Santocanale, C.; Martina, K.; Menichincheri, M. Preparation of pyridylpyrrole
derivatives active as kinase inhibitors. Int. Patent WO 2005013986, June 6, 2004.
(10) Dean, D. K.; Takle, A. K.; Wilson, D. M. Preparation of pyridylfurans
and pyridylpyrroles as Raf kinase inhibitors. Int. Patent WO 20030202832, Sep
5, 2002.
1148 J. Org. Chem. 2009, 74, 1148–1155
10.1021/jo802132z CCC: $40.75 2009 American Chemical Society
Published on Web 12/29/2008

Absolute ReactiVity of Halo(pyridyl)carbenes
pyridine ylides,11,12 which allowed this band to be assigned to
SCHEME 1
the chloro(2-pyridyl)carbene-pyridine ylide, eq 2 (X ) Cl).
LFP of the 3-chloro-3-(3-pyridyl)diazirine in isooctane also
gave results matching those published previously.3 The chloro(3-
pyridyl)carbene 3-Cl at 300 nm was observed immediately after
the laser pulse, Figure 1b. It decayed rapidly with a rate constant
that depended on the concentration of the diazirine to give a
new band at 480 nm that was previously assigned3 to the
chloro(3-pyridyl)carbene-diazirine ylide formed by reaction of
the carbene with its diazirine precursor, eq 3 (X ) Cl).
substituted cyclopropanes.2,3 In addition, the absolute reactivities
of chloro(2-pyridyl)carbene and chloro(3-pyridyl)carbene have
been studied in the presence of a series of electron-rich and
electron-deficient alkenes.3 These results indicated that both the
chloro(2-pyridyl)carbene and the chloro(3-pyridyl)carbene be-
have as ambiphilic species and that the 2-pyridyl derivative is
considerably more reactive than the 3-pyridyl derivative. The
results also demonstrated that both chloro(pyridyl)carbenes are
several times more reactive than the related chloro(phenyl)car-
bene.3 The ability of chloro(4-pyridyl)carbene and chloro(3-
pyridyl)carbene to form ylides with their diazirine precursors
has also been demonstrated in laser photolysis studies.1,3 In these
cases, ylides were generated without the need to add an
additional reagent like pyridine, since the precursor diazirines
already contain a pyridine ring that can add to the photochemi-
cally generated chloro(pyridyl)carbene.
No absorption near 300 nm due to the chloro(4-pyridyl)car-
bene 4-Cl was detected upon laser irradiation of 3-chloro-3-
(4-pyridyl)diazirine in isooctane, Figure 1c. Instead, the ylide
formed by addition of carbene 4-Cl to its diazirine precursor,
eq 4 (X ) Cl) was observed with an absorption maximum at
500 nm.1 Time-resolved growth of this ylide was readily
observed, indicating that the carbene was sufficiently long-lived
to be detected. The inability to detect the carbene therefore
indicates that the chloro(4-pyridyl)carbene 4-Cl has little
absorption above 300 nm in the spectral region accessible under
the conditions of the experiment.
In the present work, a systematic study of the absolute
reactivity of the complete family of halo(pyridyl)carbenes
generated in isooctane by laser flash photolysis (LPF) of the
corresponding diazirines, Scheme 1, is described. Spectral
features of the carbenes as well as their reactivity toward a set
of alkenes were examined. Several aspects of the reactivity of
these carbenes are addressed, such as the effect of the pyridyl
nitrogen and the effect of the halogen substituent. The discussion
is based on the experimental results as well as on theoretical
calculations of halo(pyridyl)carbenes, with the expectation that
these results can contribute to a better understanding of the
interesting chemistry of these species.
Generation of Fluoro(pyridyl)carbenes (2-F, 3-F, and
4-F). Laser irradiation of 3-fluoro-3-(2-pyridyl)diazirine in
isooctane produced no visible transient absorption above 300
nm. However, laser irradiation of the diazirine in the presence
of pyridine (0.32 mM) led to the time-resolved formation of a
transient species with a strong broad absorption band centered
at 480 nm, Figure 1d. The transient species responsible for the
absorption at 480 nm is assigned to the ylide obtained by
trapping of the fluoro(2-pyridyl)carbene 2-F with pyridine, eq
2 (X ) F). This assignment is based on the following
observations. First, the shape and position of the absorption band
at 480 nm is very similar to other halo(aryl)carbene-pyridine
ylides previously reported.11 In addition, a plot of observed rate
constant (kobs) versus concentration of pyridine gave a straight
Results
Generation of Chloro(pyridyl)carbenes (2-Cl, 3-Cl, and
4-Cl). Laser irradiation (355 nm, <8 ns/pulse, e50 mJ/pulse)
of 3-chloro-3-(2-pyridyl)diazirine in isooctane led to the forma-
tion of the previously reported1,3 chloro(2-pyridyl)carbene 2-Cl
with an absorption maximum at 310 nm and a first-order decay
in isooctane of 1.8 × 106 s-1. After addition of pyridine, the
first-order decay of the carbene at 310 nm increased in a linear
manner with respect to pyridine concentration, and this decay
was accompanied by concomitant growth in absorbance at 480
nm, Figure 1a. The absorbance at 480 nm is typical for carbene-
(11) Jackson, J. E.; Platz, M. S. Laser Flash Photolysis Studies of Ylide-
Forming Reactions of Carbenes. In AdVances in Carbene Chemistry; Brinker,
U. H., Ed.; JAI Press, Inc.: Binghamton, NY, 1994; Vol. 1, pp 89-160.
(12) Platz, M. S. Observing Invisible Carbenes by Trapping Them with
Pyridine. In Carbene Chemistry; Bertrand, G., Ed.; FontisMedia S.A. and Marcel
Dekker, Inc.: Lausanne, 2002; pp 27-56.
J. Org. Chem. Vol. 74, No. 3, 2009 1149

Moya-Barrios et al.
FIGURE 1. Transient spectra obtained upon 355 nm laser excitation of the diazirines shown in isooctane at 22 °C under the following conditions:
(a) 1.3 mM diazirine and 0.32 mM pyridine, (b) 3.0 mM diazirine, (c) 0.6 mM diazirine, (d) 1.3 mM diazirine and 0.32 mM pyridine, (e) 1.0 mM
diazirine, (f) 0.8 mM diazirine, (g) 1.3 mM diazirine and 0.32 mM pyridine, (h) 2.4 mM diazirine, and (i) 3.3 mM diazirine. Downward and upward
arrows indicate time-resolved absorption decays and growths, respectively. Legends indicate the time at which the spectra were obtained after the
laser pulse.
line with a slope corresponding to the bimolecular rate constant
for the formation of the transient at 480 nm (ky ) 2.9 × 109
M-1 s-1) that is consistent with the trapping of a carbene with
pyridine.
According to these results, none of the fluoro(pyridyl)carbenes
could be directly observed after 355 nm laser excitation of their
corresponding diazirine precursors. However, the observation
of the growth curves for ylide formation indicates that in all
cases these carbenes are sufficiently long-lived for study using
the nanosecond laser system. These results are similar to those
reported for fluoro(phenyl)carbene which absorbs at 270 nm
and has no absorption above 300 nm in the UV-vis spectrum.13
Generation of Bromo(pyridyl)carbenes (2-Br, 3-Br, and
4-Br). Laser irradiation of 3-bromo-3-(2-pyridyl)diazirine in
isooctane produced a transient spectrum that was dominated by
an absorption band centered at 330 nm. This transient absorption
band was assigned to the bromo(2-pyridyl)carbene 2-Br based
on the following observations. The location of the absorption
maximum and narrow shape of the absorption band are similar
to the known absorption spectrum for the bromo(phenyl)carbene
in solution.13 In addition, the transient showed a reactivity
pattern typical of carbenes, including a rapid reaction with
pyridine (ky ) 2.7 × 109 M-1 s-1) to form a broad and intense
absorption band at 500 nm, Figure 1g, assigned to the carbene-
pyridine ylide, eq 2 (X ) Br).
Photolysis of 3-fluoro-3-(3-pyridyl)diazirine in isooctane
produced the transient absorption spectra shown in Figure 1e.
Again, the spectra showed no absorption in the 300 nm region
due to the fluoro(3-pyridyl)carbene 3-F. However, the spectra
did show a strong absorption band centered at 450 nm that
formed in a time-resolved manner. The growth of the transient
at 450 nm was linearly dependent on the concentration of the
diazirine precursor, giving a second order rate constant, ky )
2.6 × 109 M-1 s-1. The spectral features of the transient at 450
nm, in addition to the large value of the bimolecular rate constant
for its formation, are very similar to those observed for the
chloro(pyridyl)carbene-diazirine ylides previously reported.1,3
Therefore, the absorption band at 450 nm can be confidently
identified as the fluoro(3-pyridyl)carbene-diazirine ylide, eq 3,
X ) F, formed upon reaction of the fluoro(3-pyridyl)carbene
3-F with its diazirine precursor.
Similarly, laser irradiation of 3-fluoro-3-(4-pyridyl)diazirine
in isooctane yielded an absorption spectra with no significant
absorption near 300 nm. Instead, the spectra showed intense
absorption band centered at 480 nm that grew in as a function
of time, Figure 1f, and was assigned to the fluoro(4-pyridyl-
)carbene-diazirine ylide, eq 4 (X ) F). The second-order rate
constant for the reaction of carbene 4-F with its diazirine
Laser irradiation of 3-bromo-3-(3-pyridyl)diazirine in isooc-
tane solution led to a transient absorption spectrum containing
one absorption band at 330 nm and a second at 490 nm, Figure
1h. The decay of the transient species at 330 nm is concurrent
with the growth of the species at 490 nm, showing that the
(13) Cox, D. P.; Gould, I. R.; Hacker, N. P.; Moss, R. A.; Turro, N. J.
Tetrahedron Lett. 1983, 24, 5313–5316.
precursor was determined to be 5.5 × 109 M-1 s-1
1150 J. Org. Chem. Vol. 74, No. 3, 2009
.

Absolute ReactiVity of Halo(pyridyl)carbenes
FIGURE 2. (a) Time-resolved changes in absorbance at 490 nm upon laser irradiation of 3-fluoro-3-(4-pyridyl)diazirine (1.2 × 10-3 M) in isooctane
containing (9) 0 M, (0) 0.81 mM, (b) 1.3 mM, and (O) 1.8 mM of 2,3-dimethyl-2-butene. (b) Relationship between the observed rate constant for
the growth of the ylide at 490 nm, formed by addition of the fluoro(4-pyridyl)carbene to the 3-fluoro-3-(4-pyridyl)diazirine, and the concentration
of 2,3-dimethyl-2-butene in isooctane at 22 °C.
transient at 490 nm is a product from the reaction of the transient
at 330 nm. These result are analogous to those reported for
chloro(3-pyridyl)carbene in isooctane,3 and the absorption band
at 330 nm can be assigned to bromo(3-pyridyl)carbene 3-Br,
and the broad absorption band at 490 nm to the bromo(3-
pyridyl)carbene-diazirine ylide, eq 3 (X ) Br). The second order
rate constant for the formation of carbene-diazirine ylide was
sors to generate readily observed carbene-diazirine ylides.
Therefore, in order to determine the reactivity of the halo(4-
pyridyl)- and halo(3-pyridyl)carbenes with a set of alkenes, the
growths of the carbene-diazirine ylides were measured at a
known concentration of diazirine but at different concentrations
of the alkene quencher. Under these conditions, the observed
rate constant (kobs) for the formation of a carbene-diazirine ylide
is given by eq 5
determined to be ky ) 1.4 × 109 M-1 s-1
.
Laser irradiation of 3-bromo-3-(4-pyridyl)diazirine in isooc-
tane yielded a transient absorption spectrum dominated by a
single broad absorption band centered at 520 nm, Figure 1i.
The shape and position of this absorption band are similar to
the other pyridyl carbene-diazirine absorption bands described
above and previously reported.1,3 Thus, the 520 nm absorption
band is assigned to the bromo(4-pyridyl)carbene-diazirine ylide,
eq 4 (X ) Br), formed by addition of bromo(4-pyridyl)carbene
4-Br to its diazirine precursor. The carbene-diazirine ylide is
formed with a bimolecular rate constant, ky ) 3.7 × 109 M-1
s-1. The bromo(4-pyridyl)carbene 4-Br presumably has no
strong absorbance above 300 nm, similar to chloro- and fluoro(4-
pyridyl)carbenes described above.
kobs ) ko + kdiaz[diazirine]o + kq[alkene]
(5)
where ko is the first-order rate constant that represents all the
first-order and pseudo-first-order processes that the carbene
undergoes other than the reaction with the diazirine precursor,
kdiaz is the second-order rate constant for the reaction of the
carbene with the diazirine, [diazirine]o is the known, initial
concentration of diazirine, kq is the second-order rate constant
for the reaction of the carbene with the alkene, and [alkene] is
the known concentration of the alkene added to the solution.
According to this equation, a plot of kobs versus alkene
concentration at a constant diazirine concentration should be
linear with the slope giving the second-order rate constant for
the reaction of the carbene with the alkene.
Study of the Reactivity of Halo(pyridyl)carbenes with
Alkenes. Moss and co-workers studied the reactivity of chloro(2-
pyridyl)carbene 2-Cl and chloro(3-pyridyl)carbene 3-Cl toward
electron-rich and electron-deficient alkenes.3 Their study was
carried out by monitoring the decay of the absorption band of
the two carbenes at 310 nm as a function of the concentration
of alkene. In the present work, only four of the nine halo(py-
ridyl)carbenes investigated have significant absorption in the
UV region above 300 nm and therefore the methodology used
in the previous study could not be applied in this work to all
nine carbenes. In view of this, an alternative approach based
on monitoring the time-resolved evolution of ylides was used.
The advantage of using ylide-forming reactions to study
carbenes is well documented.11,12 The ylide method is particu-
larly useful when the carbenes that are being investigated are
“invisible” in the accessible UV-vis region of the absorption
spectrum, such as the five carbenes not directly observed in the
present work, or when the absorption band of the carbene
overlaps strongly with the absorption band of their precursor.
Typically, the ylide method requires the addition of pyridine
as a reagent to quench the carbene and generate the detectable
carbene-ylide. However, in the current work, a pyridine ring
was already present as a structural feature on the diazirines used
as the carbene precursors, and as described above the halo(4-
pyridyl)- and halo(3-pyridyl)carbenes reacted with their precur-
Figure 2a shows the time-resolved growth kinetics of the ylide
formed upon reaction of the fluoro(4-pyridyl)carbene 4-F at
various concentrations of 2,3-dimethyl-2-butene. As shown in
Figure 2b, the observed rate constant for the growth of the ylide
increased in a linear manner with respect to 2,3-dimethyl-2-
butene concentration, and treatment of these data with eq 5 led
to the second-order rate constant for reaction of carbene 4-F
with the 2,3-dimethyl-2-butene of kq ) 3.5 × 109 M-1 s-1. Rate
constants for quenching of the each 3-pyridyl- (3-F, 3-Cl, and
3-Br) and 4-pyridylcarbenes (4-F, 4-Cl, and 4-Br) with a variety
of alkenes were obtained in a similar manner, and these rate
constants are summarized in Table 1.
To maintain experimental consistency, it would have been
ideal to examine the reactivity of the 2-pyridyl carbenes with
alkenes in the same manner as described for the 3-pyridyl- and
4-pyridylcarbenes. However, none of the 2-pyridylcarbenes
reacted with their diazirine precursors to form ylides. On the
other hand, all three 2-pyridylcarbenes formed strongly absorb-
ing ylides when generated in the presence of small amounts of
pyridine. Thus, absolute rate constants for the addition of
carbenes 2-Cl, 2-F, and 2-Br to the alkenes were measured using
the conventional pyridine-ylide method. This method is same
as that described above, except that the relevant rate expression
shown in eq 6 contains a term, kpyr[pyridine]o, that defines the
J. Org. Chem. Vol. 74, No. 3, 2009 1151

Moya-Barrios et al.
TABLE 1. Second-Order Rate Constants (kq) for the Reaction of the Halo(pyridyl)carbenes with a Series of Alkenes in Isooctane at 22 °C
a
kq (106 M-1 s-1
)
alkene
2-F
3-F
4-F
2-Cl
3-Cl
4-Cl
2-Br
3-Br
4-Br
(CH3)2CdC(CH3)2
(CH3)2CdCHCH3
cyclohexene
n-BuCHdCH2
CH2dCHCO2CH3
CH2dCClCN
1900
970b
130
40
44
460
520
210
8.6
2.9
27
150
3500
2100
140
54
55
260
1700 (1100)d
930 (720)d
100
710(420)d
420(180)d
15b
2400
870
150b
66
42
780
1700
860
150
39
45
1300
1400b
640b
44
2400
1400b
320c
30 (20)d
36
9.1(6.2)d
15
17
90c
26
100b
1100c
790 (460)d
300(190)d
660b
a Errors are 10 ( 5% unless otherwise indicated. b Error is 20 ( 5%. c Error is 50 ( 5%. d Data taken from ref 3.
TABLE 2. HOMO and LUMO Energies and Mulliken Atomic
Charges at the Carbenic Carbon of Halo(pyridyl)carbenes in the
Gas Phase and Carbenic Carbon-Pyridyl Ring Carbon Bond
Lengths (d(C(carbenic)-C) of Halo(pyridyl)carbenes and
Halo(phenyl)carbenes in the Gas Phase Calculated at the B3LYP/
6-31G* Level
Discussion
Reactivity of Halo(pyridyl)carbenes with Alkenes. The data
in Table 1 show that the rate constants for the reactions of the
halo(pyridyl)carbenes with electron-rich and electron-deficient
alkenes are faster than the rate constants for the reaction of the
halo(pyridyl)carbenes with 1-hexene. These results are the same
as those previously observed for the reactions of chloro(2-
pyridyl)carbene 2-Cl and chloro(3-pyridyl)carbene 3-Cl with a
similar set of alkenes,3 although the rate constants measured in
the earlier work are slightly smaller than those obtained in the
present work. In fact, the trend where carbenes are more reactive
with both electron-rich and electron-poor alkenes is often
seen17,18 and in the present case leads to the conclusion that all
of the halo(pyridyl)carbenes studied in the present work are
ambiphilic species, behaving as electrophiles when reacting with
electron-rich alkenes such as 2,3-dimethyl-2-butene and as
nucleophiles when reacting with electron-poor alkenes such as
2-chloroacrylonitrile.
HOMO LUMO
energy energy Mulliken charge d(C(carbenic)-C)
compd
(eV)
(eV)
on C: carbon
(Å)
2-PyFC: (2-F)
3-PyFC: (3-F)
4-PyFC: (4-F)
-5.951 -2.808 +0.1868
-6.092 -2.826 +0.1463
-6.279 -3.074 +0.1628
1.493
1.470
1.483
1.470
1.480
1.455
fluoro(phenyl)carbene
2-PyClC: (2-Cl)
3-PyClC: (3-Cl)
4-PyClC: (4-Cl)
chloro(phenyl)carbene
2-PyBrC: (2-Br)
3-PyBrC: (3-Br)
4-PyBrC: (4-Br)
bromo(phenyl)carbene
-5.940 -3.268 -0.08562
-6.043 -3.269 -0.1503
-6.211 -3.512 -0.1347
1.470
1.456 (1.457)a
1.467
-5.965 -3.280 +0.0006390
-6.002 -3.322 -0.06180
-6.157 -3.561 -0.04542
1.453
1.473
1.453
a Data taken from ref.14
Effect of the Position of the Pyridyl Nitrogen on the
Halo(pyridyl)carbene Reactivity. In previous work, Moss and
co-workers found that the reactivity of the chloro(2-pyridyl-
)carbene 2-Cl toward alkenes was roughly 2.5-4 times greater
than that of the chloro(3-pyridyl)carbene 3-Cl,3 Table 1. The
higher reactivity of 2-Cl compared to 3-Cl was attributed to
the fact that the electronegative nitrogen atom in 2-Cl is closer
to the carbenic center than in 3-Cl, which causes the pyridine
ring in 2-Cl to have a stronger electron-withdrawing inductive
effect than the pyridine ring in 3-Cl. As can be seen in Table
1, this trend does not extend to the chloro(4-pyridyl)carbene
4-Cl. In this carbene, the pyridyl nitrogen is furthest from the
carbenic center, but its reactivity with the different alkenes is
considerably higher than the reactivity of the chloro(3-pyridyl)
carbene 3-Cl and in most cases slightly higher than the reactivity
of 2-Cl. This order of reactivity as a function of nitrogen position
is not restricted to the R-chloro carbenes but was also observed
for the fluoro(pyridyl)- and bromo(pyridyl)carbenes. Based on
these observations, the proximity of the pyridyl nitrogen to the
carbene center does not appear to be the only factor that
contributes to the reactivity of the halo(pyridyl)carbenes. Instead,
the fact that halo(4-pyridyl)carbenes react faster than the halo(3-
pyridyl)carbenes and similar to the halo(2-pyridyl)carbenes
suggests that the mesomeric effects are also important. In
particular, resonance electron donation from the pyridine ring
to the vacant p orbital on the carbene center induces a partial
positive charge on positions 2 and 4 of the pyridine ring, but
not on position 3. When this partial positive charge is located
on the electronegative nitrogen atom as occurs for the 4- and
rate constant for the addition of the carbene to pyridine at a
constant pyridine concentration rather than a term describing
the addition of the carbene to a diazirine precursor.
kobs ) ko + kpyr[pyridine]o + kq[alkene]
(6)
Since ko and kpyr[pyridine]o in eq 6 are constant for a given
concentration of pyridine, the relationship between the observed
rate constant and alkene concentration should be linear, with kq
being obtained from the slope. In all cases, plots obtained from
the variation of observed rate constant of the halo(2-pyridyl-
)carbene-pyridine growth as a function of alkene concentration
were linear. From the slopes of these graphs, the second-order
rate constants for the carbene addition to the alkenes reported
in Table 1 were obtained.
Theoretical Calculations on Halo(pyridyl)carbenes. The
halo(pyridyl)carbenes and halo(phenyl)carbenes14 were com-
puted at the B3LYP/6-31G* level of theory to be singlet ground-
state carbenes with X-C-C angles in the range of 106-112°,
consistent with singlet state species.14-16 Data obtained from
the calculations that are relevant to the discussion of the
experimental results are given in Table 2 and include
C(carbenic)-C bond lengths, Mulliken atomic charges on the
carbenic carbon, and the HOMO and LUMO energies for all
halo(pyridyl)carbenes studied in the present work. Other results
from the computations are included as Supporting Information.
(14) Pliego, J. R. J.; De Almeida, W. B.; Celebi, S.; Zhu, Z.; Platz, M. S. J.
Phys. Chem. A 1999, 103, 7481–7486.
(15) Harrison, J. F. J. Am. Chem. Soc. 1971, 93, 4112–4119.
(16) Sulzbach, H. M.; Bolton, E.; Lenoir, D.; Schleyer, P. v. R.; Schaefer,
H. F., III. J. Am. Chem. Soc. 1996, 118, 9908–9914.
(17) Moss, R. A.; Lawrynowicz, W.; Hadel, L. M.; Hacker, N. P.; Turro,
N. J.; Gould, I. R.; Cha, Y. Tetrahedron Lett. 1986, 27, 4125–4128.
(18) Moss, R. A.; Fan, H.; Hadel, L. M.; Shen, S.; Wlostowska, J.;
Wlostowski, M.; Krogh-Jespersen, K. Tetrahedron Lett. 1987, 28, 4779–4782.
1152 J. Org. Chem. Vol. 74, No. 3, 2009

Absolute ReactiVity of Halo(pyridyl)carbenes
SCHEME 2
2-pyridyl carbenes, the carbenes are destabilized and their
reactivity increases. This is consistent with the known effect of
the nitrogen atom in pyridine rings on electrophilic substitution
reactions,19 which are most disfavored at the 2- and 4-positions
since substitution at those positions produces an unstable
intermediate with positive charge on the electronegative nitrogen.
The position of the nitrogen atom in the ring may also
influence the relative stabilities of the transition states for the
addition of the pyridyl carbenes to alkenes. The transition state
for such reactions is considered to be asymmetric,20 with charge
build-up at both the carbenic carbon and at the olefinic carbon.
For electrophilic addition of carbenes to alkenes, a partial
negative charge is found at the carbenic carbon in the transition
state as shown in Scheme 2. Such a transition state resembles
the structure of pyridylmethyl anions, which are strongly
stabilized by the resonance electron-withdrawing ability of 2-
and 4-pyridyl rings. For example, 2- and 4-methylpyridine are
much more acidic than 3-methylpyridine, and 4-methylpyridine
is approximately 3 orders of magnitude more acidic than
2-methylpyridine.21 Thus, the transition state for electrophilic
addition of halo(4-pyridyl)- and halo(2-pyridyl)carbenes to
alkenes should also be stabilized by resonance delocalization
of the negative charge to the nitrogen, and reactions progressing
through these transition states should be more rapid than
reactions involving the halo(3-pyridyl)carbenes.
The relative reactivities of carbenes toward alkenes has been
explained by differences in the HOMO and LUMO energies of
carbenes.22 In particular, the electrophilic addition of carbenes
to electron-rich alkenes is predicted to be more favorable for
carbenes having low-lying LUMO orbitals that increase the
electron-accepting ability of the carbene in comparison to
carbenes with higher energy LUMO orbitals. LUMO energies
calculated for halo(pyridyl)carbenes have been plotted in a
potential energy diagram, Figure 3. As can be seen, the LUMO
energies of halo(4-pyridyl)carbenes are in all cases significantly
lower than those for the halo(2-pyridyl)- and halo(3-pyridyl-
)carbenes, suggesting a higher reactivity of the former. This
agrees well with our experimental results showing that the
halo(4-pyridyl)carbenes were in every case more reactive toward
electron-rich alkenes than the other two groups of isomers. On
the other hand, the LUMO energies in Figure 3 for the halo(2-
pyridyl)carbenes are slightly higher than for the halo(3-
pyridyl)carbenes, which leads to the prediction that the halo(2-
pyridyl)carbenes should be the least reactive isomers. In this
case, the experimental results do not agree with the theoretical
prediction, since the reactivities of halo(2-pyridyl)carbenes
FIGURE 3. LUMO energies calculated for halo(pyridyl)carbenes at
the B3LYP/6-31G* level.
toward electron-rich alkenes were significantly higher than those
of halo(3-pyridyl)carbenes.3 Thus, the calculated LUMO ener-
gies do not provide a comprehensive explanation for the
experimental order of reactivity observed for these two groups
of carbenes.
Other computational results are consistent with the higher
reactivity of the 2- and 4-pyridylcarbenes relative to the
3-pyridylcarbenes, but these do not provide a complete explana-
tion for the higher reactivity of the 4-pyridyl carbenes relative
to the 2-pyridylcarbenes. In particular, the Mulliken charge
densities23 in Table 2 indicate that the carbenic carbons of the
2- and 4-pyridylcarbenes have larger positive charges (or smaller
negative charges) compared to the 3-pyridylcarbenes, which in
turn suggests higher electrophilicity of the 2- and 4-pyridyl-
carbenes. However, the charges at the carbenic carbon of the
2-pyridyl carbons are more positive than those of the 4-py-
ridylcarbenes, which contradict the experimental results showing
that the latter are more reactive toward electron-rich alkenes.
The computations also show that the bond between the carbenic
carbon and the aromatic carbon is substantially elongated in
the 2- and 4-pyridylcarbenes relative to the 3-pyridylcarbenes,
which in turn have C(carbenic)-C bond lengths that are almost
identical to the length of the same bond in halo(phenyl)carbenes.
These observations are consistent with the reduced resonance
electron-donating ability of the pyridine rings in the 2- and
4-pyridylcarbenes that leaves the carbenic carbon on those
carbenes with a greater positive charge (or smaller negative
charge) than the 3-pyridylcarbene. In addition, a reduction in
double bond character due to the unfavorable resonance interac-
tion between the vacant p-orbital of the carbene and the pyridine
ring in the 2- and 4-pyridylcarbenes increases the C(carbenic)-C
bond distance in 2- and 4-pyridylcarbenes compared to the same
bond distance in the halo(3-pyridyl)carbene as well as the
halo(phenyl)carbenes.
(19) Gilchrist, T. L. Heterocyclic Chemistry; Addison Wesley Longman
Limited: Essex, 1997.
(20) Moss, R. A.; Turro, N. J. Laser Flash Photolytic Studies of Arylhalo-
carbenes. In Kinetics and Spectroscopy of Carbenes and Biradicals; Platz, M. S.,
Ed.; Plenum Press: New York, 1990; pp 213-238.
Overall, the computational parameters help to understand the
higher reactivity of the 4-pyridylcarbenes, but no single
(21) Seconi, G.; Eaborn, C.; Fischer, A. J. Organomet. Chem. 1979, 177,
129–136.
(23) Mulliken, R. S. J. Chem. Phys. 1955, 23, 1833–1840.
(24) Graham, W. H. J. Am. Chem. Soc. 1965, 87, 4396–4397.
(25) Barber, J.; Slack, R. J. Am. Chem. Soc. 1944, 66, 1607–1607.
(22) Moss, R. A. Carbenic Philicity. In Carbene Chemistry; Bertrand, G.,
Ed.; FontisMedia S.A. and Marcel Dekker, Inc.: Lausanne, 2002.
J. Org. Chem. Vol. 74, No. 3, 2009 1153

Moya-Barrios et al.
FIGURE 4. Second-order rate constants for the reaction of (0) halo(phenyl)carbenes (from ref 13), (O) halo(3-pyridyl)carbenes, (b) halo(2-
pyridyl)carbenes, and (9) halo(4-pyridyl)carbene with (a) 2,3-dimethyl-2-butene, (b) 1-hexene, and (c) 2-chloroacrylonitrile in isooctane at 22 (
1 °C.
parameter provides a complete explanation for the overall
reactivity trend, 4-pyridyl > 2-pyridyl > 3-pyridyl. Thus, it is
likely that factors that affect the fundamental reactivity of the
carbenes, such as relative LUMO energies and positive charge
density, and those that affect the stability the transition state
combine to cause the observed difference in reactivities of the
carbenes as a function of the position of the nitrogen atom in
the pyridine rings. The high reactivity of 2-pyridylcarbenes
toward electron-rich carbenes, despite having high LUMO
energies, clearly indicates that the inductive-withdrawing effect
of the nitrogen atom in the pyridine ring has a major influence
on the reactivity of 2-pyridylcarbenes with alkenes. In contrast,
the reactivity of 4-pyridylcarbenes seems to be greatly dictated
by the low-lying LUMO energy of these species.
Effect of the Halogen Substituent on the Halo(pyridyl)car-
bene Reactivity. The halogen attached to the carbene center of
halo(phenyl)carbenes is known to have a significant effect on
the reactivity of the carbenes with alkenes,12 with fluoro(phe-
nyl)carbene being the least reactive and bromo(phenyl)carbene
being the most reactive. This order of reactivity20 is due to
fluorine being best able to stabilize the carbene by resonance
donation to the empty 2p orbital and by inductive withdrawal
of electron density from the filled, nonbonding sp2 orbital. The
reactivity of the halo(3-pyridyl)carbenes, 3-F, 3-Cl, and 3-Br,
with alkenes in Table 1 followed the same order, Figures 4a,b
(open circles), presumably for the same reasons as described
for the halo(phenyl)carbenes. The order of reactivities also
correlates nicely with the LUMO energies of the halo(3-
pyridyl)carbenes. The most reactive halo(3-pyridyl)carbene, the
bromo derivative 3-Br, has the lowest calculated LUMO energy,
and the least reactive fluoro(3-pyridyl)carbene 3-F has the
highest calculated LUMO energy, Table 3. The effect of halogen
substituents on the reactivity of the halo(2-pyridyl)- and halo(4-
pyridyl)carbenes with electron-deficient alkenes like 2-chloro-
acrylonitrile was the same as that observed for the halo(3-
pyridyl)carbenes and halo(phenyl)carbenes, namely that the
fluoro derivatives were least reactive, and the bromo derivatives
most reactive, Figure 4c. However, the effect of halogen
substituents on the reactivity of halo(2-pyridyl)- and halo(4-
pyridyl)carbenes with electron-rich alkenes is surprisingly small
as illustrated in Figure 4a,b, and in some cases shows a reverse
order, with the fluoro(2-pyridyl)- and fluoro(4-pyridyl)carbenes
being slightly more reactive than the chloro and bromo
derivatives. Thus, the pyridine rings in halo(2-pyridyl)- and
halo(4-pyridyl)carbenes seem to produce a leveling effect on
the carbene reactivity that reduces the effect of the halogen atom
on the reactivity of the carbene.
of the carbenes to alkenes is presumed to have a partial negative
charge at the carbenic carbon. For halo(phenyl)carbenes, the
halogen substituent can significantly affect the stability of this
transition state, with the strongly electronegative fluorine
imparting more stabilization than the less electronegative
bromine and increasing the rate constant for the addition
reaction. In the transition state for the reaction of the 2- and
4-pyridylcarbenes, the negative charge may be delocalized into
the electron-withdrawing nitrogen group. As a result, the
magnitude of the negative charge at the benzylic center is
reduced, and ability of the R-halo groups to influence the
stability of the reaction is diminished. On the other hand, for
halo(3-pyridyl)carbenes, the negative charge is more localized
on the carbene carbon and thus depends more on the electron-
withdrawing inductive effect of the halogen atom to stabilize
their transition states in the reactions with alkenes.
Conclusion
The results described demonstrate that all of the halo(py-
ridyl)carbenes studied in the present work are ambiphilic species,
a property that they share with the well-studied halo(phenyl)
carbenes. In addition, the results also show that the location of
the nitrogen within the pyridyl ring has a strong influence on
the reactivity of the carbenes, with the nitrogen in the 2- or
4-positions providing the greatest rate enhancement due to a
combination of effects of the nitrogen on the stability of the
carbene as well as the stability of the transition state for reaction
with alkenes. The presence of the nitrogen also reduces the
influence of the different halo groups on the reactivity of the
halo(2-pyridyl)- and halo(4-pyridyl)carbenes, presumably due
to the charge developed in the transition state being delocalized
into the ring nitrogen, thus reducing the effectiveness of the
halogen in stabilizing the negative charge.
Experimental Section
Materials. The synthesis of 3-chloro-3-(2-pyridyl)diazirine,1,2
3-chloro-3-(3-pyridyl)diazirine,1,2 3-chloro-3-(4-pyridyl)diazirine,1,2
3-fluoro-3-(2-pyridyl)diazirine,3 and 3-fluoro-3-(3-pyridyl)diazirine3
have been reported previously. 3-Fluoro-3-(4-pyridyl)diazirine was
prepared3,27 by exchange reactions of 3-chloro-3-(4-pyridyl)diaz-
irine with molten tetra-n-butylammonium fluoride. The 3-bromo-
3-(pyridyl)diazirines were prepared from the corresponding py-
ridylamidine hydrochlorides25,27 following a modified method27 of
the Graham reaction. Complete details regarding the synthesis and
characterization of these diazirines are provided in the Supporting
Information.
(26) Medwid, J. B.; Paul, R.; Baker, J. S.; Brockmann, J. A.; Du, M. T.;
Hallet, W. A.; Hanifin, J. W.; Hardy, R. A.; Tarrant, M. E.; Torley, L. W.; Wrenn,
S. J. Med. Chem. 1990, 33, 1230–1241.
(27) Moss, R. A.; Terpinski, J.; Cox, D. P.; Denney, D. Z.; Krogh-Jespersen,
K. J. Am. Chem. Soc. 1985, 107, 2743–2748.
A possible explanation lies in the combined effects of the
halogen and the pyridine nitrogen on the stability of the
transition state. The transition state for the electrophilic addition
1154 J. Org. Chem. Vol. 74, No. 3, 2009

Absolute ReactiVity of Halo(pyridyl)carbenes
Laser Flash Photolysis. The computer-controlled nanosecond
laser flash photolysis system employed in this study has been
previously described.28 The excitation source was the third harmonic
of a Nd:YAG laser (355 nm, 20 mJ/pulse, <8 ns/pulse). Sample
cells for laser experiments were constructed of 7 × 7 mm2 Suprasil
quartz tubing. Each sample contained 2 mL of aerated spectrograde
isooctane to which was added 10-20 µL of a diazirine stock
solution (made in dichloromethane). The final concentration of
diazirine precursor was in the range of 0.5-2 mM, with absorption
at the excitation wavelength of 355 nm in the 0.2-0.4 range. In
addition, pyridine concentrations in the range of 0.2-5 mM were
used in experiments with 3-halo-3-(2-pyridyl)diazirines. In the
quenching experiments, small amounts (1 to 50 µL) of alkene stock
solution were added to the sample cells. Samples were shaken after
every laser shot to ensure their homogeneity. All experiments were
conducted at room temperature (22 ( 1 °C).
Acknowledgment. We gratefully acknowledge the Natural
Sciences and Engineering Research Council of Canada (NSERC)
for financial support of this research.
Supporting Information Available: Synthesis and NMR
characterization of 3-fluoro-3-(4-pyridyl)diazirine and the 3-bro-
mo-3-(pyridyl)diazirines. Cartesian coordinates and absolute
energies for the halo(pyridyl)carbenes and halo(phenyl)carbenes.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO802132Z
(29) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;
Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian,
H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski,
J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg,
J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.;
Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian 03, revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.
Computational Method. The geometries of the halo(pyridyl)
carbenes and halo(phenyl)carbenes used in this work were optimized
using the Gaussian03 suite of programs.29 Geometry optimizations
were carried out at the B3LYP/6-31G* level of theory. All
stationary points were characterized by normal coordinate analysis.
(28) O’Neill, M. A.; Cozens, F. L.; Schepp, N. P. J. Am. Chem. Soc. 2000,
122, 6017–6027.
J. Org. Chem. Vol. 74, No. 3, 2009 1155