Hydration of pyridylketenes: Formation of acid enol and dihydropyridine (Eneaminone) transients

Article abstract of DOI:10.1021/ja047623n

2-, 3-, and 4-Pyridylketenes 4 formed in water by photochemical Wolff rearrangements using flash photolysis undergo rapid hydration forming transient intermediates observed by UV spectroscopy. 3-Pyridylketene (3-4) formed the acid enol intermediate 3-10 which was converted to the acid 3-11, and phenylketene gave similar behavior. 4-Pyridylketene (4-4) reacted with a similar initial rate constant of 5.0 × 10⁴ s^-1 for decay of an absorption at 275 nm, with concomitant formation of a strong absorption at 370 nm with the same rate constant. The intermediate absorbing at 370 nm decayed with a lifetime 2.4 × 10³ fold longer than that of the ketene, and is identified as 4-(carboxymethylene)-1,4-dihydropyridine (4-13), resulting from conjugate 1,6-addition of H₂O to 4-4. 2-Pyridylketene (2-4) underwent hydration with a similar rate constant of 1.1 × 10⁴ s^-1 forming a transient with a UV absorption with maxima at 310 and 380 nm that decayed with biexponetial kinetics, with rate constants slower than the rate of formation by factors of 5.2 and 110, respectively. These results are interpreted as indicating the presence of two species, namely Z- and E-2-(carboxymethylene)-1,2-dihydropyridines (2-13), resulting from conjugate 1,4-addition of H₂O to 2-4. The identifications of the 1,2- and 1,4-(carboxymethylene)dihydropyridines 2- and 4-13 were confirmed by comparison of their UV spectra with those of the corresponding N-methyl derivatives. The amination of 2-pyridylketene in CH₃CN was reinvestigated, and spectroscopic evidence, computational studies, and preparation of the N-methyl analogue demonstrated formation of the 1,2-dihydropyridine Z-2-8f as the long-lived intermediate.

Full text of DOI:10.1021/ja047623n

Published on Web 11/12/2004
Hydration of Pyridylketenes: Formation of Acid Enol and
Dihydropyridine (Eneaminone) Transients
†
Annette D. Allen, Andrei V. Fedorov, Thomas T. Tidwell,* and Sinisa Vukovic
Contribution from the Department of Chemistry, UniVersity of Toronto,
Toronto, Ontario M5S 3H6 Canada
Received April 24, 2004; E-mail: ttidwell@chem.utoronto.ca
Abstract: 2-, 3-, and 4-Pyridylketenes 4 formed in water by photochemical Wolff rearrangements using
flash photolysis undergo rapid hydration forming transient intermediates observed by UV spectroscopy.
3-Pyridylketene (3-4) formed the acid enol intermediate 3-10 which was converted to the acid 3-11, and
phenylketene gave similar behavior. 4-Pyridylketene (4-4) reacted with a similar initial rate constant of 5.0
4
-1
×
10 s for decay of an absorption at 275 nm, with concomitant formation of a strong absorption at 370
3
nm with the same rate constant. The intermediate absorbing at 370 nm decayed with a lifetime 2.4 × 10
fold longer than that of the ketene, and is identified as 4-(carboxymethylene)-1,4-dihydropyridine (4-13),
2
resulting from conjugate 1,6-addition of H O to 4-4. 2-Pyridylketene (2-4) underwent hydration with a similar
4
-1
rate constant of 1.1 × 10 s forming a transient with a UV absorption with maxima at 310 and 380 nm
that decayed with biexponetial kinetics, with rate constants slower than the rate of formation by factors of
5.2 and 110, respectively. These results are interpreted as indicating the presence of two species, namely
Z- and E-2-(carboxymethylene)-1,2-dihydropyridines (2-13), resulting from conjugate 1,4-addition of H
2
O
to 2-4. The identifications of the 1,2- and 1,4-(carboxymethylene)dihydropyridines 2- and 4-13 were confirmed
by comparison of their UV spectra with those of the corresponding N-methyl derivatives. The amination of
3
2-pyridylketene in CH CN was reinvestigated, and spectroscopic evidence, computational studies, and
preparation of the N-methyl analogue demonstrated formation of the 1,2-dihydropyridine Z-2-8f as the long-
lived intermediate.
1
The mechanisms of ketene hydration have been of great
cyclic transition state 2a leading to the enol 3 of acetic acid is
preferred (eq 2), with a much lower barrier than for addition of
a single water molecule, as confirmed by the most recent
interest since the classic experimental studies by Schulte-
Frohlinde and co-workers of the reactions of arylketenes and
of ketene itself in water, and theoretical studies of Nguyen
and Hegarty. The rate constants for reaction of arylketenes 1
with H2O were correlated with Hammett sigma parameters of
1
a
1b
2f
computation for a single water molecule. Structures with
2
a
2a,c
greater numbers of water molecules have also been considered,
and the enol 3 would also be solvated by further water
1b
the substituents with a slope of 1.2, indicative of rate-limiting
nucleophilic attack of water on the carbonyl carbon in the ketene
molecules. For hydration of some ketenes intermediate acid
1
f,g
enols have been detected by UV spectroscopy, but had not
previously been observed for phenylketene (1, R ) H) itself.
The acid enol Ar2CdC(OH)2 from ditipylketene (Ar2CdCdO,
Ar ) 2,4,6-i-Pr3C6H2) has been directly observed as a long-
plane,2
a-g
with stabilization of partial negative charge in the
2g
transition state by the aryl group (eq 1). For CH2dCdO (2)
itself there are suggestions that initial proton attack on C2 may
become competitive,2 but not for arylketenes.
b,d
3a,b
lived species in solution by NMR.
4
Pyridylketenes 4 are of interest because of the possibility of
direct involvement of the ring nitrogen in the reaction at the
ketenyl group. In particular, the 2-pyridyl group can stabilize
enols by the formation of intramolecular hydrogen bonds. We
The hydration of carbonyl compounds is known to involve
multiple water molecules in which water clusters effect net
hydroxide addition to the carbonyl carbon and proton addition
5
have reported the generation of 2-, 3-, and 4-4 as transient
intermediates by laser flash photolysis of the corresponding
diazo ketones 5 in CH3CN solution, with confirmation of the
structures by the observation of the characteristic ketenyl
2h-k
to the carbonyl oxygen through cyclic arrays.
studies of the hydration of CH2dCdO (2)2
Computational
are generally
a-e,g
in accord with this description, and for two water molecules a
-
1
†
absorptions at 2127, 2125, and 2128 cm , respectively, using
Current address: Wright Photoscience Laboratory, Department of
6a
Chemistry, Bowling Green State University, Bowling Green, OH 43403.
time-resolved infrared spectroscopy (TRIR). The same method
10.1021/ja047623n CCC: $27.50 © 2004 American Chemical Society
J. AM. CHEM. SOC. 2004, 126, 15777-15783
9
15777

A R T I C L E S
Allen et al.
was used to observe the formation and decay of amide enol
6
b
intermediates in the amination of substituted phenylketenes.
Other studies of pyridylketenes include the matrix isolation and
dimerization of 2-pyridylketene,4d the observation of pyridyl-
ketenes bonding to Pt surfaces,4 and the generation of
pyridylketenes by carbonylation of carbenes.4
e
a
2
-Pyridylketene was a conceivable candidate for the occur-
rence of assistance to amination by hydrogen bonding of the
amine hydrogen to the pyridyl nitrogen with nucleophilic attack
on the ketenyl carbonyl through a pseudopericyclic transition
The reactivities of the three isomeric ketenes 4 with n-BuNH2
in CH3CN were measured, and in all cases initial transient
intermediates described as enols of amides were observed by
UV.6 The intermediate from 2-pyridylketene was longer lived
than the amide enols from 3- and 4-pyridylketenes by factors
7
state resembling 2-8d forming a dihydropyridine Z-2-8e (eq
4
). Such a process has been implicated in the hydration of
a
imidoylketenes such as 9a, which involves a near planar
transition structure 9b leading to the product 9c (eq 5).7c
However, in amination 2-pyridylketene was the least reactive
of the isomers, so there was no kinetic evidence for acceleration
of the reaction of 2-4 with amines by a pseudopericyclic process.
7
7
6a
of 1.8 × 10 and 4.8 × 10 , respectively. This enormously
greater lifetime was attributed to the formation of an amide enol
syn-2-6 with a strong intramolecular hydrogen bond of the enolic
hydrogen to the pyridyl nitrogen (eq 3). This process was further
examined by DFT calculation of the pathway for reaction of
pyridylketene with NH3.6 The computations indicated the
hydrogen bonded amide enol 2-8a was stabilized by 15.4 kcal/
mol compared to the comparable structure 2-8b with the
a
6a
hydrogen directed away. The isomer 2-8c with the NH2 group
hydrogen bonded to the pyridyl nitrogen was also less stable
than 2-8a, by 6.5 kcal/mol.
(
1) (a) Bothe, E.; Meier, H.; Schulte-Frohlinde, D.; von Sonntag, C. Angew.
Chem., Int. Ed. Engl. 1976, 15, 380. (b) Bothe, E.; Dessouki, A. M.; Schulte-
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Kresge, A. J.; Schepp, N. P.; Tidwell, T. T. Can. J. Chem. 1987, 65, 1719-
1
723. (d) Allen, A. D.; Andraos, J.; Kresge, A. J.; McAllister, M. A. J.
Am. Chem. Soc. 1992, 114, 1878-1879. (e) Andraos, J.; Kresge, A. J. Can.
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7
3-81. (g) Chiang, Y.; Jefferson, E. A.; Kresge, A. J.; Popik, V. V. J.
Results
Am. Chem. Soc. 1999, 121, 11330-11335.
(
2) (a) Nguyen, M. T.; Hegarty, A. F. J. Am. Chem. Soc. 1984, 106, 1552-
1557. (b) Skancke, P. N. J. Phys. Chem. 1992, 96, 8065-8069. (c) Nguyen,
To further elucidate the reactivity of the pyridylketenes 4 we
M. T.; Raspoet, G. Can. J. Chem. 1999, 77, 817-829. (d) Guthrie, J. P.
Can J. Chem. 1999, 77, 934-943. (e) Duan, X.; Page, M. J. Am. Chem.
Soc. 1995, 117, 5114-5119. (f) Cannizzaro, C. E.; Houk, K. N. J. Am.
Chem. Soc. 2004, 126, 10992-11008. (g) Tidwell, T. T. Ketenes; Wiley:
New York, 1995. (h) Bell, R. P. AdV. Phys. Org. Chem. 1966, 3, 1-29. (i)
Wolfe, S.; Kim, C.-K.; Yang, K.; Weinberg, N.; Shi, Z. J. Am. Chem. Soc.
have now examined their hydration reactions. 2-, 3-, and
6
a
4-Pyridylketenes 4 were generated by laser flash photolysis
8
of the diazo ketones 5 in water, and the reactions were
monitored by UV spectroscopy. The reaction of phenylketene
1
2
5
995, 117, 4240-4260. (j) Guthrie, J. P.; Pitchko, V. J. Am. Chem. Soc.
000, 122, 5520-5528. (k) Guthrie, J. P. J. Am. Chem. Soc. 2000, 122,
529-5538.
(1, R ) H) was examined for comparison. Upon photolysis of
the diazo ketone 3-5 there was an initial increase in the UV
absorption monitored at 320 nm, near the maximum at 330 nm,
followed by a decay (Figure 1). These absorption changes gave
a good fit to a biexponential function, with derived first-order
(
3) (a) T (b) Frey, J.; Rappoport, Z. J. Am. Chem. Soc. 1996, 118, 5169-
5
181. (c) Frey, J.; Rappoport, Z. J. Am. Chem. Soc. 1996, 118, 5182-
5
191.
(
4) (a) Chapman, O. L.; Sheridan, R. S. J. Am. Chem. Soc. 1979, 101, 3690-
3
692. (b) Jaworski, T.; Kwiatkowski, S. Rocz. Chem. 1970, 44, 691-693.
(
c) Tomioka, H.; Ichikawa, N.; Komatsu, K. J. Am. Chem. Soc. 1993, 115,
4
-1
4
-1
rate constants of 2.5 × 10 s and 2.0 × 10 s , for the
increase and decrease in absorption, respectively (Table 1).
The two processes observed in the reaction of 3-pyridylketene
are assigned to the formation and decay of acid enol intermediate
8
621-8626. (d) Kuhn, A.; Pl u¨ g, C.; Wentrup, C. J. Am. Chem. Soc. 2000,
1
22, 1945-1948. (e) Pitters, J. L.; Griffiths, K.; Kovar, M.; Norton, P. R.;
Workentin, M. S. Angew. Chem., Int. Ed. 2000, 39, 2144-2147.
5) (a) Blanch, J. H. J. Chem. Soc. B 1966, 937-939. (b) Tomasik, P.; Johnson,
C. D. AdV. Hetero. Chem. 1976, 20, 1-64. (c) Carey, A. R. E.; Al-Quatami,
S.; More O’Ferrall; R. A.; Murray, B. A. J. Chem. Soc., Chem. Commun.
(
3
-10 formed by hydration of the initial ketene 3-4 (eq 6). This
1
988, 1097-1098. (d) Carey, A. R. E.; More O’Ferrall, R. A.; Murray, B.
A., Eustace, S. J. Chem. Soc., Perkin Trans. 2 1993, 2285-2496. (e) More
O’Ferrall, R. A.; Murray, B. A. J. Chem. Soc., Perkin Trans. 2 1994, 2461-
assignment is in agreement with previous theoretical studies of
ketene hydration, which predict that acid enol intermediates are
2
470. (f) Osmialowski, B.; Kolehmainen, E,; Nissinen, M.; Krygowski, T.
2
M.; Gawinecki, R. J. Org. Chem. 2002, 67, 3339-3343.
formed, and experimental studies, in which these species have
(
6) (a) Acton, A. W.; Allen, A. D.; Antunes, L. M.; Fedorov, A. V.; Najafian,
K.; Tidwell, T. T.; Wagner, B. D. J. Am. Chem. Soc. 2002, 124, 13790-
1f,g
been observed as transients by UV
or even long-lived
1
3794. (b) Wagner, B. D.; Arnold, B. R.; Brown, G. S.; Lusztyk, J. J. Am.
Chem. Soc. 1998, 120, 1827-1834. (c) de Lucas, N. C.; Netto-Ferreira, J.
C.; Andraos, J.; Scaiano, J. C. J. Org. Chem. 2001, 66, 5016-5021. (d)
Sung, K.; Tidwell, T. T. J. Am. Chem. Soc. 1998, 120, 3043-3048. (e)
Raspoet, G.; Nguyen, M. T.; Kelly, S.; Hegarty, A. F. J. Org. Chem. 1998,
(7) (a) Zhou, C.; Birney, D. M. J. Am. Chem. Soc. 2002, 124, 5231-5241. (b)
Ham, S.; Birney, D. M. J. Org. Chem. 1996, 61, 3962-3968. (c) For a
recent computational examination of pseudopericyclic reactions see Rod-
riguez-Otero, J.; Cabaleiro-Lago, E. M.; Hermida-Ram o´ n, J. M.; Pena-
Gallego, A. J. Org. Chem. 2003, 68, 8823-8830.
6
3, 9669-9677. (f) Allen, A. D.; Tidwell, T. T. J. Org. Chem. 1999, 64,
2
66-271.
(8) Ribereau, P.; Queguiner, G. Can. J. Chem. 1983, 61, 334-342.
15778 J. AM. CHEM. SOC.
9
VOL. 126, NO. 48, 2004

Hydration of Pyridylketenes
A R T I C L E S
Figure 2. Kinetic trace of UV absorption changes at 280 nm of transient
from phenylketene: (a) in 100% H2O and (b) in 75% H2O/25% CH3CN.
Experimental data are fit with a biexponential function representing growth
and decay of the transient absorption.
Figure 1. Kinetic trace of UV absorption changes of transient from
3
-pyridylketene (3-4) obtained by laser flash photolysis in 100% H2O.
Experimental data are fit with a biexponential function representing growth
and decay of the transient absorption.
maximum at longer wavelength, 370 nm (Figure 3b), followed
by a much slower decay (Figure 3c), with a first-order rate
constant of 2.1 × 10 s (Table 1).
Table 1. Rate Constants for Reactions of Ketenes with H2Oa
1
-1
k(obs) ( s-1)
k
1
k
2
ketene
transient growth
transient decay
1 2
k /k
4
3
PhCHdCdO (1a)
3.3 × 10
4.3 × 10
7.7
2.5
5.2
3
b
3 b
b
(
5.9 × 10 )
(2.4 × 10 )
4
3
c
c
2
-PyCHdCdO (2-4)
1.1 × 10
2.1 × 10 (28%)
1
2
3
9
.8 × 10 (72%)
1.1 × 10
Flash photolysis of the diazo ketone 2-5 formed 2-pyridyl-
ketene 2-4 which underwent conversion to a new transient which
showed two strong maxima at 310 and 380 nm, respectively
(Figure 4a). The conversion of 2-4 to the new transient was
monitored by observing the increase of absorption at 320 nm
4
4
3
4
-PyCHdCdO (3-4)
-PyCHdCdO (4-4)
2.5 × 10
2.0 ×10
2.1 × 10
1.2
4
d
1
5.0 × 10
2.4 × 10
a
b
Measured at ambient temperature (22 °C). 75% H2O/25% CH3CN.
c
d
Percentage of total absorbance change. Increase at 370 nm and decrease
at 275 nm.
4
-1
with a first-order rate constant of 1.1 × 10 s (Figure 4b).
Decay of this transient monitored at 320 nm at a longer time
scale was fit by a biexponential function (Figure 4c) which gave
intermediates by NMR.3b,c As noted above similar amide enol
intermediates have been directly observed by TRIR from
amination reactions of arylketenes.6b Rate constant ratios
3
-1
1
two first-order rate constants of 2.1 × 10 s and 9.8 × 10
-
1
s , attributable to 28 and 72% of the initial absorption,
respectively (Table 1).
k(ketene to amide enol)/k(amide enol to amide) of 4.0 and 6.2,
respectively, were observed for 3- and 4-pyridylketenes with
n-BuNH2 in CH3CN (eq 3).6
a
The key to the identification of the long-lived species formed
from 4-pyridylketene was the reported preparation of 1-(car-
bomethoxymethylene)-4-N-methyl-1,4-dihydropyridine (4-12, eq
9
a,b
9a
8
). The reported UV spectrum of this species is essentially
the same as that of the long-lived transient, and this was
confirmed by preparation of authentic 4-12. The long-lived
transient is therefore assigned the structure 4-13 resulting from
conjugate 1,6-addition to 4-pyridylketene (4-4) with N-proto-
nation and OH addition to the ketenyl carbon (eq 9).
Hydration of phenylketene gave very similar behavior, with
an initial increase in absorption at 280 nm followed by a decay
4
-1
(
Figure 2), and derived rate constants 3.3 × 10 s and 4.3 ×
3
-1
10 s , respectively (Table 1). In solvent, 75% H2O/25% CH3-
CN, both processes were slowed, and the growth and decay
3
were more readily resolved, with rate constants of 5.9 × 10
3
-1
and 2.4 × 10 s , respectively (Figure 2). This is in contrast
to previous studies of ketene hydration with an earlier apparatus,
1c-g
in which only the decay of the absorption was reported.
This
behavior indicates that both the conversion of the ketene 1a to
the acid enol 1b and the decay of the acid enol are observed
(eq 7).
Flash photolysis of the diazo ketone 4-5 to generate 4-
pyridylketene 4-4 gave the immediate appearance of an absorp-
tion at 275 nm which decayed with a first-order rate constant
4
-1
of 5.0 × 10 s (Figure 3a). There was concomitant growth
The UV spectrum of the analogous E-1-(carboethoxymeth-
ylidene)-2-N-methyl-1,4-dihydropyridine (E-2-12) has also been
with the same first-order rate constant of an absorption with a
J. AM. CHEM. SOC.
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A R T I C L E S
Allen et al.
Figure 4. (a) UV spectrum of transient formed from 2-pyridylketene in
100% H2O. (b) Kinetic trace for UV absorption changes at 320 nm of
transient from 2-pyridylketene (2-4) in 100% H2O. (c) Biexponential kinetic
fit of experimental trace of UV spectrum at 320 nm for transient decay
from 2-pyridylketene in 100% H2O
Figure 3. (a) Kinetic trace of UV absorption changes at 275 nm for transient
decay from 4-pyridylketene in 100% H2O. (b) Kinetic trace of UV
absorption changes at 370 nm for transient growth from 4-pyridylketene in
from n-butylamine to 2-4, which had been assigned as amide
6
a
enol 2-6 (eq 3). Therefore, this reaction was reexamined, and
transient UV absorption maxima at 310 and 380 nm in CH3CN
were observed (Figure 5a) indicating formation of the tautomer
Z-2-6a as the intermediate converted to 2-7 with catalysis by
1
00% H2O. (c) Kinetic trace of UV absorption changes at 370 nm for
transient decay from 4-pyridylketene in 100% H2O.
reported,9a and this was essentially the same as that observed
6a
n-BuNH2 (eq 10). The identification of Z-2-6a was confirmed
(Figure 4a) for the product from hydration of 2-4. This transient
is assigned as a mixture of Z- and E-2-13a based on the observed
UV spectrum and biphasic kinetics.
The finding that the hydration of 2-pyridylketene (2-2) led
to the formation of the 2-carboxymethylene-1,2-dihydropyridines
2-13 brought into question the identity of the long-lived species
15780 J. AM. CHEM. SOC.
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VOL. 126, NO. 48, 2004

Hydration of Pyridylketenes
A R T I C L E S
Discussion
Formation by hydration of 4-pyridylketene 4-4 forming
-carboxymethylene-1,4-dihydropyridine 4-13 may be depicted
4
as involving participation of a cluster of water molecules to
facilitate proton addition to nitrogen and OH addition to the
ketenyl carbon. Representations of an initial ketene complex
4
-4‚6H2O with a chain of 6 water molecules between the
nitrogen and the ketenyl group and a product 4-carboxymeth-
ylene-1,4-dihydropyridine 4-13‚5H2O with 5 coordinated water
molecules are shown (Scheme 1). The complexed ketene 4-4‚
6
H2O has the water bridge largely in the plane of the
pyridylketene, while the water bridge in 4-carboxymethylene-
,4-dihydropyridine 4-13‚5H2O is above the pyridyl plane. The
1
conversion of 4-4 to 4-13 is expected to involve a stepwise
process facilitated by water molecules forming transient
zwitterions, with significant reorganization of the solvent shell.
Many such structures with the same or different numbers of
water molecules are expected to contribute to the species present
in solution, and no single structure but rather many would be
involved in the transformation.
Scheme 1. Depiction of a 4-Pyridylketene Complex 4-4‚6H2O with
a Bridge of 6 H2O Molecules and Dihydropyridine 4-13‚5H2O from
Hydration of Ketene 4-4 with a Bridge of 5 H2O Molecules
Precedent for such a stepwise relay process is found in the
photochemically induced hydrogen transfer between oxygen and
quinolyl nitrogen utilizing a bridge of 3 NH3 molecules recently
demonstrated in an experimental and computational study
Figure 5. (a) Transient UV spectrum of amide enol Z-2-6a from
2
-pyridylketene and n-BuNH2 in CH3CNb UV spectrum of 1-N-methyl-2-
n-butylcarboxamidomethylene-1,2-dihydropyridine E-2-6b in CH3CN.
1
0a
(
eq 11). Other reactions involving chains of water molecules
1
0b-d
by preparation of the N-methyl derivative E-2-6b as a stable
solid by a route analogous to that of eq 8. The UV spectrum of
the transient identified as Z-2-6a was almost identical to that
of E-2-6b (Figure 5b), which had absorption maxima in CH3-
CN at 306 (log ꢀ 3.88), 316 (log ꢀ 3.89), and 398 (log ꢀ 3.22)
nm. The near identity of the UV spectra of similar E- and
to effect proton transfer have also been reported.
5e
Z-acylmethylene-1,2-dihydropyridines has been noted before.
Previously the energy of the hydrogen bonded amide enol
2
-8a was calculated at the B3LYP/6-31G*//B3LYP/6-31G*
6
a
level, and now further calculation of the structure and energy
The results for hydration of 3-pyridylketene (3-4) and of
phenylketene are similar in that the growth and the decay of an
absorption following ketene generation are observed in each
case, with rate ratios k(growth)/k(decay) of 1.2 and 7.7,
respectively. This resembles the results for the amination
of 2-methylene-1,2-dihydropyridine Z-2-8f at this level (Table
2, Supporting Information) reveals this to be 3.05 kcal/mol more
stable than the previously calculated amide enol, with O‚‚‚H
and N‚‚‚H hydrogen bond lengths of 1.812 and 1.643 Å in Z-2-
6
a
8
f and 2-8a, respectively. The strength of the hydrogen bond
reaction in acetonitrile solvent, in which the ketenes were
directly observed by IR, and rate constant ratios k(ketene to
amide enol)/k(amide enol to amide) of 4.0 and 22 were found
in Z-2-8f in the gas phase may be approximated from the energy
difference between Z- and E-2-8f of 9.6 kcal/mol (Table 2,
Supporting Information), but the energy difference between E
and Z structures also enters into this comparison.
6a
for 3-pyridylketene and phenylketene, respectively. In previous
studies of phenylketene hydration only the decay of an absorp-
(
9) (a) Jones, R. A.; Katritzky, A. R. Aust. J. Chem. 1964, 17, 455-460. (b)
Acheson, R. M.; Woollard, J. J. Chem. Soc., Perkin Trans 1 1975, 744-
748.
(
10) (a) Tanner, C.; Manca, C.; Leutwyler, S. Science 2003, 302, 1736-1739.
(
b) Cole, J. G.; Wan, P. Can. J. Chem. 2002, 80, 46-54. (c) Fischer, M.;
Wan, P. J. Am. Chem. Soc. 1999, 121, 4555-4562. (d) Flegel, M.;
Lukeman, M.; Huck, L.; Wan, P. J. Am. Chem. Soc. 2004, 126, 7890-
7
897.
J. AM. CHEM. SOC.
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A R T I C L E S
Allen et al.
tion was noted,1
c-e
and the acid enol has now been detected
stable than the hydrogen bonded amide enol syn-2-8a by 3.4
kcal/mol (Table 2, Supporting Information).
The rate constant ratios for formation by hydration of the
dihydropyridines Z- and E-2-13 from 2-pyridylketene relative
to their rates of decay of 110 and 5.2 (Table 1) are much less
for the first time in hydration by UV spectroscopy in this and
1
1a
a related study. However, because UV spectroscopy does not
give distinctive structural signatures for the ketene and the enol
there is some ambiguity about the specific identification of the
growth and decay as being due to the ketene and the enol for
7
6a
than that of 1.8 × 10 for the corresponding amination (eq 3).
3
-pyridylketene and phenylketene.11 The rate constants for
However, in hydration conversion to the pyridylacetic acid can
be assisted by hydrogen bonding to the solvent water molecules,
whereas in amination the solvent is acetonitrile, which has a
much weaker hydrogen bonding ability, and the amine concen-
tration is quite low. The assistance provided by additional
hydrogen bonding molecules is shown by the second-order
kinetic dependence on the concentration of n-butylamine
observed in the conversion of the intermediate Z-2-6a from
growth and decay are quite similar, and the identification of
these processes is reported elsewhere.1 In any event the
hydration of 3-4 is found to proceed through formation of the
acid enol 3-10, which is readily converted to the acid 3-11
eq 6), and phenylketene behaves analogously.
The initially formed 4-pyridylketene undergoes hydration to
1a
(
the long-lived 4-carboxymethylene-1,4-dihydropyridine 4-13 (eq
), and the identification of these two transients is unambiguous,
6
a
9
2-pyridylketene to the final product 2-7 (eq 10).
based in the latter case upon comparison of the UV spectrum
with the corresponding stable N-methyl derivative. The rate
constant for initial hydration of 4-4 is the largest of those for
the three isomers, just as it is for amination, with rate constant
ratios for 4-4/3-4/2-4 of 4.5/2.3/1.0 for hydration and 17/4.0/
In both hydration and amination, 2-pyridylketene is the least
reactive of the isomers, so there is no kinetic evidence for a
pseudopericyclic pathway (eqs 4 and 5). In amination, the
hydrogen bonded dihydropyridine Z-2-6a (eq 10) is formed and
would result from attack opposite to the pyridyl nitrogen,
whereas a pseudopericyclic pathway would form the N-n-butyl
derivative of the less stable Z-2-8e (eq 4). In hydration formation
of both Z- and E-2-carboxymethylene-1,2-dihydropyridines 2-13
also argues against a pseuodopericyclic pathway, which would
lead only to the Z-isomer.
1
.0 for amination. The computed stability of the isomers at the
6a
B3LYP/6-311+G(d,p) level is 2-4 > 4-4 > 3-4, so the most
stable 2-isomer is the least reactive in both reactions. The rate
constant ratio k(ketene-to-intermediate)/ k(intermediate-to-
product) for amination of 4-pyridylketene (4-4) is 6.2, but for
3
hydration of 4-4 this ratio is 2.4 × 10 (Table 1). The difference
For 2-pyridyketene, the transition structure 2-8d for pseudo-
between the two lies in the fact that hydration of 4-pyridylketene
results in formation of a long-lived intermediate shown to be
the 4-carboxymethylene-1,4-dihydropyridine 4-13 (Scheme 1),
whereas no such intermediate is detected in amination.
pericyclic NH addition (eq 4) lacks developing amide conjuga-
3
tion, which is also absent in the product dihydropyridine
carboxamide Z-2-8e, with the amide group twisted out of
6
a
conjugation (eq 4). This was previously noted by Birney
7
a
In the hydration of 4-pyridylketene, 1,6-addition is facilitated
by a network of water molecules through stepwise proton
transfers to form the dihydropyridine 4-13 (Scheme 1). This is
not feasible for amination, in which the concentration of
et al., for the addition of NH3 to formylketene OdCH-
CHdCdO. However amination by attack of 2 n-BuNH2
molecules on syn-2-4 from the side opposite the pyridyl group
leads to Z-2-6c with a conjugated coplanar amide group and an
intramolecular hydrogen bond (eq 12), and the pseudopericyclic
mechanism does not intervene.
-
4
-3
6a
n-butylamine in CH3CN used was between 10 to 10 M.
For hydration of 2-4 formation of the 2-carboxymethylene-
,2-dihydropyridine intermediate Z-2-13a was confirmed by
1
observation of new UV maxima at 310 and 380 nm (Figure
a), and the kinetic data suggests there are two transient species
4
that decay with rate constants 5.2 and 110 times less than the
rate constant for ketene hydration, and these account for 28%
and 72% of the dihydropyridine absorption, respectively (Table
1
). The dihydropyridine intermediates can be assigned as the
E- and Z-2-13a structures, respectively, as Z-2-13a is stabilized
by an intramolecular hydrogen bond and may be expected to
be longer lived than the E-stereoisomer.
2-Pyridylketene amination with n-BuNH2 in CH3CN gave an
intermediate previously assigned as the intramolecularly H-
bonded amide enol 2-6 that was converted to the amide with a
Conclusion
7
rate constant 1.8 × 10 less than that for conversion of the ketene
6
a
In summary, the hydration of 3-pyridylketene involves
formation of a transient acid enol that is converted to the product
acid in a subsequent rapid step. Hydration of phenylketene
occurs similarly, and the corresponding acid enol has been
detected for the first time. However, hydration of 4-pyridyl-
ketene does not lead to an acid enol, but instead to a much
longer lived 4-carboxymethylene-1,4-dihydropyridine 4-13,
which is converted to 4-pyridylacetic acid in a process slower
to 2-6 (eq 3). The stability of this species was ascribed to the
formation of the strong intramolecular H-bond, and this
intermediate can be formed without a chain of amine molecules
(
eq 3). However, the dihydropyridine Z-2-6a is now shown to
be the intermediate observed in the amination of 2-4 (Figure
a),and this is confirmed by the computational results revealing
the 2-methylene-1,2-dihydropyridine intermediate Z-2-8f is more
5
3
(
11) (a) Chiang, Y.; Fedorov, A. V.; Kresge, A. J.; Onyido, I.; Tidwell, T. T. J.
Am. Chem. Soc. 2004, 126, 9382-9386. (b) Connors, K. A. Chemical
Kinetics. The Study of Reaction Rates in Solution; VCH Publishers: New
York, 1990; pp 66-69.
than its rate of formation by a factor of 10 . 2-Pyridylketene
undergoes hydration with formation of two isomeric 2-car-
boxymethylene-1,2-dihydropyridines, one of which posseses an
15782 J. AM. CHEM. SOC.
9
VOL. 126, NO. 48, 2004

Hydration of Pyridylketenes
A R T I C L E S
intramolecular hydrogen bond to the carboxy carbonyl group,
and these undergo conversion to 2-pyridylacetic acid at inter-
mediate rates compared to the 3- and 4-pyridylketenes. The
structure of the product of amination of 2-pyridylketene has
been reinterpreted on the basis of experimental and computa-
tional results as having the corresponding 1,2-dihyropyridine
structure Z-2-6a instead of the previously proposed amide enol
structure 2-6. No kinetic evidence for a pseudopericyclic
pathway in either hydration or amination is found.
Research Fund administered by the American Chemical Society,
and a Killam Fellowship from the Canada Council for the Arts
to T.T.T. is gratefully acknowledged. This paper is dedicated
to Professor Rory More O’Ferrall in recognition of his contribu-
tions to mechanistic organic chemistry on the occasion of his
th
6
5 birthday.
6a
Supporting Information Available: Experimental and com-
putational details. This material is available free of charge via
the Internet at http://pubs.acs.org.
Acknowledgment. Financial support by the Natural Sciences
and Engineering Research Council of Canada, the Petroleum
JA047623N
J. AM. CHEM. SOC.
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