Substantial formation of hydrates and hemiacetals from pyridinium ketones

Article abstract of DOI:10.1016/j.tetlet.2009.09.054

Pyridinium ketones have been found to exist as hydrates and hemiacetals in considerable amount in aqueous and alcoholic solutions, respectively. The relative position of the pyridinium positive charge has a large effect on the equilibrium constants. The polar substituent constants, σ,* of the pyridinium group substituted at different positions can be estimated from the hydration constants.

Full text of DOI:10.1016/j.tetlet.2009.09.054

Tetrahedron Letters 50 (2009) 6584–6585
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Substantial formation of hydrates and hemiacetals from pyridinium ketones
*
Sha Huang, Amanda K. Miller, Weiming Wu
Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyridinium ketones have been found to exist as hydrates and hemiacetals in considerable amount in
Received 10 August 2009
Accepted 10 September 2009
Available online 15 September 2009
aqueous and alcoholic solutions, respectively. The relative position of the pyridinium positive charge
*
has a large effect on the equilibrium constants. The polar substituent constants,
r , of the pyridinium
group substituted at different positions can be estimated from the hydration constants.
Ó 2009 Elsevier Ltd. All rights reserved.
The reversible hydration of aldehydes and ketones in aqueous
solution is one of the simplest addition reactions to the carbonyl
group (Fig. 1). The extent to which hydrates of aldehydes and
ketones form gives a measure of the relative stability of the alde-
hydes and ketones. The greater extent to which the hydrate forms,
the less stable the starting aldehyde or ketone is. The reaction is of
great importance in understanding reactions of the carbonyl group
and has been the subject of many studies.1–4
The hydration constants of some aldehydes and ketones have
been reported.1–3 Formaldehyde exists mostly as its hydrate in
aqueous solution. Simple aliphatic aldehydes exist in equilibrium
with their hydrates. Ketones usually exist predominately in the
signals.5 Further study has revealed the existence of the compound
as the ketone and hydrate structures. The electron-withdrawing
nature of the pyridinium moiety increases the electron deficiency
of the carbonyl group and thus makes it more favorable to form
a hydrate.
O
O
+
+
N
N
CH3
CH3
We decided to study a series of methyl pyridinium ketones (acety-
lpyridinium) and phenyl pyridinium ketones (benzoylpyridinium)
to measure their equilibrium constants for hydration and hemiace-
tal formation in aqueous and alcoholic solutions, respectively, and
to investigate the effect of different positions of the positively
charged nitrogen on the equilibrium constants.4,6 The compounds
were prepared by reacting the corresponding pyridine ketones with
methyl iodide as reported.4,5 The molar ratios of ketone to hydrate
or hemiacetal in the respective D2O or CD3OD solutions were mea-
sured by integration of 1H NMR peaks. The pyridinium hydrogens
and the N-methyl groups of the hydrates and hemiacetals showed
small upfield shifts relative to those of the ketones. Furthermore,
in acetylpyridinium compounds, the acetyl methyl group has
chemical shifts of about 2.8 ppm while the chemical shifts in the
hydrate or hemiacetal form are around 1.8. The hydration constants
(Kh, [hydrate]/[ketone]) and hemiacetal formation constants
keto form, except for the
librium with their hydrates. Typically
withdrawing groups favors the formation of hydrates.
Hemiacetal formation in alcohol follows the same mechanism
as hydrate formation. The equilibrium constants for hemiacetal
formation of some aldehydes and ketones have been reported as
well.2
Hydration equilibria for most carbonyl compounds are too lop-
sided to permit their equilibrium constants to be measured accu-
rately. In our study of pyridinium compounds,5 however, we
have found that 4-acetyl-N-methylpyridinium iodide exists in
aqueous solution to a considerable extent as its hydrate. The pyrid-
inium ketones have thus provided a unique opportunity to mea-
sure the thermodynamic parameters of the formation of the
corresponding hydrates and hemiacetals. In this Letter, we report
the ready formation of hydrates and hemiacetal from N-methylpy-
ridinium ketones in aqueous and alcoholic solutions, respectively.
The effect of the relative position of the pyridinium positive charge
on the equilibrium is also studied.
a
-halogenated ones, which exist in equi-
a-substitution by electron-
O
O
HO OH
R'
+
+
H2O
R
R
R'
R'
R
During the course of our study of the NMR spectra of N-meth-
ylpyridinium compounds, we have observed that the 1H NMR spec-
trum of 4-acetyl-N-methylpyridinium iodide contains two sets of
HO OCH3
R'
CH3OH
R
* Corresponding author. Tel.: +1 415 338 1436; fax: +1 415 338 2384.
E-mail address: wuw@sfsu.edu (W. Wu).
Figure 1. Equilibrium hydration and hemiacetal formation of aldehydes and
ketones.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.054

S. Huang et al. / Tetrahedron Letters 50 (2009) 6584–6585
6585
*
Table 1
In methyl ketones, the hydration constants are related to
r by
Eq. 1 developed empirically by Greenzaid et al.1,4 The substituent
r , of the pyridinium group substituted at 2-, 3-, and
4-position were thus calculated to be 0.93, 0.76, and 1.31, respec-
Hydration constants and methanolic hemiacetal formation constants of some N-
methylpyridinium ketones
*
constants,
Substituent
Hydration, Kh
Hemiacetal, K
*
tively. These values of
r can be used to estimate the polar effects
2-Acetyl
3-Acetyl
4-Acetyl
2-Benzoyl
3-Benzoyl
4-Benzoyl
0.06
0.03
0.30
0.29
1.38
0.11
0.20
0.70
of the pyridinium group substituted at different positions.
0.26
rꢀ ꢁ 2:81
ð1Þ
<0.01a
<0.01a
0.07
log Kh ¼ 1:70
R
In summary, hydrates and hemiacetals form in substantial
amount in aqueous and alcoholic solutions of pyridinium ketones.
Unlike most ketones and aldehydes, hemiacetal formation appears
to be more favorable than hydrate formation. The hydration con-
stants of acetylpyridinium compounds provide an estimate of the
polar substituent constants and thus the polar effect of the pyrid-
inium group substituted at various positions of the heterocyclic
ring.
a
The hydration constant was measured to be about 0.008, but was deemed to be
beyond the detection limit of 1H NMR.
(K, [hemiacetal]/[ketone] in methanol) thus measured are shown in
Table 1. The hydration constant for 2-acetylpyridinium iodide is in
good agreement with the reported value.4
It is expected that the benzoyl derivatives are less likely to form
hydrates or hemiacetals due to their stronger hydrophobic nature
and/or their less reactive ketone moieties. The effect of the relative
position of the positive charge on the equilibrium is quite interest-
ing. It appears that the carbonyl groups attached to the 4-position
of the pyridinium group are substantially more reactive toward
water or alcohol than those substituted at 2- or 3-position. The
diminished reactivity of the 3-substituted pyridinium ketones is
not unexpected because there are no resonance structures putting
a positive charge adjacent to the carbonyl group. However, the
absence of enhanced reactivity in the 2-substituted pyridinium
ketones is mostly due to a steric effect. The proximity of the
N-methyl group and the carbonyl group makes it possible for the
steric interaction to be more profound in the tetrahedral structure
of the hydrate or hemiacetal than in the keto form.
Acknowledgments
This investigation was supported by the National Institutes of
Health, MBRS SCORE Program—Grant #5 S06 GM52588. We thank
Wee Tam for obtaining the NMR spectra. The NMR facility was
funded by the National Science Foundation (DUE-9451624 and
DBI 0521342). We also thank Professors James Keeffe and Ihsan
Erden at SFSU for helpful discussions.
References and notes
1. Greenzaid, P.; Luz, Z.; Samuel, D. J. Am. Chem. Soc. 1967, 89, 749–756.
2. Guthrie, J. P. Can. J. Chem. 1975, 53, 898–906.
3. Keeffe, J. R.; Kresge, A. J. In The Chemistry of Enols; Rappoport, Z., Ed.; Wiley: New
York, 1990. Chapter 7.
4. Tobin, J. B.; Frey, P. A. J. Am. Chem. Soc. 1996, 118, 12253–12260.
5. Huang, S.; Wong, J. C. S.; Leung, A. K. C.; Chan, Y. M.; Wong, L.; Fernendez, M. R.;
Miller, A. K.; Wu, W. Tetrahedron Lett. 2009, 50, 5018–5020.
6. A few ketones or aldehydes with positively charged heterocycles have been
discussed. Benzimidazolium and thiazolium ketones were reported to form
considerable amount of hydrate in water. (a) Lienhard, G. E. J. Am. Chem. Soc.
1966, 88, 5642–5649; (b) Owen, T. C. J. Heterocycl. Chem. 1990, 27, 987–990; (c)
Bunting, J. W.; Stefanidis, D. J. Am. Chem. Soc. 1988, 110, 4008–4017; (d) Soutullo,
M. D.; O’Brien, R. A.; Gaines, K. E.; Davis, J. H., Jr. Chem. Commun. 2009, 2529–
2531.
The formation of hemiacetals appears to be more favorable as
compared to that of hydrates, as in the case of aryl alkyl ketones
such as
a,a,a
-trifluoroacetophenone.2 In most ketones and alde-
hydes, however, the formation of hydrate is usually more
favorable.2
The hydration constants measured for acetylpyridinium com-
pounds can be used to estimate the polar substituent constants,
*
r
, of the pyridinium group substituted at 2-, 3-, and 4-position.