Excellent correlation between substituent constants and pyridinium N-methyl chemical shifts

Article abstract of DOI:10.1016/j.tetlet.2009.06.081

Substituents on the pyridinium ring of N-methylpyridinium derivatives, especially those on the 2- or 4-position, have a large effect on the ¹H and ¹³C NMR chemical shifts of the N-methyl group. Reasonable correlations between the chemical shift changes and the resonance substituent constants are observed. The dual substituent parameter approach provides an excellent correlation when a combination of polar and resonance substituent constants is employed.

Full text of DOI:10.1016/j.tetlet.2009.06.081

Tetrahedron Letters 50 (2009) 5018–5020
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Excellent correlation between substituent constants and pyridinium N-methyl
chemical shifts
Sha Huang, Jesse C. S. Wong, Adam K. C. Leung, Yee Man Chan, Lili Wong, Myrien R. Fernendez,
*
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:
Substituents on the pyridinium ring of N-methylpyridinium derivatives, especially those on the 2- or 4-
Received 20 May 2009
Accepted 16 June 2009
Available online 23 June 2009
1
13
position, have a large effect on the H and C NMR chemical shifts of the N-methyl group. Reasonable
correlations between the chemical shift changes and the resonance substituent constants are observed.
The dual substituent parameter approach provides an excellent correlation when a combination of polar
and resonance substituent constants is employed.
Ó 2009 Elsevier Ltd. All rights reserved.
The determination of the electronic effect that substituents have
on reactions is very important in the elucidation of reaction mecha-
nisms, especially the nature of the transition state. The Hammett
compounds. The upfield chemical shifts are a result of the lower
charge density on the nitrogen atom due to the resonance struc-
tures as shown in Figure 1.
1
constants,
r
meta and
r
para, were first calculated from the comparison
If a good correlation were to be found between the chemical
shift of the N-methyl group and the ability of substituents to do-
nate electrons, it would be a valuable tool in the measurement of
the resonance effects of substituents due to the ready availability
of the N-methylpyridinium compounds. Therefore, we have pre-
pared a series of substituted N-methylpyridinium molecules to
investigate the relationship between the chemical shifts of the
N-methyl group and the nature of the substituents. The 1H and
2
of ionization constants of substituted benzoic acids. Two new types
+
ꢀ
of
r constants, r and r , were introduced for structures in which
the substituent is able to come to direct resonance interaction with
electron-deficient and electron-rich reaction sites, respectively.
Later, the separation of polar and resonance parts of the substituent
effect has led to the establishment of the polar substituent constant,
3
,4
ꢁ
ꢀ
7
r
r
I
, andfour sets of resonancesubstituent constants,
r
,
r
R(BA)
,
r
and
R
R
1
,5
13
R
.
The four sets of resonance parameters are used for relatively
C NMR chemical shifts and the relevant substituent constants
unperturbed systems, substituted benzoic acids, electron-deficient
are listed out in Table 1.
1,5
and electron-rich benzene rings, respectively. In this Letter, we
N-Methylpyridinium compounds substituted at the 2- or 4-
position were treated separately because the chemical shifts were
quite different for the two sets of molecules. A better fit was found
for 4-substituted pyridinium compounds. This result was reason-
able considering the fact that the substituent constants were de-
will describe the excellent correlation between the 1H and
13
C
NMR chemical shifts of substituted N-methylpyridinium and the
substituentconstants
approach (Eq. 1):
r
I
and
r
R
usingthedualsubstituent parameter
rived with para-substituted benzene derivatives. When
differences between the substituted and parent pyridinium mole-
Dd (the
logðk=k
0
Þ ¼ qI
r
I
þ
qR
r
R
ð1Þ
We have recently examined the acidity of the
a-CH group of 2-
methoxy and 4-methoxypyridinium compounds through kinetic
measurement of hydrogen–deuterium exchange.6 The pK
values
a
of these two compounds in aqueous solution were found to be sur-
prisingly high and a large solvent effect was observed for the
hydrogen–deuterium exchange reactions. In our effort to investi-
gate the effect of various substituents on the rate of hydrogen-
deuterium exchange, we have found that these groups, and other
Y
Y = H, NH , NHCOCH , OCH , CH ,
2 3 3 3
+
N
Cl, Br, CN, CO CH , COCH
2 3 3
CH3
p-electron-donating groups, on the 2- or 4- position have a large
+
+
N
OCH3
N
OCH
3
effect on the chemical shifts of the N-methyl group in pyridinium
CH3
CH3
*
Corresponding author. Tel.: +1 415 338 1436; fax: +1 415 338 2384.
Figure 1. N-Methylpyridinium derivatives and representative resonance structures
E-mail address: wuw@sfsu.edu (W. Wu).
with electron-donating groups.
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.081

S. Huang et al. / Tetrahedron Letters 50 (2009) 5018–5020
5019
Table 1
Polar and resonance substituent constants and the corresponding 1H and 13C NMR chemical shifts of the N-methyl group in substituted pyridinium compounds
a
ꢁ
þ
1
d (13C, ppm)
Substituent
r
m
r
I
r
r
R(BA)
r
d ( H, ppm)
R
R
–
–
H
NH
0.00
ꢀ.16
0.00
.12
0.00
ꢀ.48
0.00
ꢀ.82
0.00
ꢀ1.61
4.426
3.834 (2ꢀ)
51.043
2
44.055 (2ꢀ)
50.813 (3ꢀ)
47.552 (4ꢀ)
47.079 (2ꢀ)
49.445 (4ꢀ)
44.153 (2ꢀ)
51.230 (3ꢀ)
49.071 (4ꢀ)
48.419 (2ꢀ)
50.747 (3ꢀ)
50.153 (4ꢀ)
50.390 (2ꢀ)
51.357 (3ꢀ)
51.204 (3ꢀ)
51.457 (2ꢀ)
51.982 (3ꢀ)
52.206 (4ꢀ)
51.608 (4ꢀ)
51.478 (3ꢀ)
51.416 (4ꢀ)
4
3
.243 (3ꢀ)
.936 (4ꢀ)
–
NHAc
OCH
—
.26
.27
ꢀ.25
ꢀ.34
ꢀ.36
ꢀ.61
ꢀ.86
4.243 (2ꢀ)
4
.235 (4ꢀ)
–
3
.12
ꢀ1.02
4.276 (2ꢀ)
4
4
.390 (3ꢀ)
.182 (4ꢀ)
–
CH
3
ꢀ.07
ꢀ.04
ꢀ.11
ꢀ.23
ꢀ.11
ꢀ.23
ꢀ.25
ꢀ.36
4.258 (2ꢀ)
4
4
.366 (3ꢀ)
.330 (4ꢀ)
–
Cl
.37
.46
4.415 (2ꢀ)
4
.431 (3ꢀ)
–
–
Br
CN
.39
.56
.44
.56
ꢀ.19
ꢀ.19
ꢀ.30
4.415 (3ꢀ)
.13
.13
.13
4.636 (2ꢀ)
4
4
.511 (3ꢀ)
.521 (4ꢀ)
–
–
CO
COCH
2
CH
3
.37
.38
.30b
.28
.14
.16
.14
.16
.14
.16
4.486 (4ꢀ)
4.517 (3ꢀ)
3
4.501 (4ꢀ)
a
Taken from Refs. 1 and 5.
Reported for –CO Et.
2
b
cules) were plotted against resonance substituent constants alone,
ꢁ
þ
ꢀ
3.0
r
,
r
R(BA) and
r
gave reasonable fits. The poor correlation with
r
A
R
R
R
was fully expected because of the electron-deficient nature of the
pyridinium ring.
One interesting observation is the relative electron-withdraw-
ing ability of the cyano (–CN) and the ester group (–CO CH ). The
2 3
cyano group appears to be less electron-withdrawing than the
ester group, based on the comparison of their resonance substitu-
ent constants. However, it is apparent from the reactivity of benzyl
bromide derivatives in their oxidation to benzaldehyde derivatives
1
.0
CN
CH
COCH
CO
2
3
3
H
Δδ
ppm)
CH
3
-
-
1.0
3.0
(
that
a p-CO
One explanation is the strong polar effect associated with the
cyano group, as evident from the larger value. When the dual
a
p-CN substituent is more electron-withdrawing than
NHAc
OCH
8
2
CH
3
group.
3
Ι
ρ = 1.21
r
I
ρR = 2.26
λ = 1.86
NH
2
substituent parameter approach was applied to the data, an excel-
2
lent correlation (R = 0.99) was observed between the chemical
shift changes and the sum of polar and resonance effects (
q
I
r
-
þ
-5.0
-
I
+
R
q r
R
) when
r
R
was used as shown in Figure 2. The ratio of
5.0
-3.0
-1.0
1.0
3.0
the coefficients
q
I
and (as indicated by k = ) signified the
q
R
R I
q /q
ρ σ + ρ σ
R R
Ι
Ι
larger contribution from the resonance effect. A good correlation
2
9
(
R = 0.96) was also observed when
r
R(BA) was employed. The bet-
þ
0.2
0.0
ter fit with
r
is expected because of the electron-deficient nature
B
R
of the system studied here.
CN
3
COCH
For the 2-substituted pyridinium compounds, the correlation
was not as good when the chemical shift changes were plotted
against the resonance substituent constants alone or a combina-
2 3
CO CH
H
CH
3
tion of polar and resonance substituent constants,
I I R R
q r + q r . This
kind of poor correlation has been regularly observed with ortho-
substituted benzene systems and was attributed to the proximity
of the substituents to the reaction site and thus contributions from
Δδ
(ppm)
-
-
0.2
0.4
NHAc
OCH
3
5
the proximity effect.
ρ
Ι = 0.12
For the 3-substituted pyridinium compounds, no good correla-
ρR = 0.29
λ = 2.49
tion was found between the
I
Dd and rmeta or r , although a reason-
NH
2
1
9
ably good correlation has been reported between the F NMR
1
0
chemical shifts of fluorobenzene derivatives and
dual substituent approach was employed using
r
I
.
When the
-0.6
-0.6
ꢁ
-0.4
-0.2
0
0.2
r
I
and
r
, a good
R
2
13
1
ρ
Ι
σ
Ι
+ ρ σ
R R
correlation (R = 0.94) was found for C but not for H NMR chem-
ical shifts. The coefficients and k are 1.37, 0.74 and 0.54 for
C NMR, respectively.11 These numbers indicate the greater
contribution from the polar effect, as expected. However, the con-
q
I
,
q
R
Figure 2. Correlation of 13C (A) and 1H (B) NMR chemical shifts of the N-methyl
group in substituted N-methylpyridiniums with the polar and resonance sub-
1
3
þ
stituent constants (
r
I
and
r
).
R

5
020
S. Huang et al. / Tetrahedron Letters 50 (2009) 5018–5020
tribution from resonance effect does play a role, presumably by
reducing the overall charge of the pyridinium ring.
References and notes
In summary, reasonable correlations between the 1H and 13
1.
Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic Chemistry, 3rd
ed.; Harper & Row: New York, 1987.
C
NMR chemical shifts of the N-methyl group on pyridinium com-
pounds and the resonance substituent constants have been ob-
served. The best fit was found with 4-substituted pyridinium
molecules. This could be a useful way to assess the resonance elec-
2.
Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96–103.
3. Ritchie, C. D.; Sager, W. F. Prog. Phys. Org. Chem. 1964, 2, 323–400.
4
5
6
.
.
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Stock, L. M.; Brown, H. C. Adv. Phys. Org. Chem. 1963, 1, 35–154.
Ehrensen, S.; Brownlee, R. T. C.; Taft, R. W. Prog. Phys. Org. Chem. 1973, 10, 1–80.
Wong, F. M.; Capule, C. C.; Chen, D. X.; Gronert, S.; Wu, W. Org. Lett. 2008, 10,
2757–2760.
tronic effects of various substituents. When both the polar substi-
þ
tuent constant (
r
I
) and the resonance substituent constants (
r
)
7. Typical experimental procedures: Pyridine (1 g) was dissolved in 5 mL anhydrous
ethyl ether in a pressure tube. Methyl iodide (3 g) was added to the solution
and the mixture was stirred overnight at room temperature. The resulting
solid was filtered, washed with anhydrous ethyl ether, and dried to give
N-methylpyridinium iodide as a white solid. In cases when the pyridine
derivatives are not soluble enough in ether, ethyl acetate was used as the
reaction solvent. All chemicals are commercially available and are used without
further purification. NMR spectra were obtained with either QE 300 or
Bruker 500 instruments. All chemical sifts are referenced to sodium 3-trimeth-
ylsilylpropionate at 0.00 ppm.
R
were considered, excellent correlations were observed. The results
have further demonstrated the advantage of the dual substituent
1
,5
parameter approach.
Acknowledgements
8
.
Chen, D. X.; Ho, C. M.; Wu, Q. Y. R.; Wu, P. R.; Wong, F. M.; Wu, W. Tetrahedron
Lett. 2008, 49, 4147–4148.
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. In addition, we are in-
debted to Joan Wu for her assistance in the statistical analysis
of the data.
9. The dual substituent parameter approach using rR may underestimate the
contribution from the polar effect in this case, as evident from the coefficients.
I R
q , q
and k are 0.61, 4.12 and 6.78 for 13C NMR and 0.04, 0.54
The coefficients
and 13.62 for 1H NMR, respectively.
10. Taft, R. W.; Price, E.; Fox, I. R.; Lewis, I. C.; Anderson, K. K.; Davis, G. T. J. Am.
Chem. Soc. 1963, 85, 709–724.
11. When
r
R
was used, a reasonable correlation was also found for 13C NMR
2
chemical shifts only (R = 0.92). The coefficients
I R
q , q and k are 1.37, 0.49 and
13
0
.36 for C NMR, respectively.