Ambident reactivities of pyridone anions

Article abstract of DOI:10.1021/ja106962u

The kinetics of the reactions of the ambident 2- and 4-pyridone anions with benzhydrylium ions (diarylcarbenium ions) and structurally related Michael acceptors have been studied in DMSO, CH₃CN, and water. No significant changes of the rate constants were found when the counterion was varied (Li⁺, K⁺, NBu₄⁺) or the solvent was changed from DMSO to CH₃CN, whereas a large decrease of nucleophilicity was observed in aqueous solution. The second-order rate constants (log k₂) correlated linearly with the electrophilicity parameters E of the electrophiles according to the correlation log k₂ = s(N + E) (Angew. Chem., Int. Ed. Engl. 1994, 33, 938-957), allowing us to determine the nucleophilicity parameters N and s for the pyridone anions. The reactions of the 2- and 4-pyridone anions with stabilized amino-substituted benzhydrylium ions and Michael acceptors are reversible and yield the thermodynamically more stable N-substituted pyridones exclusively. In contrast, highly reactive benzhydrylium ions (4,4′-dimethylbenzhydrylium ion), which react with diffusion control, give mixtures arising from N- and O-attack with the 2-pyridone anion and only O-substituted products with the 4-pyridone anion. For some reactions, rate and equilibrium constants were determined in DMSO, which showed that the 2-pyridone anion is a 2-4 times stronger nucleophile, but a 100 times stronger Lewis base than the 4-pyridone anion. Quantum chemical calculations at MP2/6-311+G(2d,p) level of theory showed that N-attack is thermodynamically favored over O-attack, but the attack at oxygen is intrinsically favored. Marcus theory was employed to develop a consistent scheme which rationalizes the manifold of regioselectivities previously reported for the reactions of these anions with electrophiles. In particular, Kornblum's rationalization of the silver ion effect, one of the main pillars of the hard and soft acid/base concept of ambident reactivity, has been revised. Ag ⁺ does not reverse the regioselectivity of the attack at the 2-pyridone anion by increasing the positive charge of the electrophile but by blocking the nitrogen atom of the 2-pyridone anion.

Full text of DOI:10.1021/ja106962u

Published on Web 10/13/2010
Ambident Reactivities of Pyridone Anions
Martin Breugst and Herbert Mayr*
Department Chemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse 5-13,
81377 Mu¨nchen, Germany
Received August 4, 2010; E-mail: Herbert.Mayr@cup.uni-muenchen.de
Abstract: The kinetics of the reactions of the ambident 2- and 4-pyridone anions with benzhydrylium ions
(diarylcarbenium ions) and structurally related Michael acceptors have been studied in DMSO, CH3CN,
and water. No significant changes of the rate constants were found when the counterion was varied (Li+,
K+, NBu4+) or the solvent was changed from DMSO to CH3CN, whereas a large decrease of nucleophilicity
was observed in aqueous solution. The second-order rate constants (log k2) correlated linearly with the
electrophilicity parameters E of the electrophiles according to the correlation log k2 ) s(N + E) (Angew.
Chem., Int. Ed. Engl. 1994, 33, 938-957), allowing us to determine the nucleophilicity parameters N and
s for the pyridone anions. The reactions of the 2- and 4-pyridone anions with stabilized amino-substituted
benzhydrylium ions and Michael acceptors are reversible and yield the thermodynamically more stable
N-substituted pyridones exclusively. In contrast, highly reactive benzhydrylium ions (4,4′-dimethylbenzhy-
drylium ion), which react with diffusion control, give mixtures arising from N- and O-attack with the 2-pyridone
anion and only O-substituted products with the 4-pyridone anion. For some reactions, rate and equilibrium
constants were determined in DMSO, which showed that the 2-pyridone anion is a 2-4 times stronger
nucleophile, but a 100 times stronger Lewis base than the 4-pyridone anion. Quantum chemical calculations
at MP2/6-311+G(2d,p) level of theory showed that N-attack is thermodynamically favored over O-attack,
but the attack at oxygen is intrinsically favored. Marcus theory was employed to develop a consistent scheme
which rationalizes the manifold of regioselectivities previously reported for the reactions of these anions
with electrophiles. In particular, Kornblum’s rationalization of the silver ion effect, one of the main pillars of
the hard and soft acid/base concept of ambident reactivity, has been revised. Ag+ does not reverse the
regioselectivity of the attack at the 2-pyridone anion by increasing the positive charge of the electrophile
but by blocking the nitrogen atom of the 2-pyridone anion.
Scheme 1. Ambident Reactivities of Pyridone Anions
Introduction
The anions of 2-pyridone (1) and 4-pyridone (2) are possibly
the least understood ambident nucleophiles. As the selective
formation of N-alkylated pyridones and alkoxypyridines ac-
cording to Scheme 1 is of eminent importance for the synthesis
of many biologically active compounds,1 control of the regio-
selectivitiy of electrophilic attack at 1 and 2 has intrigued
chemists for many decades.2
Kornblum rationalized the predominant formation of 2-ethoxy-
pyridine from the silver salt of 2-pyridone with ethyl iodide by
the “great carbonium character” of the electrophile in the
presence of silver ions.3 Systematic investigations of the
alkylations of 2-pyridone salts by Tieckelmann4 showed “that
the results are completely consistent with Kornblum’s proposal
that the silVer ion enhances unimolecular character in the silVer
salt reactions, thereby faVoring alkylation at the more electro-
negatiVe oxygen atom”.4a However, at the end of his thorough
investigation, Tieckelmann stated: “The mechanism which leads
to oxygen alkylation of the silVer salts of 2-pyridones also needs
further examination and may be more related to heterogeneous
reaction than to the ability of the silVer ion to promote
unimolecular reaction as preViously suggested”.4a
(1) (a) Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992,
114, 10971–10972. (b) Liu, H.; Ko, S.-B.; Josien, H.; Curran, D. P.
Tetrahedron Lett. 1995, 36, 8917–8920. (c) Conreaux, D.; Bossharth,
E.; Monteiro, N.; Desbordes, P.; Balme, G. Tetrahedron Lett. 2005,
46, 7917–7920. (d) Tipparaju, S. K.; Joyasawal, S.; Forrester, S.;
Mulhearn, D. C.; Pegan, S.; Johnson, M. E.; Mesecar, A. D.;
Kozikowski, A. P. Bioorg. Med. Chem. Lett. 2008, 18, 3565–3569.
(2) (a) Meislich, H. In Pyridine and Its DeriVatiVes, Part III; Klingsberg,
E., Ed.; Interscience Publisher: New York, 1962; pp 511-890. (b)
Keller, P. A. In Science of Synthesis, Vol. 15; Thieme: Stuttgart, 2005;
pp 285-387
Kornblum’s rule was later integrated in Pearson’s concept
of “Hard and Soft Acids and Bases” (HSAB) which became
(4) (a) Hopkins, G. C.; Jonak, J. P.; Minnemeyer, H. J.; Tieckelmann, H.
J. Org. Chem. 1967, 32, 4040–4044. (b) Chung, N. M.; Tieckelmann,
H. J. Org. Chem. 1970, 35, 2517–2520.
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Chem. Soc. 1955, 77, 6269–6280.
9
15380 J. AM. CHEM. SOC. 2010, 132, 15380–15389
10.1021/ja106962u  2010 American Chemical Society

Ambident Reactivities of Pyridone Anions
A R T I C L E S
Table 1. Reference Electrophiles Employed in this Work and
Wavelengths Monitored in the Kinetic Experiments
Figure 1. Plot of the absorbance at 393 nm, A393, vs time for the reaction
of 3m with the anion of 2-pyridone (1) in DMSO at 20 °C and correlation
of the first-order rate constants kobs with the concentration of 1 (inset).
reactivities of these nucleophiles.15 We now report on a
systematic experimental and quantum chemical investigation of
the ambident reactivities of 1 and 2, and demonstrate that
Marcus theory also provides a consistent rationalization of the
ambident reactivities of pyridone anions.
In previous work, we have shown that the benzhydrylium
ions 3a-h and the structurally related quinone methides 3i-o
(Table 1) are electrophiles, which differ by approximately 20
orders of magnitude in reactivity while the steric surroundings
of the reaction center are kept constant.7 We now use these
compounds as reference electrophiles to investigate the influence
of electrophilicity on regioselectivity and kinetics of the reactions
of the pyridone anions 1 and 2.
Results
Kinetic Investigations. The reactions of the pyridone anions
1 and 2 with the quinone methides 3i-o and the benzhydrylium
ions 3d-h were performed in DMSO, acetonitrile, or water at
20 °C and monitored by UV-vis spectroscopy at or close to
the absorption maxima of the electrophiles (354 < λ < 635 nm)
(Table 1). While the anions of 2-pyridone (1) reacted smoothly
with the quinone methides 3k-o, no reactions were observed
when the anion of 4-pyridone (2) was employed. Reactivities
of the more electrophilic benzhydrylium ions 3a-c could not
be determined, because the laser-flash-photolytic generation of
benzhydrylium ions, which we usually employ for studying fast
reactions, was not applicable due to the absorption of the
pyridone anions 1 and 2 (ε ) 1.85 × 103 L mol-1 cm-1) at 266
nm, i.e., the excitation wavelength of the laser.
a Electrophilicity parameters from ref 7.
the best known approach to rationalize ambident reactivity in
general.5 Remarkably few investigators have employed the
HSAB model on the pyridone anions,6 and a consistent
rationalization of the large diversity of experimental results with
1 and 2 is lacking despite the great importance of these anions
in synthesis.
Systematic experimental investigations of the reactivities of
cyanide,8 cyanate,9 thiocyanate,10 nitrite,11 and phenyl sulfinate12
demonstrated that not even the behavior of the prototypes of
ambident nucleophiles can be explained by the HSAB model5
or the related Klopman-Salem concept of charge and orbital
controlled reactions.13 Recently, we have shown that Marcus
theory14 provides a consistent rationalization of the ambident
By using the nucleophiles 1 and 2 in large excess over the
electrophiles, their concentrations remained almost constant
throughout the reactions, and pseudo-first-order kinetics were
obtained in all runs. The first-order rate constants kobs were then
(8) Tishkov, A. A.; Mayr, H. Angew. Chem., Int. Ed. 2005, 44, 142–145.
(9) Schaller, H. F.; Schmidhammer, U.; Riedle, E.; Mayr, H. Chem.sEur.
J. 2008, 14, 3866–3868.
(5) (a) Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533–3539. (b) Pearson,
R. G. Science 1966, 151, 172–177. (c) Pearson, R. G. J. Chem. Educ.
1968, 45, 581–587. (d) Pearson, R. G. J. Chem. Educ. 1968, 45, 643–
648. (e) Pearson, R. G. Chemical Hardness; Wiley-VCH: Weinheim,
1997.
(6) (a) Zaragoza Do¨rwald, F. Side Reactions in Organic Synthesis; Wiley-
VCH: Weinheim, 2005, pp 1-16. (b) Ho, T.-L. Chem. ReV. 1975,
75, 1–20.
(10) Loos, R.; Kobayashi, S.; Mayr, H. J. Am. Chem. Soc. 2003, 125,
14126–14132.
(11) Tishkov, A. A.; Schmidhammer, U.; Roth, S.; Riedle, E.; Mayr, H.
Angew. Chem., Int. Ed. 2005, 44, 4623–4626.
(12) Baidya, M.; Kobayashi, S.; Mayr, H. J. Am. Chem. Soc. 2010, 132,
4796–4805.
(7) (a) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker,
B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel,
H. J. Am. Chem. Soc. 2001, 123, 9500–9512. (b) Lucius, R.; Loos,
R.; Mayr, H. Angew. Chem., Int. Ed. 2002, 41, 91–95. (c) Richter,
D.; Hampel, N.; Singer, T.; Ofial, A. R.; Mayr, H. Eur. J. Org. Chem.
2009, 3203–3211.
(13) (a) Klopman, G. J. Am. Chem. Soc. 1968, 90, 223–234. (b) Salem, L.
J. Am. Chem. Soc. 1968, 90, 543–552.
(14) (a) Marcus, R. A. Annu. ReV. Phys. Chem. 1964, 15, 155–196. (b)
Marcus, R. A. Pure Appl. Chem. 1997, 69, 13–29.
(15) Breugst, M.; Zipse, H.; Guthrie, J. P.; Mayr, H. Angew. Chem., Int.
Ed. 2010, 49, 5165–5169.
9
J. AM. CHEM. SOC. VOL. 132, NO. 43, 2010 15381

A R T I C L E S
Breugst and Mayr
Table 2. Second-Order Rate Constants for the Reactions of the
2-Pyridone Anion 1 with Reference Electrophiles at 20 °C
derived by least-squares fitting of the time-dependent absor-
bances At of the electrophiles to the exponential function At )
A0exp(-kobst) + C. Second-order rate constants were obtained
as the slopes of the plots of kobs versus the concentration of the
nucleophiles (Figure 1).
solvent
N/s
electrophile
k2/L mol-1 s-1
DMSO
19.91/0.60
3o
3n
3m
3l
1.51 × 101
3.68 × 101
1.94 × 102
2.44 × 102
1.66 × 102,a
3.06 × 103
6.49 × 103
4.05 × 104
2.64 × 104,a
8.69 × 105
1.65 × 106
1.94 × 101
3.84 × 101
1.72 × 102
2.38 × 102
2.34 × 103
5.79 × 103
3.12 × 104
2.04 × 101
3.42 × 101
8.50 × 101
1.56 × 102
3.37 × 102
Due to the low acidities of the pyridones 1-H (pKa ) 11.74)16a
and 2-H (pKa ) 11.12),16a aqueous solutions of the pyridone
anions 1 and 2 are partially hydrolyzed and contain hydroxide
anions. For that reason, three competing reactions may account
for the decay of the benzhydrylium ions in water and the
observed rate constants kobs for the consumption of the elec-
trophiles in water reflect the sum of their reactions with the
pyridone anions 1 or 2 (k2), hydroxide (k2,OH),17 and water (kw)
(eq 1).
3k
3j
3i
3h
3g
3o
3n
3m
3l
3k
3j
3i
3h
3g
3f
3e
3d
CH3CN
20.11/0.57
12.47/0.52
kobs ) k2[1 or 2] + k2,OH[OH-] + kw
(1)
(2)
keff ) kobs - k2,OH[OH-] ) k2[1 or 2] + kw
water
All equilibrium concentrations in eq 2 were calculated from
the initial concentrations and the pKaH values, as described in
the Supporting Information. Rearrangement of eq 1, i.e.,
subtraction of the contribution of hydroxide from the observed
rate constant kobs, yields eq 2, and the second-order rate constants
for the reactions of the benzhydrylium ions with 1 and 2 can
then be obtained from plots of keff versus the concentration of
the nucleophiles. By combining the pyridones 1-H and 2-H,
which are used in high excess over the electrophiles 3 (pseudo-
first-order conditions), with only 0.02-0.2 equiv of KOH, we
were able to realize conditions, where the correction term
k2,OH[OH-] never exceeded 10% of kobs, thus giving rise to
highly reliable values of k2. The intercepts of these plots
correspond to the reactions of the electrophiles with water and
are generally negligible in agreement with previous work, where
water (N ) 5.20)18 was demonstrated to react much more slowly
with benzhydrylium ions than the nucleophiles investigated in
this work.
a Li+ as counterion.
Table 3. Second-Order Rate Constants for the Reactions of the
4-Pyridone Anion 2 with Reference Electrophiles at 20 °C
solvent
N/s
electrophile
k2/L mol-1 s-1
DMSO
18.97/0.62
3k
3j
3i
3h
3g
3l
3k
3j
7.28 × 102
2.75 × 103
1.34 × 104
3.26 × 105
7.45 × 105
1.61 × 102
5.53 × 102
2.25 × 103
9.14 × 103
1.93 × 102
2.99 × 102
6.61 × 102
1.35 × 103
2.34 × 103
CH3CN
water
20.22/0.49
14.76/0.48
3i
3h
3g
3f
3e
3d
As shown for several examples in the Supporting Information,
kobs values obtained for 1-K and 2-K in the presence and in the
absence of 18-crown-6 are on the same kobs vs [1] or kobs vs [2]
plots, indicating that in the concentration range under investiga-
tion (c < 4 × 10-3 M) reactivities of the free anions 1 (Table 2)
and 2 (Table 3) are observed.
Scheme 2. Solvent Dependence of the Rate Constant of the
Reactions of 1-K and 2-K with 3h at 20 °C and the Corresponding
pKa Values (pKa from ref 16)
Furthermore, an exchange of K+ by Li+ only moderately
reduces the rate constant in DMSO by a factor of 0.65 (Table
2), in line with previous findings by Tieckelmann.4
Solvent Effects. Tables 2 and 3 show that the reactivities of
1 and 2 toward benzhydrylium ions and quinone methides (3)
are almost identical in DMSO and CH3CN. The rate constants
in these solvents differ by less than a factor of 1.5, and we can
neglect differential solvent effects when comparing rate con-
stants determined in DMSO and CH3CN. The rate constants
for the reaction of 1 and 2 with benzhydrylium ions show a
different order in DMSO and water. As depicted in Scheme 2
for the reactions with 3h, 2-pyridone anion (1) reacts ap-
proximately 48000 times faster in DMSO than in water, while
the reactions of 4-pyridone anion (2) differ by a factor of only
∼2000. The resulting reversal of the relative reactivities of 1
and 2 in the two solvents indicates that the 2-pyridone anion 1
is better stabilized by hydrogen bonding in water than the
4-pyridone anion 2. In line with this interpretation the significant
(16) (a) pKa in H2O Bunting, J. W.; Toth, A.; Heo, C. K. M.; Moors, R. G.
J. Am. Chem. Soc. 1990, 112, 8878–8885. (b) pKa in DMSO: 1-H:
17.0, 2-H: 14.8 Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463.
(17) Minegishi, S.; Mayr, H. J. Am. Chem. Soc. 2003, 125, 286–295.
(18) Minegishi, S.; Kobayashi, S.; Mayr, H. J. Am. Chem. Soc. 2004, 126,
5174–5181.
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Ambident Reactivities of Pyridone Anions
A R T I C L E S
Scheme 3. Reaction of Pyridone Anions 1 and 2 with the
Electrophiles 3a-o in DMSO
were performed by NMR spectroscopy in d6-DMSO solution
(see the Supporting Information for NMR spectra).
The carbonyl carbon of the 4-pyridones (δ 177.4 for 5g-N)
is considerably more deshielded than the oxy-substituted 4-posi-
tion of the 4-oxysubstituted pyridines (δ 164 for 5a-O and 5b-
O) which allows a straightforward differentiation of the two
isomers.
In contrast, the carbonyl group of the 2-pyridones 4(a-o)-N
and the alkoxy-substituted ring carbon in the pyridines 4(a-o)-O
have similar 13C NMR chemical shifts. Therefore, the site of
attack at the 2-pyridone anion 1 cannot directly be derived from
the appearance of a 13C NMR signal for the carbonyl group,
and the differentiation between N- and O-alkylated products was
based on 2D-NMR experiments.
In cases where the reaction products are isolable, the structural
assignment can be confirmed by IR-spectroscopy. While the
N-alkylated pyridones 4l-N, 4k-N, 4b-N, and 4a-N show a
strong band at ∼1660 cm-1, the alkoxypyridines 4a-O and 5a-O
absorb at ∼1590 cm-1. Further structural evidence comes from
the crystal structure of 4l-N (Figure 3, Table 4).
Figure 2. Plots of the rate constants log k2 for the reaction of the pyridone
anions 1 and 2 with reference electrophiles versus their electrophilicity
parameters E (correlation in CH3CN are shown in the Supporting Informa-
tion).
difference between the acidities of 2-pyridone (1-H) and
4-pyridone (2-H) in DMSO is almost canceled in aqueous
solution (Scheme 2, right).
Correlation Analysis. In line with the linear free-energy
relationship (eq 3), where the second-order rate constant (log
k2) is described by the nucleophile-specific parameters s and N
and the electrophile-specific parameter E,19 plots of log k2 for
the reactions of the pyridone anions 1 and 2 with the reference
electrophiles 3d-o versus their electrophilicity parameters E
were linear.
log k2 ) s(N + E)
(3)
Independent of the counterion and the solvent, the anion of
2-pyridone (1) gives exclusive N-alkylation with the quinone
methides 3l and 3k and with the weakly electrophilic benzhy-
drylium ions 3c and 3g (Table 5, entries 1-7). Mixtures
resulting from O- and N-attack were obtained, when 1 was
treated with the tetrafluoroborate of the more electrophilic
ditolylcarbenium ion 3b (entry 8) or the corresponding benz-
The slopes of these correlations correspond to the nucleophile-
specific sensitivity parameters s, whereas the negative intercepts
on the abscissa yield the nucleophilicity parameters N. For
reasons of clarity the rate constants determined in CH3CN are
not shown in Figure 2, but all individual correlations are depicted
in the Supporting Information. The almost parallel correlation
lines in Figure 2 which refer to N-attack (see below) imply that
the relative reactivities of 2- and 4-pyridone anions (1 and 2)
are nearly independent of the reactivities of the electrophiles.
Reaction Products. Scheme 3 specifies the general Scheme
1 for the reaction of the pyridone anions 1 and 2 with the
benzhydrylium ions 3a-h and the quinone methides 3i-o. The
letters in the products 4 and 5 identify their origin; thus, 4k-N
is formed from 1 and 3k via N-attack.
When the potassium salts of 1 or 2 (1 to 5 equiv) were
combined with the quinone methides 3l and 3k in dry DMSO
or dry CH3CN, the solutions remained colored, indicating
incomplete reactions. Equilibria and nonoptimized workup
procedures account for the fact that some reaction products were
only obtained in moderate yields (Table 5). The reactions of 1
and 2 with the weakly stabilized benzhydrylium ions 3c-h
resulted in colorless solutions, but as the investigated pyridone
anions 1 and 2 are weak bases in water (pKaH(1) ) 11.74 and
pKaH(2) ) 11.12),16a the resulting products undergo heterolytic
cleavage during aqueous workup. In these cases, product studies
Figure 3. Crystal structure of the reaction product 4l-N obtained from
1a-K and 2l (50% probability ellipsoids).
(19) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 938–957.
9
J. AM. CHEM. SOC. VOL. 132, NO. 43, 2010 15383

A R T I C L E S
Breugst and Mayr
Table 4. Crystallographic Data of 4l-N
Scheme 4. Products of the Reactions of the Pyridone Anions 1
and 2 with the Michael Acceptors 6 and 7
empirical formula
Mr/g mol-1
crystal size/mm
T/K
C27H33NO2
403.556
0.41 × 0.10 × 0.09
173(2)
radiation
MoKR
diffractometer
crystal system
space group
a/Å
b/Å
c/Å
Oxford XCalibur
monoclinic
P21/c
10.6093(6)
10.9456(8)
20.9242(13)
90
94.074(5)
90
2423.7(3)
4
R/deg
ꢀ/deg
γ/deg
V/Å3
Z
calc. density/g cm-3
1.10596(14)
0.069
µ/mm-1
absorption correction
transmission factor range
reflections measured
Rint
mean σ(I)/I
θ range
observed reflections
x, y (weighting scheme)
hydrogen refinement
reflections in refinement
parameters
‘multiscan’
0.95407-1.00000
9587
0.0884
0.1934
4.19-25.37
1693
0.0293, 0
constr
4391
278
0
0.0563
0.1005
0.776
0.001
0.153
-0.147
Reactions with Other Types of Michael Acceptors. NMR
studies showed that the Michael acceptors 6a,b and 7a-c also
exclusively attack the nitrogen atom of the pyridone anions 1
and 2 and that oxygen attack did not occur (Scheme 4).
Comparison of the experimentally determined rate constants
(Table 6) with those calculated by eq 3 from the N/s-parameters
of 1 and 2 (Tables 2 and 3) and the previously published
electrophilicity parameters20 of 6a,b and 7a-c is an impressive
demonstration of the predictive power of the three-parameter
eq 3, which presently covers 40 orders of magnitude. While
the calculated rate constants for 1 are 1.5-3 times larger
than the experimental values, kcalc for 2 are 2.5-7 times smaller
than the experimental numbers.
restraints
R(Fobs
)
Rw(F2)
S
shift/errormax
max electron density/e Å-3
min electron density/e Å-3
Equilibrium Constants and Intrinsic Barriers. In DMSO the
pyridone anions 1 and 2 reacted quantitatively with all inves-
tigated benzhydrylium ions and with quinone methides of E >
-14, while incomplete reactions were observed with less
reactive electrophiles. As the quinone methides are colored and
the reaction products are colorless, we were able to determine
equilibrium constants for these reactions (Table 7) by UV/vis
spectrometry as described on pp S4 and S41-46 of the
Supporting Information.
hydryl bromides 3b-Br and 3a-Br (entries 9-10, 12). Only
when the silver salt of 1 was treated with 3b-Br, exclusive
O-attack took place (entry 11).
A different behavior was found for the 4-pyridone anion (2).
While the weakly electrophilic benzhydrylium ion 3g gave
exclusive N-attack (entry 14), only alkoxypyridines were isolated
in the reactions of 2 with the more electrophilic benzhydrylium
ion 3b or the corresponding benzhydrylium bromides 3b-Br
and 3a-Br (entries 15-18).
The availability of rate and equilibrium constants allows us
to employ Marcus theory14 (eq 4) for calculating the intrinsic
Table 5. Products of the Reactions of the Pyridone Salts (1 and 2) with Electrophiles
electrophile
product (yield %)
entry
pyridone
No
Ea
solvent
N-attack
O-attack
1
2
3
4
5
6
7
8
1-K
3l
3l
3l
3l
-15.83
-15.83
-15.83
-15.83
-14.32
-9.45
-7.02
+3.63
+3.63
+3.63
+3.63
+5.90
-15.83
-9.45
+3.63
+3.63
+3.63
+5.90
DMSO
DMSO
CH3CN
CH3CN
DMSO
DMSO
DMSO
CH3CN/CH2Cl2
CH3CN
CH3CN/H2O (9:1)
CH3CN
CH3CN
DMSO
DMSO
CH3CN/CH2Cl2
CH3CN
CH3CN
4l-N (88%)
4l-N (80%)
4l-N (79%)
4l-N (89%)
4k-N (84%)
-
1-Li
-
1-K
-
-
1-NBu4
1-K
3k
-
1-K
3g
4g-N (NMR)
4c-N (NMR)
4b-N (49%)c
4b-N (50%)
4b-N(53%)
-
-
1-K
3c
-
1-K
3bb
4b-O (17%)
4b-O (38%)
4b-O (41%)
4b-O (92%)
4a-O (38%)
9
1-NBu4
1-NBu4
1-Agd
1-NBu4
2-K
3b-Br
3b-Br
3b-Br
3a-Br
3l
10
11
12
13
14
15
16
17
18
4a-N (60%)
no reaction
2-K
2-K
2-NBu4
2-Agd
2-NBu4
3g
3b
3b-Br
3b-Br
3a-Br
5g-N (NMR)
-
-
-
-
-
5b-O (74%)
5b-O (71%)
5b-O (72%)
5a-O (77%)
CH3CN
b
a Empirical electrophilicity parameters from ref 7. 3b-Br was ionized with 1 equiv of AgOTf; as AgBr precipitates, there are no Ag+ ions in
solution. c Along with 31% (tol2CH)2O. d 3b-Br was added to heterogeneous systems obtained by treatment of 1-NBu4 or 2-NBu4 with AgNO3.
9
15384 J. AM. CHEM. SOC. VOL. 132, NO. 43, 2010

Ambident Reactivities of Pyridone Anions
A R T I C L E S
Table 6. Rate Constants (in L mol-1 s-1) for the Reactions of 1 and 2 with Michael Acceptors 6 and 7 at 20 °C
a Electrophilicities E from ref 20.
‡
Table 7. Equilibrium Constants, Gibbs Reaction Energies ∆G0, Gibbs Activation Energies ∆G‡, and Intrinsic Barriers ∆G0 for the Reactions
of Pyridone Anions with Electrophiles in DMSO at 20 °C (all energies in kJ mol-1
)
c
a From Tables 2, 3, and 6 using the Eyring equation (eq 5). b From eq 4. ∆G‡ was calculated from k2 obtained from eq 3 with N/s from Table 3 and
E(3) from Table 1.
‡
barriers ∆G0 (defined as the activation energy for a thermo-
neutral reaction, Table 7) from the Gibbs energy of activation
∆G‡ (derived from the rate constants, eq 5) and the Gibbs energy
of reaction ∆G0 (derived from the equilibrium constants, eq 6).
of magnitude larger than those of analogous reactions of 2. On
the other hand, 1 reacts only 2-4 times faster than 2 with neutral
(3i-k) and charged electrophiles (3g,h) in DMSO. Obviously,
the reactions of the 2-pyridone anion 1 require a considerably
higher reorganization energy than the analogous reactions of
the 4-pyridone anion 2, as quantitatively expressed by the
∆Gq ) ∆Gq + 0.5∆G0 + ∆G /16∆G
(4)
(5)
(6)
0 2
q
0
(
)
[
]
0
‡
intrinsic barriers ∆G0 in the last column of Table 7.
∆Gq ) -RT ln[(kh)/(kbT)]
Quantum Chemical Calculations. Extending earlier work by
Wolfe and Schlegel,21 as well as by Schaefer,22 we have recently
demonstrated that the directly calculated activation energies of
C- and O-alkylation of enolate anions with methyl halides agree
well with those derived from eq 4 using calculated Gibbs
∆G0 ) -RT ln K
Table 7 shows that the equilibrium constants for the reactions
of 1 with quinone methides in DMSO are more than 2 orders
9
J. AM. CHEM. SOC. VOL. 132, NO. 43, 2010 15385

A R T I C L E S
Breugst and Mayr
q
reaction energies ∆G0 and intrinsic barriers ∆G0 which were
Table 8. Intrinsic Barriers, Reaction Free Energies, and Activation
Free Energies for the Methylation of Pyridone Anions 1 and 2 by
Methyl Chloride in the Gas Phase (MP2/6-311+G(2d,p), in kJ
obtained as the arithmetic mean of the corresponding identity
reactions.15 Calculated values of ∆G0 and ∆G0 for the
‡
mol-1
)
methylation of enolate, cyanide, cyanate, thiocyanate, and nitrite
in combination with the Marcus equation were reported to
provide a consistent rationalization of the ambident reactivities
of these nucleophiles.
In order to employ this method also on the ambident
reactivities of the pyridone anions 1 and 2, we have calculated
the Gibbs energies of activation for the identity methyl-transfer
reactions in eqs 7-10 at the MP2/6-311+G(2d,p) level, as this
method was found to give similar results as G3(+) calculations
of related systems.15 The barriers for O-attack (97.5 and 85.9
kJ mol-1, eqs 8, 10) are smaller than the corresponding barriers
for the attack at nitrogen (108 and 93.4 kJ mol-1, eqs 7, 9)
which is in agreement with Hoz’s findings that the barriers of
identity SN2 reactions decrease when the center of nucleophi-
licity is positioned further right in the periodic table.23 Intrinsi-
cally preferred is, hence, oxygen attack in the reactions of 2-
and 4-pyridone anions.
a
‡
‡
‡
∆G0 ) 0.5[∆G0 (eqs 7-10) +∆G0 (Cl- + MeCl)].
Comparison of eqs 7 and 9 as well of eqs 8 and 10
furthermore shows that the reactions of the 4-pyridone anion 2
are intrinsically favored over the corresponding reactions of the
2-pyridone anion 1, a trend which is also observed experimen-
tally in reactions with the electrophiles 3 (see Table 7).
Using Marcus’ additivity rule,25 which yields the intrinsic
barriers for nonidentity reactions as the arithmetic means of the
q
corresponding identity reactions, ∆G0 for the reactions of 1
and 2 with CH3Cl (Table 8) are obtained from the identity
reactions in eqs 7-10 and the intrinsic barrier for the chloride
(20) (a) Seeliger, F.; Berger, S. T. A.; Remennikov, G. Y.; Polborn, K.;
Mayr, H. J. Org. Chem. 2007, 72, 9170–9180. (b) Berger, S. T. A.;
Seeliger, F. H.; Hofbauer, F.; Mayr, H. Org. Biomol. Chem. 2007, 5,
3020–3026.
Furthermore, we have calculated the Gibbs reaction energies
for the methylation of the ambident pyridone anions 1 and 2
with methyl chloride at MP2/6-311+G(2d,p) level of theory.
Table 8 shows that the N-methyl pyridones are thermodynami-
cally favored over the corresponding methoxypyridines by 32.9
kJ mol-1 (for 2-pyridone) and 13.7 kJ mol-1 (for 4-pyridone).
In agreement with these calculations, calorimetric measurements
by Beak showed that the rearrangement 4Me-O f 4Me-N (eq
11) is considerably more exothermic than the analogous
rearrangement in the 4-pyridone series (eq 12).24 The absolute
values of the experimental enthalpies of rearrangement are
considerably larger than the calculated numbers as specified in
eqs 11 and 12, but the differences of the two series (∆∆rH) are
similar (19.2 kJ mol-1 calculated gas phase vs 15.1 kJ mol-1
calorimetric).
(21) (a) Wolfe, S.; Mitchell, D. J.; Schlegel, H. B. J. Am. Chem. Soc. 1981,
103, 7692–7694. (b) Wolfe, S.; Mitchell, D. J.; Schlegel, H. B. J. Am.
Chem. Soc. 1981, 103, 7694–7696.
(22) (a) Gonzales, J. M.; Cox, R. S., III; Brown, S. T.; Allen, W. D.;
Schaefer, H. F., III. J. Phys. Chem. A 2001, 105, 11327–11346. (b)
Gonzales, J. M.; Pak, C.; Cox, R. S.; Allen, W. D.; Schaefer, H. F.,
III; Csaszar, A. G.; Tarczay, G. Chem.sEur. J. 2003, 9, 2173–2192.
(c) Gonzales, J. M.; Allen, W. D.; Schaefer, H. F., III. J. Phys. Chem.
A 2005, 109, 10613–10628.
(23) Hoz, S.; Basch, H.; Wolk, J. L.; Hoz, T.; Rozental, E. J. Am. Chem.
Soc. 1999, 121, 7724–7725.
(24) Beak, P.; Bonham, J.; Lee, J. T., Jr. J. Am. Chem. Soc. 1968, 90,
1569–1582.
(25) (a) Marcus, R. A. J. Am. Chem. Soc. 1969, 91, 7224–7225. (b) Albery,
W. J.; Kreevoy, M. M. AdV. Phys. Org. Chem. 1978, 16, 87–157. (c)
Shaik, S. S.; Schlegel, H. B.; Wolfe, P. Theoretical Aspects of Physical
Organic Chemistry: The SN2 Mechanism; Wiley: New York, 1992.
9
15386 J. AM. CHEM. SOC. VOL. 132, NO. 43, 2010

Ambident Reactivities of Pyridone Anions
A R T I C L E S
Scheme 5. Gibbs Energy Profile for the Methylation of the
Table 9. Effect of Alkylating Agent and Counterion on the N/
O-Alkylation Ratio in DMF4
Pyridone Anions with Methyl Chloride (MP2/6-311+G(2d,p), all in
kJ mol-1
)
entry
electrophile
salt
N/O-ratio
1
2
3
4
5
6
7
MeI
MeI
PhCH2Cl
PhCH2Br
PhCH2I
EtI
1-Na
1-K
1-Na
1-Na
1-Na
1-Na
1-Na
95:5
92:8
94:6
97:3
98:2
69:31
iPrI
30:61a
a 2-Pyridone was partially recovered.
Scheme 7. Calculated Thermodynamic Difference ∆G0 for O- and
N-alkylated 2-Pyridones in the Gas Phase
Scheme 6. Selective N-Alkylation of 2-Pyridone Anion with
Acrylonitrile26
15
exchange in CH3Cl (38.2 kJ mol-1
footnote of Table 8.
)
as formulated in the
Scheme 8. Selective O- and N-Tritylation of Pyridone Salts in
Acetonitrile27
The Gibbs energies of activation for the methylation of the
pyridone anions 1 and 2 by methyl chloride (∆G‡) have then
been calculated by the Marcus equation (eq 4) from the
‡
corresponding intrinsic barriers ∆G0 and the Gibbs energies
of reaction ∆G0 (Table 8).
Discussion
control. As reported by Tieckelmann,4 the sodium and potassium
salt of 1 react with 92-98% nitrogen attack when treated with
methyl iodide and different benzyl halides in DMF at room
temperature (entries 1-5, Table 9).
MP2/6-311+G(2d,p) calculations show that the thermody-
namic preference for N-attack shrinks when the steric bulk of
the alkylation agent is increased (Scheme 7).
Alkylation of Alkali Salts. Scheme 5 which summarizes the
results presented in Table 8, can now be used to rationalize the
experimental findings on the reactivities of pyridone anions. In
the case of both pyridones, N-alkylation is generally preferred
thermodynamically, but the preference of the N-alkylated
pyridone over the isomeric alkoxypyridine is considerably
greater in the 2-pyridone than in the 4-pyridone series. The
exclusive observation of N-attack with highly stabilized carbe-
nium ions (E < -7) and Michael acceptors (-17 < E < -11)
reported in Table 6 and Scheme 4 can be explained by the
reversibility of these reactions and the formation of the
thermodynamically more stable product. Support for this
interpretation comes from the fast dissociation reactions of the
adducts which can be calculated from the equilibrium constants
in Table 7 and the rate constants of the reactions of the pyridone
anions with the quinone methides reported in Tables 2 and 3.
Furthermore, the adducts 4-N and 5-N obtained from amino
substituted benzhydrylium ions were observed to dissociate into
the carbenium ions 3 and the pyridone anions 1 and 2 when
treated with water.
The decreasing N/O ratio when turning from MeI to EtI and
iPrI (entries 1, 6, 7, Table 9) can therefore be explained by the
fact that the intrinsically preferred O-attack is gaining impor-
tance as the ∆∆G0 term, which favors N-attack, decreases.
Qualitatively speaking: An increase of the size of R introduces
more strain into the N-alkylated product 4R-N than in the
O-alkylated product 4R-O, and a fraction of this effect is already
noted in the corresponding transition states.
Exclusive O-attack was observed, when 1-Na was treated with
the even bulkier tritylating agent Ph3CCl, while 1-Li gave
exclusive N-attack under the same conditions (Scheme 8). Since
4Tr-O was found to isomerize into 4Tr-N in the presence of
Lewis acids, one can conclude that also for tritylations, N-attack
is thermodynamically favored over O-attack. The smaller ∆∆G0
term in favor of N-attack (extrapolate data in Scheme 7) cannot
any longer overcome the intrinsic preference for O-attack.
The exclusive N-tritylation of 1-Li (Scheme 8) cannot be the
result of thermodynamic product control because the rearrange-
ment 4Tr-O to 4Tr-N is very slow under the reaction conditions.
We therefore join Effenberger’s rationalization that Li+ blocks
the attack at oxygen; obviously this ion-pairing plays a role in
The exclusive formation of N-alkylated products from 2-py-
ridone anions with acrylonitrile26 or with related Michael
acceptors16 can analogously be rationalized by the reversibility
of these additions (Scheme 6).
According to Scheme 5, the higher thermodynamic stabilities
of the N-methylated pyridones (∆∆G0 term) are also responsible
for the lower transition state for N-attack, i.e., for the preferred
N-alkylations of the pyridone anions under conditions of kinetic
(27) Effenberger, F.; Brodt, W.; Zinczuk, J. Chem. Ber. 1983, 116, 3011–
(26) Adams, R.; Jones, V. V. J. Am. Chem. Soc. 1947, 69, 1803–1805.
3026.
9
J. AM. CHEM. SOC. VOL. 132, NO. 43, 2010 15387

A R T I C L E S
Breugst and Mayr
Scheme 9. Regioselectivities in the Alkylation of Potassium29b and
Scheme 10. Comparison of the Thermodynamic Differences of
N- and O-Methylated Ordinary Amides, 2-Pyridones, and
4-Pyridones [Gas Phase, MP2/6-311+G(2d,p)]
Silver30 Salts of Pyridones
the more concentrated solutions used for the synthesis of 4Tr-
N,27 though in the highly dilute solutions of 1-K and 1-Li in
DMSO used for the kinetic investigations, only a slight
difference of reactivity was observed (1 + 3l, 3i, Table 2).
Almost exclusive N-attack in the reactions of 2- and 4-py-
ridone anions with 6-(mesyloxymethyl)purines in THF and
acetonitrile28 is also in line with the Marcus model illustrated
in Scheme 5. Analogously, Ra¨th obtained N-alkylated pyridones
in 30-85% yield from the potassium salt of 2-pyridone (1-K)
and various alkyl halides or dimethyl sulfate (Scheme 9).29
Extrapolation of the correlations shown in Figure 2 shows
that the reactions of 1 and 2 with carbocations will be diffusion
controlled, when their electrophilicty exceeds -2 (Figure 4).
As the mechanism of the reactions of the pyridone anions 1
and 2 with the benzhydryl bromides 3a-Br and 3b-Br was not
clear (SN1 or SN2), we have treated 3b-Br with AgOTf before
the pyridone anion was added in order to study the selectivity
of the free ditolylcarbenium ion 3b. The observation of
comparable amounts of O- and N-attack in the reactions of 1
with 3a (E ) 5.90) and 3b (E ) 3.63) (entries 9, 10, 12 in
Table 5) therefore reflects the result of barrierless reactions and
cannot be explained by transition state models. Surprisingly,
the diffusion-controlled reaction of 2 with 3a and 3b occurs
exclusively at oxygen, indicating that site-selectivity is not
necessarily lost when both competing reactions proceed without
barrier.
tion3 that the preferred O-attack in the presence of silver ions
is due to the increased charge of the electrophile cannot hold.
As in the case of the ordinary amide anions,32 silver ions
may coordinate to the nitrogen atom of 1 and thus direct the
electrophile to the oxygen.33 The same reason, which is
responsible for the formation of isonitriles from alkyl halides
and silver cyanide (Ag+ blocks C),8 thus also controls the
site of alkylation of amide and pyridone anions in the
presence of silver ions. However, the blocking of nitrogen
by silver ions does not occur in the vinylogous amide 2, as
2-Ag is attacked at nitrogen by methyl iodide and phenacyl
bromide in ethanol.31
Conclusion
The large thermodynamic preference of amides over
imidates is strongly reduced in the pyridone analogues due
to the aromatic character of the O-alkylated compounds
(Scheme 10). However, N-alkylated pyridones are still
thermodynamically favored over alkoxypyridines that Michael
additions and other reversible reactions generally give
N-alkylated pyridones.
In kinetically controlled reactions of pyridone anions, N-attack
is mostly preferred because the thermodynamic contribution to
the Gibbs energy of activation, which favors N-attack, out-
matches the contribution of the intrinsic barriers which favor
O-attack. Only when ∆∆G0 for O- and N-attack is becoming
small, which is the case for bulky alkylating agents, O-attack
becomes more favorable.
Alkylation of Silver Salts. Already in 1891, von Pechmann
and Baltzer30 reported that exclusive N-attack took place when
2-pyridone was heated with an excess of ethyl iodide, whereas
2-ethoxypyridine (O-attack) was isolated when the silver salt
of 2-pyridone (1-Ag) was employed (Scheme 9). Analogously,
Takahasi and Yoneda reported that phenacyl bromide in ethanol
react at nitrogen of 1-Na and at oxygen of 1-Ag.31
Since we have shown that carbocations also give significant
amounts of N-alkylated pyridones, Kornblum’s rationaliza-
While diffusion-controlled reactions of the 2-pyridone anion
1 give mixtures of O- and N-attack, exclusive O-attack was
observed in diffusion-controlled reactions with the 4-pyridone
anion 2. The O-directing effect of silver ions is not due to the
ˇ
(28) Silha´r, P.; Hocek, M.; Pohl, R.; Votruba, I.; Shih, I.-h.; Mabery, E.;
Mackman, R. Bioorg. Med. Chem. 2008, 16, 2329–2366.
(29) (a) Ra¨th, C. Liebigs Ann. Chem. 1930, 484, 52–64. (b) Ra¨th, C. Liebigs
Ann. Chem. 1931, 489, 107–118.
(30) v. Pechmann, H.; Baltzer, O. Ber. Dtsch. Chem. Ges. 1891, 24, 3144–
3153.
(31) Takahashi, T.; Yoneda, F. Chem. Pharm. Bull. 1958, 6, 365–369.
(32) Breugst, M.; Tokuyasu, T.; Mayr, H. J. Org. Chem. 2010, 75, 5250–
5258.
(33) (a) Bancroft, D. P.; Cotton, F. A.; Falvello, L. R.; Schwotzer, W. Inorg.
Chem. 1986, 25, 763–770. (b) Bancroft, D. P.; Cotton, F. A. Inorg.
Chem. 1988, 27, 1633–1637. (c) Rawson, J. M.; Winpenny, R. E. P.
Coord. Chem. ReV. 1995, 139, 313–374.
Figure 4. Estimated influence of the diffusion limit on the rate of the
reactions of 1 with carbocations and Michael acceptors in DMSO.
9
15388 J. AM. CHEM. SOC. VOL. 132, NO. 43, 2010

Ambident Reactivities of Pyridone Anions
A R T I C L E S
Kinetics. As the reactions of colored benzhydrylium ions or
quinone methides with colorless pyridone anions 1 and 2 result in
colorless products, the reactions could be followed by UV-vis
spectroscopy. Slow reactions (τ1/2 > 10 s) were determined by using
conventional UV/vis-spectrophotometers. Stopped-flow techniques
were used for the investigation of rapid reactions (τ1/2 < 10 s). The
temperature of all solutions was kept constant at 20.0 ( 0.1 °C
during all kinetic studies by using a circulating bath thermostat. In
all runs the nucleophile concentration was at least 10 times higher
than the concentration of the electrophile, resulting in pseudo-first-
order kinetics with an exponential decay of the electrophile’s
concentration. First-order rate constants kobs were obtained by least-
squares fitting of the absorbance data to a single-exponential At )
A0 exp(-kobst) + C. The second-order rate constants k2 were
obtained from the slopes of the linear plots of kobs against the
nucleophile’s concentration.
Determination of Equilibrium Constants. Equilibrium con-
stants were determined by UV/vis spectroscopy by adding small
volumes of stock solutions of the potassium salts of 2- or 4-pyridone
(1-K and 2-K) to solutions of the quinone methides in DMSO.
The decay of the electrophiles’ absorbances was monitored, and
when the absorbance was constant (typically after less than a
minute), another portion of the nucleophile was added. This
procedure was repeated several times. In order to determine the
equilibrium constants K, the molar absorptivities ε of the electro-
philes were determined from the initial absorbance, assuming the
validity of Lambert-Beer’s law.
increased positive charge in the electrophile but due to blocking
of N-attack by coordination with the silver ion.
Experimental Section
Materials. Commercially available DMSO and acetonitrile (both
with H2O content <50 ppm) were used without further purification.
Water was distilled and passed through a Milli-Q water purification
system. The reference electrophiles used in this work were
synthesized according to literature procedures.7 Potassium and
tetrabutylammonium salts of 1-H and 2-H were prepared by
treatment of the corresponding pyridones with KOtBu in ethanol
or nBu4NOH in water. The synthetic procedures for 1-K and 4l-N
are described as representative examples for the product studies.
A complete description for the preparation of all other products is
given in the Supporting Information.
2-Pyridone-potassium (1-K). 2-Pyridone (1.80 g, 18.9 mmol)
was added to a solution of KOtBu (2.00 g, 17.8 mmol) in dry
ethanol (25 mL) and stirred for 30 min. The solvent was evaporated
at low pressure and the solid residue was washed several times
with dry diethyl ether to afford 2-pyridone potassium (1-K, 2.20 g,
1
16.5 mmol, 93%) as a colorless solid. H NMR (d6-DMSO, 400
MHz) δ ) 5.81-5.84 (m, 2 H), 6.94-6.98 (m, 1 H), 7.60-7.62
(m, 1 H). 13C NMR (d6-DMSO, 101 MHz) δ ) 103.9 (d), 113.8
(d), 136.0 (d), 147.7 (d), 173.0 (s).
1-((3,5-Di-tert-butyl-4-hydroxyphenyl)(p-tolyl)methyl)pyridin-
2(1H)-one (4l-N). 2-pyridone-potassium (1-K, 63.8 mg, 0.479
mmol) was dissolved in dry DMSO (5 mL) and a solution of 3l
(147 mg, 0.477 mmol) in DMSO (5 mL) was added. The mixture
was stirred for 15 min before 0.5% acetic acid (∼50 mL) was
added. The mixture was extracted with dichloromethane (3 ×
40 mL) and the combined organic phases were washed with
saturated NaCl-solution (3 × 50 mL), dried over Na2SO4 and
evaporated under reduced pressure. Purification by column
chromatography on silica gel yielded 1-((3,5-di-tert-butyl-4-
hydroxyphenyl)(p-tolyl)methyl)pyridin-2(1H)-one (4l-N, 170 mg,
0.421 mmol, 88%) as colorless crystals; mp 164-165 °C (from
Quantum Chemical Calculations. Free energies G298 were
calculated at MP2/6-311+G(2d,p) or B3LYP/6-31+G(d,p) level
of theory. Thermal corrections to 298.15 K have been calculated
using unscaled harmonic vibrational frequencies. All calculations
were performed with Gaussian 03.34
Acknowledgment. We thank the Fonds der Chemischen In-
dustrie (scholarship to M.B.) and the Deutsche Forschungsgemein-
schaft (SFB 749) for financial support. We are grateful to Professor
Hendrik Zipse, Dr. Armin Ofial, Tanja Kanzian, and Thorsten
Allscher for helpful discussions. We thank Dr. Peter Mayer for
determining the crystal structure of 4l-N.
1
CHCl3/pentane). H NMR (CDCl3, 599 MHz) δ ) 1.35 (s, 18
H, 12-H), 2.33 (s, 3 H, 10-H), 5.23 (s, OH), 6.10-6.12 (m, 1
3
H, 14-H), 6.62 (d, J ) 9.1 Hz, 1 H, 16-H), 6.90 (s, 2 H, 3-H),
3
7.01 (d, J ) 8.0 Hz, 2 H, 7-H), 7.12-7.16 (m, 3 H, 8-H, 13-
H), 7.29-7.32 (m, 1 H, 15-H), 7.38 (s, 1H, 5-H). 13C NMR
(CDCl3, 151 MHz) δ ) 21.1 (q, C-10), 30.2 (q, C-12), 34.4 (s,
C-11), 61.9 (d, C-5), 105.5 (d, C-14), 120.7 (d, C-16), 125.6 (d,
C-3), 128.5 (d, C-7), 129.1 (s, C-4), 129.3 (d, C-8), 136.0 (d,
C-13), 136.1 (s, C-2), 136.5 (d, C-13), 137.3 (s, C-9), 138.9 (d,
C-15, 153.4 (s, C-1), 162.7 (s, C-17); numbering according to
page S8 in the Supporting Information. IR (neat, ATR) V˜ ) 3377
(w), 2959 (m), 2922 (m), 2870 (m), 1658 (vs), 1574 (m), 1538
(m), 1432 (m), 1230 (m), 1222 (m), 1142 (w) 1065 (m), 1020
(w), 892 (w), 874 (w), 796 (w), 760 (m), 732 (w). HR-MS (ESI)
[M - H]-: m/z calcd for [C27H32NO2]-: 402.2439; found:
402.2447.
Supporting Information Available: Details of kinetic experi-
ments and product studies, archive entries for the MP2 calcula-
tions, CIF file for 4l-N, complete ref 34 (reference6 in SI). This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA106962U
(34) Frisch, M. J.; et al. Gaussian 03, Revision E.01; Gaussian, Inc.:
Wallingford, CT, 2004; see reference 6 in the Supporting Informa-
tion.
9
J. AM. CHEM. SOC. VOL. 132, NO. 43, 2010 15389