Does aromaticity in a reaction product increase or decrease the intrinsic barrier? Kinetics of the reversible deprotonation of benzofuran-3(2H)-one and benzothiophene-3(2H)-one

Article abstract of DOI:10.1021/ja067118l

A kinetic study of the reversible deprotonation of benzofuran-3(2H)-one (3H-O) and benzothiophene-3(2H)-one (3H-S) by amines and hydroxide ion in water at 25 °C is reported. The respective conjugate bases, 3^--O and 3^--S, represent benzofuran and benzothiophene derivatives, respectively, and thus are aromatic. The main question addressed in this paper is whether this aromaticity has the effect of enhancing or lowering intrinsic barriers to proton transfer. These intrinsic barriers were either determined from Bronsted plots for the reactions with amines or calculated on the basis of the Marcus equation for the reaction with OH^-; they were found to be lower for the more highly aromatic benzothiophene derivative, indicating that aromaticity lowers the intrinsic barrier. It is shown that the reduction in the intrinsic barrier is not an artifact of other factors such as inductive, steric, resonance, polarizability, and π-donor effects, although these factors affect the intrinsic barriers in a major way. Our results imply that aromatic stabilization of the transition state is ahead of proton transfer; this contrasts with simple resonance effects, which typically lag behind proton transfer at the transition state, thereby increasing intrinsic barriers.

Full text of DOI:10.1021/ja067118l

Published on Web 02/14/2007
Does Aromaticity in a Reaction Product Increase or Decrease
the Intrinsic Barrier? Kinetics of the Reversible Deprotonation
of Benzofuran-3(2H)-one and Benzothiophene-3(2H)-one
Claude F. Bernasconi* and Moise´s Pe´rez-Lorenzo
Contribution from the Department of Chemistry and Biochemistry, UniVersity of California,
Santa Cruz, California 95064
Received October 4, 2006; E-mail: bernasconi@chemistry.ucsc.edu
Abstract: A kinetic study of the reversible deprotonation of benzofuran-3(2H)-one (3H-O) and ben-
zothiophene-3(2H)-one (3H-S) by amines and hydroxide ion in water at 25 °C is reported. The respective
conjugate bases, 3--O and 3--S, represent benzofuran and benzothiophene derivatives, respectively, and
thus are aromatic. The main question addressed in this paper is whether this aromaticity has the effect of
enhancing or lowering intrinsic barriers to proton transfer. These intrinsic barriers were either determined
from Brønsted plots for the reactions with amines or calculated on the basis of the Marcus equation for the
reaction with OH-; they were found to be lower for the more highly aromatic benzothiophene derivative,
indicating that aromaticity lowers the intrinsic barrier. It is shown that the reduction in the intrinsic barrier
is not an artifact of other factors such as inductive, steric, resonance, polarizability, and π-donor effects,
although these factors affect the intrinsic barriers in a major way. Our results imply that aromatic stabilization
of the transition state is ahead of proton transfer; this contrasts with simple resonance effects, which typically
lag behind proton transfer at the transition state, thereby increasing intrinsic barriers.
Introduction
involving normal acids. A major factor that accounts for the
slow rates is that the transition states of these reactions are
This paper deals with an important and fundamental question
regarding chemical reactivity: how does aromatic stabilization
of a reactant or product affect the intrinsic barrier1 of reactions?
Surprisingly, this is a question that only recently started to get
the attention it deserves.
Inasmuch as aromaticity is a special case of resonance or
delocalization of electrons, one might expect that the effect of
aromaticity on intrinsic barriers is qualitatively similar to that
of resonance. There exists a large body of evidence that shows
that resonance effects tend to increase intrinsic barriers of
reactions. Most of the early examples referred to proton transfers
involving carbon acids activated by strong π-acceptors.4-12
These reactions are typically much slower than proton transfers
imbalanced, in the sense that charge delocalization lags behind
proton transfer,8-12 which results in an increase of the intrinsic
q
1
1
barrier, ∆Go (decrease in the intrinsic rate constant, ko ).
Thus, the greater the resonance stabilization of the carbanion,
the greater the imbalance, and hence the larger the intrinsic
barrier.
This relationship between intrinsic barriers and transition-
state imbalances holds not only for proton transfers but for any
chemical reaction that leads to resonance-stabilized/delocalized
products13-15 and is the manifestation of a general principle
called the principle of nonperfect synchronization (PSN).8 The
(10) (a) Nevy, J. B.; Hawkinson, D. C.; Blotny, G.; Yao, X.; Pollack, R. M. J.
Am. Chem. Soc. 1997, 119, 12722. (b) Yao, X.; Gold, M.; Pollack. R. M.
J. Am. Chem. Soc. 1999, 121, 6220.
(11) Zhon, Z.; Snowden, T. S.; Best, M. D.; Anslyn, E. V. J. Am. Chem. Soc.
2004, 126, 3488.
(1) The intrinsic barrier (intrinsic rate constant) of a reaction with a forward
rate constant k1 and a reverse rate constant k-1 is defined as ∆Gqo ) ∆G1q
) ∆Gq-1 when ∆Go ) 0 (as ko ) k1 ) k-1 when K1 ) 1).2,3
(2) Marcus, R. A. J. Phys. Chem. 1968, 72, 891.
(12) (a) Bernasconi, C. F.; Sun, W.; Garc´ıa-R´ıo, L.; Kin-Yan Kittredge, K. J.
Am. Chem. Soc. 1997, 119, 5583. (b) Bernasconi, C. F.; Ali, M. J. Am.
Chem. Soc. 1999, 121, 3039. (c) Bernasconi, C. F.; Sun, W. J. Am. Chem.
Soc. 2002, 124, 2799. (d) Bernasconi, C. F.; Ali, M.; Gunter, J. C. J. Am.
Chem. Soc. 2003, 125, 151. (e) Bernasconi, C. F.; Fairchild, D. E.;
Montan˜ez, R. L.; Aleshi, P.; Zheng, H.; Lorance, E. J. Org. Chem. 2005,
70, 7721. (f) Bernasconi, C. F.; Ragains, M. L. J. Organomet. Chem. 2005,
690, 5616.
(13) Nucleophilic addition to alkenes: (a) Bernasconi, C. F. Tetrahedron 1989,
45, 4017. (b) Bernasconi, C. F.; Ketner, R. J.; Ragains, M. L.; Chen, X.;
Rappoport, Z. J. Am. Chem. Soc. 2001, 123, 2155. (c) Bernasconi, C. F.;
Ketner, R. J.; Chen, X.; Rappoport, Z. ARKIVOC (GainesVille, FL, U.S.)
2002, xii, 161.
(3) Keeffe, J. R.; Kresge, A. J. In InVestigation of Rates and Mechanisms of
Reactions; Bernasconi, C. F., Ed.; Wiley-Interscience: New York, 1986;
Part 1, p 747.
(4) Eigen, M. Angew. Chem., Int. Ed. Engl. 1964, 1, 3.
(5) Bell, R. P. The Proton in Chemistry; Cornell University Press: Ithaca, NY,
1973; Chapter 10.
(6) Caldin, E. F.; Gold, V. Proton-Transfer Reactions; Wiley & Sons: New
York, 1975.
(7) Hibbert, F. Compr. Chem. Kinet. 1977, 8, 97.
(8) (a) Bernasconi, C. F. Acc. Chem. Res. 1987, 20, 301. (b) Bernasconi, C. F.
Acc. Chem. Res. 1992, 25, 9. (c) Bernasconi, C. F. AdV. Phys. Org. Chem.
1992, 27, 119.
(9) (a) Terrier, F.; Lelie`vre, J.; Chatrousse, A.-P.; Farrell, P. J. Chem. Soc.,
Perkin Trans. 1985, 2, 1479. (b) Terrier, F.; Xie, H.-Q.; Lelie`vre, J.;
Boubaker, T.; Farrell, P. G. J. Chem. Soc., Perkin Trans. 1990, 2, 1899.
(c) Moutiers, G.; El Fahid, B.; Collet, A.-G.; Terrier, F. J. Chem. Soc.,
Perkin Trans. 1996, 2, 49. (d) Moutiers, G.; El, Fahid, B.; Goumont, R.;
Chatrousse, A.-P.; Terrier, F. J. Org. Chem. 1996, 61, 1978.
(14) Formation to carbocations: (a) Richard, J. P. J. Am. Chem. Soc. 1989,
111, 1455. (b) Richard, J. P. J. Org. Chem. 1994, 59, 25. (c) Richard, J.
P.; Amyes, T. L.; Toteva, M. M. Acc. Chem. Res. 2001, 34, 981.
(15) Reactions of Fischer carbene complexes: (a) Bernasconi, C. F. Chem. Soc.
ReV. 1997, 26, 299. (b) Bernasconi, C. F. AdV. Phys. Org. Chem. 2002,
37, 13.
9
2704
J. AM. CHEM. SOC. 2007, 129, 2704-2712
10.1021/ja067118l CCC: $37.00 © 2007 American Chemical Society

Aromaticity and the Intrinsic Barrier to Proton Transfer
A R T I C L E S
PNS states that any product-stabilizing feature whose develop-
ment at the transition state lags behind bond changes invariably
increases the intrinsic barrier, while a product-stabilizing features
whose development is more advanced than bond changes lowers
the intrinsic barrier.
the heteroatoms (O vs S), might mask the effect of the difference
in aromaticity between 2--O and 2--S. This may have led to
the observed trends in ∆Gqo and ko, even though aromatic
stabilization at the transition state would still be ahead of proton
transfer.
Recently, we have turned our attention to proton transfers
from carbon acids that lead to aromatic conjugated bases.16-18
The question we are asking is whether the effect of product
aromaticity is qualitatively the same as that of product reso-
nance; i.e., does the development of aromaticity at the transition
state also lag behind proton transfer, leading to a higher intrinsic
barrier? Results obtained from kinetic studies of the reaction
systems shown in eqs 116 and 218 have led to some conflicting
conclusions. In both systems, the respective conjugate bases are
One factor, not related to aromaticity, that is likely to play
an important role is the reactant-stabilizing π-donor effect of
the heteroatom (eq 3), which is stronger for X ) O than for X
) S. The study of a system without such π-donor effects could
therefore be revealing. The isomeric carbon acids 3H-X
represent such a system. The present paper reports a kinetic
study of the reactions of 3H-O and 3H-S with OH- and amine
bases. The results remove the above ambiguities and support
the notion that aromaticity develops ahead of proton transfer
and that it is the combination of inductive, steric, and π-donor
effects which is responsible for the fact that ko(O) > ko(S) in
the 2H-X system. We note that there is some overlap between
our study and that of Capon and Kwok,22 although the emphasis,
approach, objectives, and even some of the results in the two
papers are quite different, as described in the Discussion.
derivatives of aromatic heterocycles, and their relative stabilities
are expected to reflect the aromaticity order furan < selenophene
< thiophene,19-21 or benzofuran < benzothiophene,19-21 re-
spectively. This expectation is confirmed by the relative acidities
of the respective carbon acids, i.e., 1H+-O (pKa ) 5.78)16
<
1H+-Se (pKa ) 4.18)16 < 1H+-S (pKa ) 2.51)16 and 2H-O
(pKa ) 11.68)18 < 2H-S (pKa ) 8.82).18
For the 1H+-X system, the intrinsic barriers for proton transfer
to amine bases and carboxylate ions were found to follow the
order ∆Gqo(O) > ∆Goq(Se) > ∆Gqo(S), or, in terms of intrinsic
rate constants, the order was ko(O) < ko(Se) < ko(S); i.e., the
intrinsic barrier is reduced (the intrinsic rate constant is
enhanced) as the aromaticity of 1-X increases. This order is
the opposite of that found for reactions that lead to products
stabilized by simple resonance effects. Unless there are other
factors present that completely overshadow the effect of
aromaticity, according to the PNS these results therefore imply
that aromatic stabilization of the transition state is ahead of
proton transfer. On the other hand, for the 2H-X system, the
order of the intrinsic barriers for proton transfer to amine bases
was found to be ∆Gq(O) < ∆Gq(S) (ko(O) > ko(S)); i.e., here
Results
General Features. All kinetic experiments were conducted
in water at 25 °C and an ionic strength of 0.5 M (KCl).
Reactions were performed in KOH solutions and amine buffers.
The kinetic scheme can be described by eq 5, where H3-X is
the enol form of 3H-X, which is in rapid acid-base equilibrium
with the enolate ion, B is the buffer base, and BH+ is the buffer
acid. The acidities of the keto forms (pKKa H) as well as those of
the enol forms (pKEa H) were determined kinetically; for 3H-O,
the pKKa H was also confirmed by a spectrophotometric method.
All kinetic experiments were run under pseudo-first-order
conditions with the substrate as the minor component. The
observed pseudo-first-order rate constants for the equilibrium
approach are given by eq 6. All rates were in the stopped-flow
time range.
o
o
the intrinsic barrier is enhanced (the intrinsic rate constant
reduced) as the aromaticity of 2--X increases, which is the same
trend as for reactions that lead to resonance-stabilized products.
However, a detailed analysis suggested that other factors, such
as differences in the inductive, steric, and π-donor effects of
(16) (a) Bernasconi, C. F.; Ragains, M. L. J. Am. Chem. Soc. 2001, 123, 11890.
(b) Bernasconi, C. F.; Ragains, M. L.; Bhattacharya, S. J. Am. Chem. Soc.
2003, 125, 12328.
(17) Bernasconi, C. F. J. Phys. Org. Chem. 2004, 17, 951.
(18) Bernasconi, C. F.; Zheng, H. J. Org. Chem. 2006, 71, 8203.
(19) Fringuelli, F.; Marino, G.; Taticchi, A. J. Chem. Soc., Perkin Trans. 1974,
2, 322.
(20) Bird, C. W. Tetrahedron 1985, 41, 1409; 1987, 43, 4725.
(21) Minkin, V. I.; Glukhovtsev, M. N.; Simkin, B. Y. Aromaticity and
Antiaromaticity; Wiley & Sons: New York, 1994; p 217.
In highly basic solution (pH > pKKa H), the reactions were
run in the “forward direction”, i.e., by mixing the keto form
with KOH or the appropriate buffer; in solutions at pH <
(22) Capon, B.; Kwok, F.-C. J. Am. Chem. Soc. 1989, 111, 5346.
9
J. AM. CHEM. SOC. VOL. 129, NO. 9, 2007 2705

A R T I C L E S
Bernasconi and Pe´rez-Lorenzo
kobsd ) k1H O + k1OH[OH-] + k1B[B] +
2
KEa H
KEa H + aH
(kH-1aH+ + kH-21O + kBH[BH+])
(6)
-1
+
pKKa H, the runs were performed in the “reverse direction”, i.e.,
the ketone was first incubated in a 0.025 M KOH solution in
order to generate the enolate ion, followed by mixing the enolate
ion solution with the appropriate buffer.
Benzofuran-3(2H)-one, 3H-O. A. Spectrophotometric
pKKa H Determination. The pKKa H of 3H-O was determined by
classic spectrophotometric methodology applying eq 7, where
AC- - A
A - ACH
pKKa H ) pH + log
(7)
A is the absorbance at pH ≈ pKKa H measured in piperidine
-
buffers, ACH is the absorbance of 3H-O, and AC is the
absorbance of 3-O-, respectively. A plot of pH versus log(AC
Figure 1. Reactions of 3H-O (O, left axis) and 3H-S (b, right axis)
with KOH.
-
- A)/(A - ACH) is shown in Figure S1 (Supporting Informa-
tion).23 It yields pKKa H ) 11.71 ( 0.05.
the value of 11.75 obtained in KOH solution and by the
spectrophotometric method. We shall adopt the average value,
B. Kinetics in KOH Solutions. Rates were measured at seven
KOH concentrations ranging from 0.005 to 0.05 M. In this
range, eq 6 simplifies to eq 8. The results are shown in Figure
11.72, as the pKaKH of 3H-O. Using the relationship kB1 /kBH
)
-1
KKa H/KBa H and pKaBH ) 11.39, one calculates kBH ) 90.7 ( 1.1
-1
kobsd ) kH1 O + k1OH[OH-]
(8)
M-1 s-1
.
2
+
A similar plot of slope versus aH for the n-butylamine
reactions (not shown) yields pKKa H ) 11.45 ( 0.05. However,
since the data were obtained at lower pH values than for the
piperidine reaction, the intercept of this plot is quite small and
potentially associated with a larger error than suggested by its
standard deviation. Hence, this pKKa H value is deemed less
reliable than the other values. For the same reason, the adopted
kB1 value (Table 2, below) is that obtained from the slope (kB1 /
KKa H) using pKKa H ) 11.72 rather than from the intercept (kB1 ).
For the reactions with piperazine (conducted at pH 9.65-
10.65) and 2-methoxyethylamine (conducted at pH 9.10-10.10),
the slope in eq 10 (plots not shown) is completely dominated
1. They yield kO1 H ) 83.7 ( 0.4 M-1 s-1 and kH2O ) 1.09 (
-1
0.01 s-1, from which KaKH ) (kO1 H/k-H1O)Kw24 ) (1.80 ( 0.04) ×
2
10-12 M-1 or pKKa H ) 11.75 ( 0.02 was obtained.
C. Kinetics in Amine Buffers. Proton-transfer rates were
measured with four primary aliphatic amines (n-butylamine,
2-methoxyethylamine, glycinamide, and aminoacetonitrile) and
four secondary alicyclic amines (piperidine, piperazine, 1-(2-
hydroxyethyl)piperazine (HEPA), and morpholine). For each
amine, rates were determined at seven different pH values and
at seven amine concentrations for any given pH. Representative
plots of kobsd versus free amine concentration for the reaction
with piperidine are shown in Figure S2.23 According to eq 6,
the slopes of these plots are given by eq 9. For the reactions
by the (kB1 /KaKH)aH term. For the reactions with glycinamide
+
(pH 7.73-8.73), HEPA (pH 8.93-9.93), and morpholine (pH
8.47-9.47), kB1 contributes even less to the slopes. Further-
aH
KEa H
KBa H KEa H + aH
+
+
more, the plots of slope versus aH are characterized by
slope ) kB1 + kBH
)
-1
downward curvature, as shown in Figure 2 for the glycinamide
reaction. The curvature is due to the enolate ion/enol equilib-
rium, which becomes important in this pH range; i.e., the
+
aH
KEa H
KKa H KEa H + aH
+
kB1 + kB1
(9)
KEa H/(KEa H + aH ) term in eq 9 is no longer equal to 1, and eq
+
+
11 applies.26
with piperidine and n-butylamine which were conducted in the
pH ranges of 10.89-11.89 (piperidine) and 10.28-11.28 (n-
aH
KEa H
KKa H KEa H + aH
+
butylamine), the relationship KEa H . aH holds, and hence eq 9
+
slope ) kB1
(11)
(12)
+
+
simplifies to eq 10. A plot of slope versus aH for the piperidine
KKa H
kB1 KEa H kB1 aH
KKa H
aH
KBa H
aH
KKa H
+
+
1
)
slope ) kB1 + kBH
) kB1 + kB1
(10)
+
-1
slope
+
reaction is shown in Figure S3.23 It yields k1B ) 41.7 ( 0.5
M-1 s-1 and pKKa H ) 11.68 ( 0.04, in close agreement with
From inversion plots according to eq 12 (Figure S423) and using
the known KKa H value, one can calculate k1B and KEa H. The
following pKEa H values were obtained: 8.62 ( 0.05 from the
(23) See paragraph concerning Supporting Information at the end of this paper.
(24) pKw ) 13.63 at µ ) 0.5 M (KCl).25
(25) Brandariz, I.; Fiol, S.; Sastre Vicente, M. Ber. Bunsenges. Chem. 1995,
99, 749.
(26) Even for the reaction with 2-methoxyethylamine, there is an onset of slight
curvature at the highest amine concentrations.
9
2706 J. AM. CHEM. SOC. VOL. 129, NO. 9, 2007

Aromaticity and the Intrinsic Barrier to Proton Transfer
A R T I C L E S
+
+
Figure 2. Reaction of 3H-O with glycinamide. Plot of slopes versus aH
Figure 3. Reaction of 3H-S with morpholine. Plot of slopes versus aH
according to eq 11.
according to eq 8.
HEPA reaction, 8.81 ( 0.04 from the morpholine reaction, and
lamine behaves similarly; it also yields a linear plot (not shown)
B
of slope versus aH , from which k1 ) 8.04 ( 0.03 M-1 s-1 and
+
8.56 from the glycinamide reaction. We shall adopt the average
value, 8.66, as the actual pKaEH
.
pKKa H ) 9.39 ( 0.02 can be calculated. This pKKa H value is in
good agreement with that obtained from the HEPA reaction.
We shall adopt the average of the two values, 9.45, as the actual
pKKa H of 3H-S.
The aminoacetonitrile reaction was conducted in the pH range
of 5.11-6.11. In this range, KEa H , aH , and eq 9 simplifies to
+
eq 13; i.e., the slopes should be pH independent, as observed
(plot not shown).
For the reactions with piperidine, piperazine, and n-buty-
lamine, eq 10 was used to calculate kB1 on the basis of pKKa H
)
KEa H
KKa H
9.45; kBH was obtained as kBH ) k1B KBa H/KKa H
.
slope ) kB1
(13)
-1
-1
For the reactions of glycinamide (pH 7.73-8.73) and
morpholine (pH 8.47-9.47), the enolate ion/enol equilibrium
becomes significant, which leads to nonlinear plots of slope
Benzothiophene-3(2H)-one, 3H-S. This compound was
subjected to the same kinetic experiments as 3H-O. However,
because the pKKa H of 3H-S is much lower than that of 3H-O
and the difference between pKEa H and pKaKH for 3H-S is much
smaller than for 3H-O, significant differences were observed
in the kinetic behavior of 3H-S; a spectrophotometric pKaKH
determination was also impractical.
+
versus aH , as shown in Figure 3 for the reaction with
morpholine. Because the pKKa H of 3H-S is much lower than
that of 3H-O and quite close to the pKEa H, the k1B term is not
negligible, even at these relatively low pH values, and hence
the full eq 9 applies here. A nonlinear least-squares analysis
yields kB1 ) (3.64 ( 0.38) × 102 M-1 s-1 and pKEa H ) 8.76 (
0.10 for the morpholine reaction. Analysis of the data for the
glycinamide reaction using pKKa H ) 9.45 yields k1B ) 26.6 (
A. Kinetics in KOH Solution. A plot of kobsd vs [KOH] is
shown in Figure 1. Because of the relatively high acidity of
2.2 M-1 s-1
.
H2O
-1
3H-S, k
, kO1 H[OH-] under all experimental conditions, as
For the aminoacetonitrile reaction, the slope of a plot of kobsd
versus amine concentration is given by eq 13, from which k1B
) 1.95 ( 0.03 M-1 s-1 was calculated.
indicated by the absence of a measurable intercept. The slope
yields kO1 H ) (2.30 ( 0.06) × 103 M-1 s-1. In contrast to the
situation with 3H-O, these data do not allow a determination
of the pKKa H from the k1OH/kH2O ratio.
-1
Discussion
B. Kinetics in Amine Buffers. With 2-methoxyethyalmine
(pH 9.10-10.10), glycinamide (pH 7.73-8.73), HEPA (pH
9.43-10.43), and morpholine (pH 8.47-9.47), rates were
determined at seven different pH values and at six amine
concentrations for any given pH. With the other amines, the
reactions were run at one pH only: pH 10.78 for n-butylamine,
pH 5.61 for aminoacetonitrile, pH 11.39 for piperidine, and pH
10.15 for piperazine.
Rate constants and pKa values are summarized in Tables 1
and 2.
pKKa H and pKEa H. A. Comparisons with Previous Work.
Capon and Kwok22 published an extensive study on the
tautomerism of the monohydroxy derivatives of a series of
heterocycles, a series that includes the enol forms of 3H-O and
3H-S, i.e., H3-O and H3-S, respectively. The pKKa H and pKaEH
determined by these authors are included in Table 1. For reasons
that are not clear, the agreement between our results and theirs
is not very good, especially with respect to the pKKa H of 3H-O,
which in our hands (11.72) is 1.50 pK units lower than theirs
(13.22). The discrepancies are less severe for the pKEa H of
A representative series of plots of kobsd versus free amine
concentration is shown in Figure S523 for the reaction with
+
HEPA. The slopes of these plots depend linearly on aH , as
called for by eq 10; they yield kB1 ) (6.20 ( 0.15) × 102 M-1
s-1 and pKKa H ) 9.51 ( 0.04. The reaction of 2-methoxyethy-
9
J. AM. CHEM. SOC. VOL. 129, NO. 9, 2007 2707

A R T I C L E S
Bernasconi and Pe´rez-Lorenzo
Table 1. Rate Constants, Intrinsic Barriers, and pKa Values for the Reversible Deprotonation of 3H-O, 3H-S, 2H-O, and 2H-S by OH- in
Water at 25 °C, µ ) 0.5 M (KCl)
3H-O
3H-S
parameter
this work
Capon et al.a
this work
Capon et al.a
2H-Ob
2H-Sb
pKKa H
pKEa H
11.72 ( 0.03c
8.66 ( 0.12d
3.06 ( 0.15
83.7 ( 0.4
1.09 ( 0.01
16.0 ( 0.1
13.22
9.16
4.06
9.45 ( 0.04
8.76 ( 0.14e
0.69 ( 0.14
9.93
8.86
1.07
11.68
8.10
8.82
5.82
3.00
1.05 × 104
0.113
15.1
pKE ) pKKH - pKEa H
3.58
a
kO1 H, M-1 s-1
(2.30 ( 0.06) × 103
(1.52 ( 0.18) × 10-1
15.5 ( 0.1
2.44 × 103
H2O
k - , s-1
20.2
1
∆Gqo, kcal/mol
14.1
a Reference 22. b Reference 18; µ ) 0.1 M (KCl). c Average pKKa H determined from kinetic measurements with KOH and piperidine and the
spectrophotometric determination. d Average pKaEH determined from kinetic measurements with 1-(2-hydroxyethyl)piperazine, morpholine, and glycinamide.
e pKEa H determined from kinetic experiments with morpholine.
Table 2. Rate Constants for the Reversible Deprotonation of
3H-O and 3H-S by Amines in Water at 25 °C, µ ) 0.5 M (KCl)
0.69), while for H2-O (pKE ) 3.58) versus H2-S (pKE ) 3.00)
they are very similar.
pKBaH
kB1 (M-1 s-
)
kBH1 (M-1 s-
)
1
1
B
-
These patterns may be understood as the result of an interplay
between charge delocalization, π-donation, polarizability, and
anomeric effects as follows.
(1) 2H-X is stabilized by π-donation from the ring heteroatom
(eq 3); this leads to a reduction in acidity. This effect is more
important for 2H-O than for 2H-S because oxygen is a better
π-donor.27 There is no comparable effect in 3H-X.
(2) The conjugate base of 2H-X can delocalize its negative
charge into the benzene ring (structure E in eq 14); this leads
to an increase in acidity. Inasmuch as the resonance form E
3H-O (pKKa H ) 11.72 ( 0.03)
10.78 6.59 ( 0.18
n-BuNH2
MeOCH2CH2NH2 9.60
H2NCOCH2NH2
NCCH2NH2
piperidine
(5.37 ( 0.08) × 101
(2.16 ( 0.09) × 102
(6.46 ( 0.18) × 102
(9.07 ( 0.11) × 101
(9.32 ( 0.42) × 102
(2.59 ( 0.03) × 103
(3.16 ( 0.13) × 103
1.53 ( 0.07
0.20 ( 0.01
8.23
5.61
(3.90 ( 0.17) × 10-3 (5.40 ( 0.23) × 103
11.39 (4.17 ( 0.05) × 101
10.15 (2.31 ( 0.10) × 101
piperazine
HEPAa
9.43
8.97
(1.24 ( 0.02) × 101
5.25 ( 0.21
morpholine
3H-S (pKKa H ) 9.45 ( 0.04)
n-BuNH2
10.78 (3.79 ( 0.09) × 102
(1.77 ( 0.04) × 101
(5.18 ( 0.14) × 101
(4.42 (0.02) × 102
(1.35 ( 0.02) × 104
(2.75 ( 0.14) × 101
(2.49 ( 0.16) × 102
(7.18 ( 0.58) × 102
(1.10 ( 0.22) × 103
MeOCH2CH2NH2 9.60
(8.04 ( 0.03) × 101
(2.66 ( 0.22) × 101
1.95 ( 0.03
H2NCOCH2NH2
NCCH2NH2
piperidine
8.23
5.61
11.39 (2.39 ( 0.13) × 103
piperazine
10.15 (1.25 ( 0.08) × 103
HEPAa
9.43
8.97
(6.20 ( 0.15) × 102
(3.64 ( 0.39) × 102
morpholine
carries a fractional charge close to the X atom, the acidity of
2H-S will be enhanced more than that of 2H-O because the
sulfur can stabilize this fractional charge more effectively than
oxygen due to its greater polarizability.29 There is no analogous
effect on the conjugate base of 3H-X.
a 1-(2-Hydroxyethyl)piperazine.
H3-O (0.50 pK unit), the pKKa H of 3H-S (0.48 pK unit), and the
pKEa H of H3-S (0.10 pK unit).
We submit that the pKKa H value reported by Capon and
Kwok for 3H-O (13.22) cannot be correct for the following
reasons. (1) If their value were correct, this would require the
slope/intercept ratio of the plot of kobsd versus [KOH] (Figure
1) to be 2.57 instead of the observed 83.7. (2) It would also
mean that, at the KOH concentrations used in our study (0.005-
0.05 M), the deprotonation reaction would be unfavorable, so
much so at the low end of the concentration range that virtually
no absorbance change would have been observable. This
contrasts with the fact that we observed strong absorbance
changes even at the lowest [KOH]. (3) The fact that our
spectrophotometric and two kinetic determinations yielded the
same result constitutes strong evidence that our pKKa H value is
the correct one.
B. Comparison with 2H-O and 2H-S. 3H-S (pKKa H ) 9.45)
is substantially more acidic than 3H-O (pKKa H ) 11.72),
which, as with the higher acidity of 2H-S (pKKa H ) 8.82)
relative to that of 2H-O (pKKa H ) 11.68), can be mainly
attributed to the greater anion aromaticity of the respective
thiophene derivatives. Regarding the enol forms, the pKaEH
values of H3-O (8.66) and H3-S (8.76) are very similar to each
other, but for H2-O (8.10) and H2-S (5.82) they are very
different from each other. As a result, the enolization constants
are very different for H3-O (pKE ) 3.06) versus H3-S (pKE )
What is the result of the interplay of these factors? For 2H-
O, the acidity-reducing π-donor effect and the acidity-enhancing
delocalization effect essentially offset each other, as can be seen
from the almost identical pKKa H values of 3H-O and 2H-O. On
the other hand, for 2H-S, the weaker acidity-reducing π-donor
effect and the stronger acidity-enhancing delocalization effect
lead to a net increase in acidity, as is apparent from the lower
pKKa H of 2H-S (8.82) compared to that of 3H-S (9.45).
Regarding the various enols, the aromaticity of the enolate
ions and that of the respective enols are probably quite similar
and hence should not substantially affect the pKEa H values. The
fact that the pKEa H values of 3H-O (8.66) and 3H-S (8.76) are
nearly equal is consistent with this notion. By the same token,
since the enolization constant (pKEa ) is related to the pKaKH and
pKEa H values through eq 15, the more favorable enolization of
pKE ) pKKa H - pKEa H
(15)
(27) For example, the σR value for MeO (-0.43) is much more negative than
that for MeS (-0.15).28
(28) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165.
(29) (a) Streitwieser, A., Jr.; Williams, J. E. J. Am. Chem. Soc. 1975, 97, 191.
(b) Lehn, J.-M.; Wipff, G. J. Am. Chem. Soc. 1976, 98, 7498. (c) Bernardi,
F.; Cszizmadia, I. G.; Mangini, A.; Schlegel, H. B.; Whangbo, M.-H.;
Wolfe, S. J. Am. Chem. Soc. 1975, 97, 2209. (d) Schleyer, P. v. R.; Clark,
T.; Kos, A. J.; Spitznagel, G. W.; Rhode, C.; Arad, D.; Houk K. N.; Rondan,
N. G. J. Am. Chem. Soc. 1984, 106, 6467.
9
2708 J. AM. CHEM. SOC. VOL. 129, NO. 9, 2007

Aromaticity and the Intrinsic Barrier to Proton Transfer
A R T I C L E S
3H-S (pKE ) 0.69) than that of 3H-O (pKE ) 3.06) can then
be understood as being mainly the result of the greater
aromaticity of H3-S compared to that of H3-O, just as the higher
acidity of 3H-S is mainly the result of the greater aromaticity
of 3S- compared to that of 3-O-.
There are two factors that render the pKEa H value of H2-S
(5.82) so much lower than that of H2-O (8.10). The first is the
greater stabilization of the resonance form E of the sulfur
derivative (eq 14), which was invoked as a partial explanation
of why 2H-S is more acidic than 3H-S. The second, more
important factor is the stabilizing effect of having two geminal
oxygen atoms in the enol form of 2H-O (H2-O), which lowers
Figure 4. Statistically corrected Brønsted plots for the reactions of 3H-O
the acidity of H2-O and thus enhances the pKEa H difference
between H2-S and H2-O. This kind of anomeric stabilization
is well documented for systems where the two oxygens are
attached to sp3 carbons30 but has also been found in systems
where the oxygens are attached to sp2 carbons.31,32 If the geminal
oxygen stabilization of H2-O by the geminal oxygen effect is
a significant factor, it would also help explain why the
enolization of 2H-S (pKE ) 3.00) is only slightly more favorable
than that of 2H-O (pKE ) 3.58): the geminal oxygen effect
would partially offset the greater aromaticity of H2-S compared
to that of H2-O.
with amine buffers: open symbols, kB1 ; filled symbols, kBH. O and b,
-1
primary aliphatic amines; 0 and 9, secondary alicyclic amines. The dashed
line goes through the points where the log(kB1 /q) and log(kBH/p) lines
-1
intersect, which corresponds to log ko.
Brønsted Plots and Intrinsic Rate Constants. Brønsted plots
for the reactions of 3H-O with amines are shown in Figure 4,
and those for 3H-S in Figure 5. The Brønsted R and â values
are summarized in Table 3. Included in Table 3 are the log ko
values for the intrinsic rate constants,1 determined from the
points where the lines for k1B and kBH intersect, and the intrinsic
-1
barriers,1 ∆Gq, calculated from the respective ko values by
o
means of the Eyring equation.
The R and â values are in the normal range for proton
transfers involving carbon acids.5,34,35 The fact that the intrinsic
rate constants are higher (∆Goq lower) for the reactions with the
secondary alicyclic amines than with the primary aliphatic
amines is also typical; it reflects the greater solvation energies
of the respective protonated primary amines, combined with
the fact that the transition-state solvation of the incipient
protonated amines lags behind proton transfer.5,36
Figure 5. Statistically corrected Brønsted plots for the reactions of 3H-S
with amine buffers: open symbols, kB1 ; filled symbols, kBH. O and b,
-1
primary aliphatic amines; 0 and 9, secondary alicyclic amines. The dashed
line goes through the points where the log(kB1 /q) and log(kBH/p) lines
-1
intersect, which corresponds to log ko.
The main focus of our results is on the comparison between
the intrinsic rate constants (intrinsic barriers) for the reactions
of 3H-O versus 3H-S as well as the corresponding comparisons
for the reactions of 2H-O, 2H-S, 1H+-O, and 1H+-S; all these
parameters are summarized in Table 4. The following points
are of interest.
(30) (a) Hine, J.; Klueppel, A. W. J. Am. Chem. Soc. 1974, 96, 2924. (b) Wiberg,
K. B.; Squires, R. R. J. Chem. Thermodyn. 1979, 11, 773. (c) Harcourt,
M. P.; More O’Ferrall, R. A. Bull. Soc. Chim. Fr. 1988, 407.
(31) Sklena´k, S.; Apeloig, Y.; Rappoport, Z. J. Am. Chem. Soc. 1998, 120, 10359.
(32) Based on B3LYP/6-311G* calculations, the gas-phase isodermic reaction
2-hydroxyfuran + 2 cyclopentane f tetrahydrofuran + cyclopentadiene
+ hydroxycyclopentane is about 7 kcal/mol more endothermic than the
corresponding reaction 2-hydroxythiophene + 2 cyclopentane f tetrahy-
drothiophene + hydroxycyclopentane + cyclopentadiene.33 This implies a
rather strong anomeric stabilization of 2-hydroxyfuran relative to that of
2-hydroxythiophene and suggests that 2H-O may enjoy a stabilization
comparable to that of 2H-S.
(1) The intrinsic rate constants for the deprotonation of 3H-S
by amines are higher (the intrinsic barrier is lower) than for the
deprotonation of 3H-O derivatives (∆ log ko ) 0.56 for the
primary amines, ∆ log ko ) 1.02 for the secondary amines).
This contrasts with the reactions of 2H-O and 2H-S, where it
(33) Karni, M. personal communication.
(34) Kresge, A. J. In Proton Transfer Reactions; Caldin, E. F., Gold, V., Eds.;
Wiley: New York, 1975; p 179.
(35) (a) Bernasconi, C. F.; Paschalis, P. J. Am. Chem. Soc. 1986, 108, 2969.
(b) Bernasconi, C. F.; Terrier, F. J. Am. Chem. Soc. 1987, 109, 7115. (c)
Bernasconi, C. F.; Kliner, D. A. V.; Mullin, A. S.; Ni, X. J. Org. Chem.
1988, 53, 3342.
is the furan derivative which has the higher log ko (lower ∆Gq)
o
values (∆ log ko ) -0.69 for the primary amines, ∆ log ko )
-0.24 for the secondary amines), but our results are comparable
(36) Jencks, W. P. Catalysis in Chemistry and Enzymology; McGraw-Hill: New
York, 1969; p 178.
9
J. AM. CHEM. SOC. VOL. 129, NO. 9, 2007 2709

A R T I C L E S
Bernasconi and Pe´rez-Lorenzo
(b) The stronger resonance stabilization of 2-S- due to the
polarizability effect of the sulfur atom on the resonance form E
(eq 13) is expected to lower ko of 2H-S relative to that of 2H-
O. This is because the transition state does not benefit
significantly from this stabilization, since delocalization of the
charge into the benzene ring has made very little progress. Note
that in our previous discussion18 this factor was neglected; our
analysis of the pKKa H values presented above suggests that this
factor is not negligible.
Table 3. Brønsted R and â Values, log ko for the Intrinsic Rate
Constants, and Intrinsic Barriers (∆Gqo) for the Reversible
Deprotonation of 3H-O and 3H-S by Amines in Water at 25 °C
â )
R )
d log kB1/
d pKBaH
d log kBH
/
1
∆G o
q
-
d log KBaH
log ko
(kcal/mol)
3H-O
primary amines
0.63 ( 0.02 0.37 ( 0.02 1.16 ( 0.06 15.8 ( 0.1
secondary amines 0.34 ( 0.06 0.66 ( 0.06 1.64 ( 0.11 15.1 ( 0.1
3H-S
primary amines
0.44 ( 0.02 0.56 ( 0.02 1.72 ( 0.05 15.0 ( 0.1
(c) The larger size of the sulfur atom creates more crowding
at the transition state, which lowers ko for the thiophene
derivative more than for the furan derivative.
secondary amines 0.32 ( 0.04 0.64 ( 0.04 2.64 ( 0.05 13.8 ( 0.1
(d) The heteroatom may exert two opposing effects, leading
to either a net increase or decrease in ko. The first factor (type
I π-donor effect) is the loss of the resonance stabilization of
the keto form (eq 3) upon deprotonation. According to the PNS,8
this loss is expected to lower ko, because it runs ahead of proton
transfer at the transition state.37 The decrease in ko should be
stronger for the reactions of 2H-O due to the greater π-donor
strength of oxygen compared to that of sulfur.27 This effect
parallels the stronger pKKa H enhancing effect on 2H-O relative
to that on 2H-S. The second factor (type II π-donor effect) is
the preorganization of the carbonyl group toward its electronic
configuration in the anion (C is the main resonance in eq 14).
By virtue of the resonance structure B (eq 3), this preorgani-
zation facilitates and enhances the delocalization of charge into
the carbonyl group at the transition state. The result is a
reduction of the imbalance, which is the main reason for the
rather low intrinsic rate constants in the deprotonation of carbon
acids activated by π-acceptors.38 2H-O should benefit more from
this preorganization effect than 2H-S.
Table 5 provides a schematic summary of the various effects
discussed above on the intrinsic rate constants of 2H-O(ko(O))
and 2H-S(ko(S)) as well as on the ko(S)/ko(O) ratio. Ignoring
the potential influence of anion aromaticity for a moment, there
is only one factor, the type I π-donor effect, that increases the
ko(S)/ko(O) ratio, but four factors, the inductive, resonance,
steric, and type II π-donor effects, contribute to a lowering of
this ratio. This preponderance of ko(S)/ko(O) ratio-reducing
factors suggests that, even if the aromaticity effect were to
increase the intrinsic rate constants (hypothesis B)18 and hence
raise the ko(S)/ko(O) ratios, this increase may not be sufficient
to offset all the decreases, and thus ko(S)/ko(O) may still be <1,
as observed. By the same token, if the effect of aromaticity is
to decrease intrinsic rate constants (hypothesis A)18 and thereby
lower the ko(S)/ko(O) ratios further, these ratios should be
significantly lower than the observed values (log(ko(S)/ko(O))
) -0.69 and -0.24, respectively, see Table 4); they also should
be lower than the corresponding ratios for the deprotonation of
4H-O and 4H-S12b (log(ko(S)/ko(O)) ) -0.95 for primary
to those for the 1H+-X system (∆ log ko ) 1.10 and 1.51,
respectively).
A similar conclusion emerges from a comparison of the
intrinsic barriers for deprotonation of 3H-O and 3H-S by OH-,
with approximate ∆Gqo values calculated by applying the
Marcus2 relationship (eq 16), where ∆Gq refers to the actual
2
∆G°
∆Gq ) ∆Gqo 1 +
(16)
q
(
)
4∆Go
barrier and ∆G° is the standard free energy of the reaction.
∆Gqo for 3H-S (15.5 kcal/mol) is seen to be 0.5 kcal/mol lower
than for 2H-O (16.0 kcal/mol) (Table 1).
(2) The intrinsic reactivity of 3H-O is substantially lower
than that of 2H-O: for the reactions with the primary amines,
log(ko(3H-O)/ko(2H-O)) ) -1.61, while for the reactions with
the secondary amines the value is -1.59. On the other hand,
the intrinsic rate constants for 3H-S and 2H-S are only
marginally different, with log(ko(3H-S)/ko(2H-S)) ) -0.36 for
the primary amines and -0.33 for the secondary amines,
respectively.
The key question we are asking in this paper is whether anion
aromaticity increases or decreases the intrinsic rate constants
(decreases or increases the intrinsic barriers). No definite answer
emerged from the study of the reactions of 2H-O and 2H-S,18
because several factors besides aromaticity may contribute to
the differences in their intrinsic reactivities. These factors were
discussed in detail before18 and can be summarized as follows.
(a) The stronger electron-withdrawing inductive effect of the
ring oxygen compared to that of the ring sulfur enhances ko for
2H-O relative to that of 2H-S. The reason for this is that, at
the transition state (TS(2H-X)), the delocalization of the
incipient anionic charge lags behind proton transfer (transition-
state imbalance), and hence the bulk of this charge is on carbon
rather than on the carbonyl oxygen, which makes it more
susceptible to inductive stabilization. It is this disproportionately
strong transition-state stabilization relative to that of the anion
that enhances the intrinsic rate constant.8
amines, -1.09 for secondary amines), where no aromaticity and
(37) The effect of resonance in a reactant being lost ahead of proton transfer at
the transition state is equivalent to resonance development in the product
lagging behind proton transfer.8
(38) For a more detailed discussion, see ref 39 and references cited therein.
(39) Bernasconi, C. F.; Ali, M. J. Am. Chem. Soc. 1999, 121, 3039.
9
2710 J. AM. CHEM. SOC. VOL. 129, NO. 9, 2007

Aromaticity and the Intrinsic Barrier to Proton Transfer
A R T I C L E S
Table 4. Intrinsic Rate Constants and Intrinsic Barriers of the Reversible Deprotonation of Carbon Acids Whose Conjugate Bases are
Aromatic
primary amines
log ko
secondary amines
log ko
q
q
q
q
carbon
acid
∆
)
∆
Go
∆∆G o
∆
)
∆
Go
∆∆Go
log ko
log(ko(S)/ko(O))
(kcal/mol)
(kcal/mol)
log ko
log(ko(S)/ko(O))
(kcal/mol)
(kcal/mol)
3H-Oa
3H-Sa
2H-Ob
2H-Sb
1H+-Oc
1H+-Sc
1.16 ( 0.06
1.72 ( 0.05
15.8 ( 0.1
15.0 ( 0.1
1.64 ( 0.11
2.64 ( 0.05
15.1 ( 0.1
13.8 ( 0.1
0.56 ( 0.11
-0.76 ( 0.15
1.02 ( 0.16
-1.39 ( 0.21
}
}
}
}
}
}
}
}
}
}
}
}
2.77 ( 0.03
2.08 ( 0.05
13.6 ( 0.1
14.5 ( 0.1
3.23 ( 0.08
2.99 ( 0.08
13.0 ( 0.1
13.3 ( 0.1
-0.69 ( 0.08
1.10 ( 0.56
0.94 ( 0.16
-0.24 ( 0.16
1.51 ( 0.89
0.33 ( 0.21
-0.83 ( 0.22
0.27 ( 0.34
18.5 ( 0.3
17.0 ( 0.5
-0.46 ( 0.35
1.05 ( 0.54
17.9 ( 0.5
15.9 ( 0.7
-1.50 ( 0.76
-2.05 ( 1.21
a In water at 25 °C, this work. b In water at 25 °C, ref 18. c In 50% MeCN-50% water (v/v) at 25 °C, ref 16.
Table 5. Effect of Heteroatom on Intrinsic Rate Constantsa
is only marginally larger than for 3H-S (0.36 log unit for the
primary amines, 0.33 log unit for the secondary amines)? Since
the combined result of the inductive, steric, and resonance effects
on ko for 2H-X is unlikely to be much different than the
combined result of the inductive and steric effects on ko for
3H-X, the key factor must be π-donation by the heteroatom.
Specifically, π-donation must be mainly responsible for the
much larger ko(O) value for 2H-O compared to that for 3H-O.
This implies that the type II π-donor effect is more important
than the type I effect, leading to a net increase in intrinsic rate
constants.40 The much smaller difference in the ko(S) values
between 2H-S and 3H-S is also consistent with this interpreta-
tion, since π-donor effects are smaller for the sulfur derivative.
The main conclusion from the above analysis is that the
previous ambiguity regarding which type of π-donor effect is
dominant has been removed; i.e., it is now clear that all factors
outside of aromaticity, namely the inductive, steric, resonance,
and net π-donor effects, reduce the ko(S)/ko(O) ratios for the
2H-X system. It therefore greatly strengthens our previous
hypothesis that the aromaticity of 2--X increases the intrinsic
rate constants and would have resulted in ko(S)/ko(O) ratios
greater than unity were it not for the strong reduction of those
values by the four factors mentioned above. Turning to the ko-
(S)/ko(O) ratios for the 3H-X system, the fact that these ratios
are substantially larger than unity, despite the strongly depressing
influence of the inductive and steric effects, would be an
unambiguous indication that aromaticity enhances the ko values
if no other factor were to contribute to an increase in the ko-
(S)/ko(O) ratios. However, there is such a factor: the high
polarizability of sulfur. Since polarizability acts only at very
short distances,42 its main stabilizing effect is on the incipient
anionic charge of TS(3H-S) but not on the delocalized charge
of 3-S-. This leads to an increase in ko(S)44 for 3H-S and hence
to an increase in the ko(S)/ko(O) ratio.
a Arrows pointing up imply an increase, and arrows pointing down imply
a decrease. The length of the arrows indicates whether the effect is large or
small. The heavier arrows for the 3H-O/3H-S system indicate stronger
effects than those for the 2H-O/2H-S system. b Loss of resonance stabiliza-
tion of the carbon acid. c Preorganization factor. d Aromaticity lags behind
proton transfer. e Aromaticity is ahead of proton transfer.
no delocalization effects contribute to the lowering of the ko-
(S)/ko(O) rates. On the basis of this type of reasoning, we
tentatively favored hypothesis B in our previous paper.18
The results for 3H-O and 3H-S greatly strengthen hypothesis
B, because differences between the 2H-X and 3H-X systems
with regard to the factors outside of aromaticity that affect the
respective intrinsic rate constants (Table 5) eliminate some
ambiguities. First, there are no π-donor effects on 3H-O and
3H-S and no charge delocalization into the benzene rings of
3--O and 3--S. The inductive and steric effects are qualitatively
the same as in the 2H-X system, but they are stronger, as
indicated by the heavier arrows in Table 5. The inductive effect
is stronger because the incipient charge at the transition states,
TS(3H-X), is closer to the heteroatom than at the transition states
of the 2H-X system (TS(2H-X)). The steric effect is stronger
because of the closer proximity of the acidic proton to the
heteroatom.
Could the large ko(S)/ko(O) ratios be entirely due to this
polarizability effect while aromaticity has no effect or even
decreases this ratio? This is highly unlikely. A detailed analysis
of the potential magnitude of the polarizability effect on the
deprotonation of PhSCH2NO2 suggested that the enhancement
(40) Other examples where type II π-donor effects override type I π-donor effects
have been reported.41
(41) (a) Bernasconi, C. F.; Renfrow, R. A.; Tia, P. R. J. Am. Chem. Soc. 1986,
108, 4541. (b) Bernasconi, C. F.; Zitomer, J. L.; Schuck, D. F. J. Org.
Chem. 1992, 57, 1132.
(42) Polarizability effects fall off with the fourth power of distance; in contrast,
In view of these differences between the 2H-X and 3H-X
systems, how can we understand that ko(O) for 2H-O is so much
greater than for 3H-O (1.61 log units with the primary amines,
1.59 log units with the secondary amines), while ko(S) for 2H-S
inductive effects fall off with the square of distance.43
(43) (a) Taft, R. W. Prog. Phys. Org. Chem. 1983, 14, 247. (b) Taft, R. W.;
Topsom, R. D. Prog. Phys. Org. Chem. 1987, 16, 1.
(44) Similar increases in the intrinsic rate constants have been observed in the
deprotonation of PhSCH2NO2 and other carbon acids.46
45
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J. AM. CHEM. SOC. VOL. 129, NO. 9, 2007 2711

A R T I C L E S
Bernasconi and Pe´rez-Lorenzo
of the intrinsic rate constant would be less than a factor of 10.45
Furthermore, the deprotonation of nitroalkanes is characterized
by much larger transition-state imbalances than the deprotona-
tion of any other carbon acids,8 which renders the polarizability
effect on the intrinsic rate constants in the deprotonation of
nitroalkanes particularly large.47 This implies that the polariz-
ability effect on ko for the deprotonation of 3H-S should be
quite small and cannot account for the observed positive log-
(ko(S)/ko(O)) values.
charge transferred from the base to the carbon acid. This means
that, at the transition state, the charge on Y can never be very
high, since it represents only a fraction of a fraction.
Our results suggest that no such constraint applies to the
development of aromaticity. One way to envision how aroma-
ticity may develop early is to assume that the conversion of the
sp3 orbital of the breaking C-H bond into a p orbital has made
disproportionate progress at the transition state. Or it may be
that only relatively minor progress in the conversion of the sp3
orbital to a p orbital is needed for aromatic stabilization to
become disproportionately effective.
Conclusions
Why Does Aromaticity Affect Intrinsic Barriers Differ-
ently than Resonance? The main conclusion from this work
is that the aromaticity of the enolate ions 2--X and 3--X
increases the intrinsic rate constants (decreases the intrinsic
barriers) of the deprotonation of the respective carbon acids
2H-X and 3H-X. This conclusion is consistent with an earlier
suggestion that the aromaticity of 1-X lowers the intrinsic
barriers to the deprotonation of 1H+-X (eq 1). It also agrees
with preliminary ab initio calculations on the gas-phase proton
transfers from benzenium ion to benzene and from cyclopen-
tadiene to its conjugate anion.17,48 Since aromaticity is a product-
stabilizing feature, the PNS8 implies that the development of
aromaticity along the reaction coordinate must be ahead of
proton transfer; i.e., the stabilization of the transition state by
the developing aromaticity is disproportionately strong relative
to the degree of proton transfer, and this is what lowers the
intrinsic barrier. This contrasts with simple resonance/delocal-
ization effects, whose development at the transition state always
lags behind proton transfer.
Why are the effects of simple resonance and of aromaticity
on intrinsic barriers so different? In the case of resonance, there
exists an insurmountable constraint that prevents charge delo-
calization at the transition state. The gist of this constraint was
captured in a model initially proposed by Kresge49 in the context
of proton transfers from nitroalkanes, a model we have
refined8,50 and applied to the generalized reaction scheme of
eq 17. The basic idea is that the delocalization of the negative
Experimental Section
Substrates. 3H-O was purchased from Acros and used without
further purification. 3H-S was synthesized by converting 3-bromoben-
zothiophene (Aldrich) into 3-methoxybenzothiophene (5) according to
Fournier Dit Chabert et al.51 and hydrolyzing the methoxy compound
as follows. To a 100 mL round-bottom flask were added 5 (1.24 g,
7.55 mmol), CH3CN (45 mL). and HCl 20% (5 mL), and the solution
was refluxed for 24 h. CH3CN was then evaporated, and the residue
was washed several times with dichloromethane. The extracted organic
layer was dried over MgSO4, filtered, and evaporated. The resulting
purple tar was then purified by flash chromatography using a linear
gradient of 0-5% ethylacetate in hexane to yield an orange solid. The
dried product was recrystallized from EtOH to give 3H-S as a pink
solid, mp 63-65 °C (lit.52 mp 62-64 °C). The spectral data are as
follows: 1H NMR δ (500 MHz, CDCl3) 3.81 (s, 2H, -SCH2-), 7.23
(t, 1H), 7.45 (d, 1H), 7.57 (t, 1H), 7.79 (d, 1H).
Buffers and Other Reagents. Amines were obtained from Aldrich
and Acros as analytical grade and purified as follows. Piperidine,
morpholine, n-butylamine, methoxyethylamine, and HEPA were re-
fluxed over CaH2 for 1 h and distilled under nitrogen. Aminoacetonitrile
hydrochloride and glycinamide hydrochloride were recrystallized twice
from 1:1 2-propanol/ethanol; piperazine was used without further
purification. KOH and HCl solutions were made from DILUT-IT
analytical concentrates (J.T. Baker). Ultrapure water was obtained from
a Millipore MILLI-Q Plus water system.
Kinetic Experiments. All kinetic experiments were conducted in
water at 25 °C and µ ) 0.5 M (KCl). Rates were measured in a stopped-
flow apparatus. Kinetics were followed by monitoring the reaction at
330 (3H-O) or 370 nm (3H-S). In highly basic solution (pH > pKKa H),
the reactions were run by mixing the keto form with KOH or amine
buffer. In solutions at pH < pKKa H, runs were performed generating
either 3--O or 3--S by means of a 0.025 M KOH solution and
subsequently mixing the enolate ion with the appropriate buffer. Typical
substrate concentrations were (1-3) × 10-4 M. KOH, amine, and acid
concentrations were always in large excess over the substrate, ensuring
pseudo-first-order conditions. All pH measurements were carried out
with an Orion 611 pH meter equipped with a glass electrode and a
Sure-Flow (Corning) reference electrode and calibrated with standard
aqueous buffers.
charge into the π-acceptor Y can occur only if there is
development of the C-Y π-bond. Hence, the fraction of charge
on Y depends on the fraction of π-bond formation, and the
fraction of π-bond formation in turn depends on the fraction of
Acknowledgment. This research has been supported by Grant
No. CHE-046622 from the National Science Foundation. We
thank Mirjam Karni for the DFT calculations and discussion of
the anomeric effect.
(45) Bernasconi, C. F.; Kittredge, K. W. J. Org. Chem. 1998, 63, 1944.
(46) Bernasconi, C. F.; Fairchild, D. E. J. Phys. Org. Chem. 1992, 5, 409.
(47) A detailed discussion of the relationship between the degree of transition-
state imbalance and the potential ko-enhancing effect of a polarizable group
has been presented elsewhere.8b
(48) Bernasconi, C. F.; Ragains, M. L.; Wenzel, P. J. To be published.
(49) Kresge, A. J. Can. J. Chem. 1974, 52, 1897.
Supporting Information Available: Figures S1-S5, showing
kinetic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(50) Bernasconi, C. F.; Wenzel, P. J. J. Org. Chem. 2001, 66, 968.
(51) Fournier Dit Chabert, J.; Joucla, L.; David, E.; Lemaire, M. Tetrahedron
2004, 60, 3221.
(52) Mukherjee, C. Tetrahedron 2003, 59, 4676.
JA067118L
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2712 J. AM. CHEM. SOC. VOL. 129, NO. 9, 2007