Structure-reactivity effects on primary deuterium isotope effects on protonation of ring-substituted α-methoxystyrenes

Article abstract of DOI:10.1021/ja905080e

Primary product isotope effects (PIEs) on L⁺ and carboxylic acid catalyzed protonation of ring-substituted α-methoxystyrenes (X-1) to form oxocarbenium ions X-2⁺ in 50/50 (v/v) HOH/DOD were calculated from the yields of the α-CH

Full text of DOI:10.1021/ja905080e

Published on Web 09/14/2009
Structure-Reactivity Effects on Primary Deuterium Isotope
Effects on Protonation of Ring-Substituted r-Methoxystyrenes
Wing-Yin Tsang and John P. Richard*
Department of Chemistry, UniVersity of Buffalo, SUNY, Buffalo, New York 14260-3000
Received June 22, 2009; E-mail: jrichard@buffalo.edu
Abstract: Primary product isotope effects (PIEs) on L+ and carboxylic acid catalyzed protonation of ring-
substituted R-methoxystyrenes (X-1) to form oxocarbenium ions X-2+ in 50/50 (v/v) HOH/DOD were
1
calculated from the yields of the R-CH3 and R-CH2D labeled ketone products, determined by H NMR. A
plot of PIE against reaction driving force shows a maximum PIE of 8.7 for protonation of 4-MeO-1 by
Cl2CHCOOH (∆G° ) 1.0 kcal/mol). The PIE decreases to 8.1 for protonation of 4-MeO-1 by L3O+ (∆G° )
-2.8 kcal/mol) and to 5.1 for protonation of 3,5-di-NO2-1 by MeOCH2COOH (∆G° ) 13.1 kcal/mol). The
PIE maximum is around ∆G° ) 0. Arrhenius-type plots of PIEs on protonation of 4-MeO-1 and 3,5-di-
NO2-1 by L3O+ and on protonation of X-1 by MeOCH2COOH in 50/50 (v/v) HOH/DOD give similar slopes
and intercepts. These were used to calculate values of [(Ea)H - (Ea)D] ) -1.2 kcal/mol and (AH/AD) ) 1.0
for the difference in activation energy for reactions of A-H and A-D and for the limiting PIE at infinite
temperature, respectively. These parameters are consistent with reaction of the hydron over an energy
barrier. There is no evidence for quantum mechanical tunneling of the hydron through the barrier. These
PIEs suggest that the transferred hydron at the transition state lies roughly equidistant between the acid
donor and base acceptor and contrast with the recently published Brønsted parameters [Richard, J. P.;
Williams, K. B. J. Am. Chem. Soc. 2007, 129, 6952-6961], which are consistent with a product-like transition
state. An explanation for these seemingly contradictory results is discussed.
1. Introduction
tational methods are adequate for their intended purpose,
particularly for the modeling of acid-base catalyzed proton
transfer at carbon in water. This provides a simple rationale for
continued experimental studies on proton transfer at carbonsthese
are needed to provide the large body of data required to
demonstrate that modern computational results are able to
reproduce experimental reaction rate and equilibrium constants.
Brønsted acid-base catalyzed proton transfer at carbon (eq
1) is an apparently simple but profoundly important reaction in
chemical and biological processes.1 The results of investigations
of the effect of changing substituent -X at the base catalyst
and -Y at the carbon acid on rate constants for proton transfer
provide considerable insight into the bonding changes that occur
on proceeding from reactants to the transition state.2-6 This
experimental work defines the relative free energies for the
formation of a large number of transition states and has allowed
investigators to draw inferences about transition state structure,
without the direct observation of these species. By comparison,
computational studies have the potential to provide a more
detailed description of the reaction coordinate profile and
transition state structure for proton transfer at carbon.7-12
However, there is no general agreement about which compu-
There have been relatively few studies in recent years on
kinetic isotope effects on proton transfer at carbon, despite the
clear need for experimental data to evaluate the contribution of
the pathway for quantum mechanical tunneling to the observed
rate constants for these proton transfer reactions.13-18 We
recently reported a fast, convenient, and general method to
determine primary product isotope effects (PIEs) on proton
transfer reactions in hydroxylic solvents.19 This method was
(1) Hynes, J. T.; Klinman, J. P.; Limbach, H.-H.; Schowen, R. L. Hydrogen-
Transfer Reactions; Wiley-VCH: Weinheim, 2007.
(2) Jencks, W. P. Bull. Soc. Chim. France 1988, 218–224.
(3) Jencks, W. P. Chem. ReV. 1985, 85, 511–527.
(4) Bernasconi, C. F. Acc. Chem. Res. 1992, 25, 9–16.
(5) Bernasconi, C. F. Acc. Chem. Res. 1987, 20, 301–308.
(6) Kresge, A. J. Chem. Soc. ReV. 1973, 2, 475–503.
(7) Bernasconi, C. F.; Wenzel, P. J. J. Am. Chem. Soc. 1994, 116, 5405–
5413.
(13) Heeb, L. R.; Peters, K. S. J. Phys. Chem. B 2008, 112, 219–226.
(14) Fillaux, F.; Cousson, A.; Gutmann, M. J. Pure. App. Chem. 2007, 79,
1023–1039.
(8) Bernasconi, C. F.; Wenzel, P. J. J. Org. Chem. 2003, 68, 6870–6879.
(9) Sato, M.; Kitamura, Y.; Yoshimura, N.; Yamataka, H. J. Org. Chem.
2009, 74, 1268–1274.
(15) Cui, Q.; Karplus, M. J. Am. Chem. Soc. 2002, 124, 3093–3124.
(16) Gao, J.; Wong, K.-Y.; Major, D. T. J. Comput. Chem. 2007, 29, 514–
522.
(10) Kiefer, P. M.; Hynes, J. T. J. Phys. Chem. A 2004, 108, 11809–11818.
(11) Costentin, C.; Saveant, J.-M. J. Am. Chem. Soc. 2004, 126, 14787–
14795.
(17) Truhlar, D. G.; Gao, J.; Alhambra, C.; Garcia-Viloca, M.; Corchado,
J.; Sanchez, M. L.; Villa, J. Acc. Chem. Res. 2002, 35, 341–349.
(18) Alhambra, C.; Gao, J.; Corchado, J. C.; Villa, J.; Truhlar, D. G. J. Am.
Chem. Soc. 1999, 121, 2253–2258.
(12) Saunders, W. H. J. Am. Chem. Soc. 1994, 116, 5400–5404.
9
13952 J. AM. CHEM. SOC. 2009, 131, 13952–13962
10.1021/ja905080e CCC: $40.75  2009 American Chemical Society

Primary Deuterium Isotope Effects on Protonation
A R T I C L E S
which shows a much larger KIE.25 We have therefore examined
the temperature dependence of the PIE on protonation of X-1
by lyonium ion and by a carboxylic acid, to evaluate the
importance of tunneling.
Scheme 1
2. Experimental Section
The procedures for the preparation of 3,5-dinitroacetophenone
and ring-substituted R-methoxystyrenes and the sources for the other
reagents used in this work were given in an earlier publication.24
Solvents were used without further purification unless otherwise
indicated. Water was first distilled and then further purified with a
Milli-Q water apparatus. Deuterium labeled water (99.9% D), DCl
(35% w/w, 99.9%D), and KOD (40 wt %, >98%D) were purchased
from Cambridge Isotope Laboratories.
used to determine PIEs on protonation of ring-substituted
R-methoxystyrenes X-1 by lyonium ion (Scheme 1) over a broad
range of temperature and thermodynamic driving force (Scheme
1).19 We now report the full details of our experiments to
determine PIEs and extensive new data for protonation of X-1
by carboxylic acids. Our work was initiated with the following
goals in mind.
(1) We wanted to increase the number of experimental
determinations of isotope effects on protonation of structurally
homologous carbon bases, that may be directly compared with
the isotope effects determined in computational studies. We have
compared these experimentally determined isotope effects with
isotope effects calculated using a novel approach based on
Kleinert’s variational perturbation theory within the framework
of Feynman path integrals.20-22
(2) Primary kinetic isotope effects on Brønsted acid catalyzed
reactions in water are normally estimated from the ratio of
second-order rate constants for reactions in HOH and DOD.23
We wanted to show that these primary isotope effects might be
determined more easily and accurately from the ratio of -H
and -D labeled products of protonation of X-1 in the common
solvent of 50/50 HOH/DOD.
(3) We recently reported the effect of changing reaction
driving force on the Brønsted structure-reactivity coefficients
R and ꢀ, determined for variations in the acidity of the
carboxylic acid proton donor and in the basicity of the vinyl
ether proton acceptor X-1, respectively.24 We wanted to compare
these changes in Brønsted parameters with the corresponding
changes in the kinetic isotope effect for the protonation of X-1,
to more fully define the changes in transition state structure that
occur with changing reaction driving force.
1
2.1. 1H NMR Analyses. H NMR spectra at 500 MHz were
recorded on a Varian UNITY INOVA 500 MHz spectrometer as
described in earlier work.28,29 The following relaxation times T1
were determined in CDCl3 for the R-CH2D protons of the
monodeuteriated ring substituted acetophenones: 3,5-dinitroac-
etophenone, 3 s; 4-methoxyacetophenone, 3 s; 4-nitroacetophenone,
1
3 s; and acetophenone, 4 s. H NMR spectra of the products of
hydrolysis of X-1 in 50/50 (v/v) HOH/DOD (a mixture of R-CH3
and R-CH2D labeled ketone X-3) were recorded in CDCl3 (30-60
transients) with a pulse angle of 90°, an acquisition time of 7-10
s, and a relaxation delay of 7T1. All spectra were referenced to
CHCl3 at 7.27 ppm, and base lines were drift-corrected before
integration of the signals due to the R-CH3 and R-CH2D groups.
2.2. Preparation of Solutions. The concentrations of solutions
of strong acids and bases were standardized by titration using
phenolphthalein as an indicator. A stock solution of 50/50 (v/v)
HOH/DOD, obtained by mixing equal volumes of HOH and DOD,
was used to prepare solutions of KCl. A 4.5 M solution of LO-
and a 1.0 M solution of LCl in 50/50 (v/v) HOH/DOD were
prepared, respectively, by mixing equal volumes of 4.5 M KOH
and 4.5 M KOD or of 1.0 M HCl and 1.0 M DCl.
Solutions of CH3COOL in 50/50 (v/v) HOH/DOD were prepared
by adding equal molar amounts of CH3COOH and CH3COOD to
50/50 (v/v) HOH/DOD. Other solutions of carboxylic acids in 50/
50 (v/v) HOH/DOD were prepared by dissolving the acid RCO2H
in 50/50 (v/v) HOH/DOD and then adding a small amount of D2O
to balance the acidic hydrogen of RCO2H. These solutions were
adjusted to the appropriate [RCO2L]/[RCO2-] ratio by adding
measured amounts of KOL in 50/50 (v/v) HOH/DOD.
2.3. Product Studies. The hydrolysis of X-1 was initiated by
making a 1/100 dilution of the reactant in acetonitrile into acidic
solutions of 50/50 (v/v) HOH/DOD (v/v) (I ) 1.0 KCl) to give the
following final substrate concentrations: 4-MeO-1, 0.3 mM in 25
mL of 50/50 (v/v) HOH/DOD; H-1, 0.8 mM in 10 mL of 50/50
(v/v) HOH/DOD; 4-NO2-1, 0.09 mM in 50 mL of 50/50 (v/v) HOH/
DOD; and, 3,5-di-NO2-1, 0.06 mM in 50 mL of 50/50 (v/v) HOH/
DOD.
The half times for hydrolysis of X-1 in dilute solutions of LCl
were estimated using second-order rate constants determined for
hydrolysis in HOH and DOD,24,30 and assuming a linear depen-
dence of the observed rate constant on the deuterium composition
of solvent. Acidic solutions of 50/50 (v/v) HOH/DOD were
vortexed during the addition of the reactive substrate 4-MeO-1 to
ensure rapid mixing. In cases where the half time for the specific
acid and buffer catalyzed solvolysis in 50/50 HOH/DOD (v/v) was
>1 min, a 1.0 mL aliquot was transferred to a cuvette immediately
after initiation, and the reaction was monitored by UV spectros-
copy.24 The lyonium ion and buffer catalyzed reactions of 4-MeO-1
(4) Two explanations have been offered to explain the
changes in primary isotope effects on hydron transfer at carbon
that have been observed to occur with changing reaction driving
force:23,25 (a) These changes may be due to changes in the
structure of the transition state for the hydron transfer reaction,26,27
or (b) they may be due to changes in the relative importance of
the reaction by hydron transfer over a reaction barrier, which
shows a primary KIE of ca 7, compared to the reaction of the
hydron by quantum-mechanical tunneling through the barrier,
(19) Tsang, W.-Y.; Richard, J. P. J. Am. Chem. Soc. 2007, 129, 10330–
10331.
(20) Wong, K.-Y.; Richard, J. P.; Gao, J. J. Am. Chem. Soc. 2009, http://
dx.doi.org/10.1021/ja905081x.
(21) Wong, K.-Y.; Gao, J. J. Chem. Theory Comput. 2008, 4, 1409–1422.
(22) Wong, K.-Y.; Gao, J. J. Chem. Phys. 2007, 127, 211103.
(23) Kresge, A. J.; Sagatys, D. S.; Chen, H. L. J. Am. Chem. Soc. 1977,
99, 7228–7233.
(24) Richard, J. P.; Williams, K. B. J. Am. Chem. Soc. 2007, 129, 6952–
6961.
(28) Amyes, T. L.; Richard, J. P. J. Am. Chem. Soc. 1992, 114, 10297–
(25) Bell, R. P. The Proton in Chemistry, 2nd ed.; Cornell University Press:
Ithaca, NY, 1973; pp 250-296.
10302.
(29) Amyes, T. L.; Richard, J. P. J. Am. Chem. Soc. 1996, 118, 3129–
(26) Westheimer, F. H. Chem. ReV. 1961, 61, 265–273.
(27) Melander, L. Isotope Effects on Reaction Rates; Ronald Press: New
York, 1960; pp 24-32.
3141.
(30) Williams, K. Chemistry, Ph.D. Thesis; University at Buffalo: Buffalo,
1998; p 208.
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A R T I C L E S
Tsang and Richard
were quenched (see below) after a 1-5 min reaction time, which
was at least 10 half times for the hydrolysis reaction of 4-MeO-1.
The hydrolysis reactions of other X-1 were monitored by UV
spectroscopy and allowed to proceed to at least 50% conversion to
ketone product X-3.
These reactions were quenched by extraction of the organic
material into 1-2 mL of CDCl3 at the following reaction times:
H-1, 7-10 reaction half times; 4-NO2-1, 1-7 reaction half times,
depending upon the buffer catalyst; 3, 5-di-NO2-1, 1-5 reaction
half times, depending upon the buffer catalyst. The organic layer
was separated from the aqueous layer using a disposable pipet and
then dried by filtration through a short column of MgSO4 directly
into an NMR tube. The samples were stored at -15 °C for 1 or 2
days, until the analysis for deuterium enrichment of the R-carbonyl
methyl group using 1H NMR. It has been shown that the R-hydrogen
of a simple methyl ketone is stable for exchange for at least one
month under these conditions.31 The reactions at elevated temper-
atures (>25 °C) were rapidly cooled to room temperature in an ice
bath prior extraction of products into CDCl3.
The ratio of the yields of products of solvolysis of X-1 in 50/50
(v/v) HOH/DOD (I ) 1.0 KCl) labeled with an R-CH3 and an
R-CH2D group was determined using eq 2, where ACH is the area
of the singlet due to the -CH3 group and ACH D is the 3area for the
downfield shifted triplet (JHD ) 2 Hz) due to2 the -CH2D group:
MeO-3, δ ) 2.553 (CH3), 2.536 ppm, (CH2D); H-3, 2.614 (CH3),
2.598 ppm (CH2D); 4-NO2-3, 2.681 (CH3), 2.665 ppm (CH2D);
3,5-di-NO2-3, 2.777 (CH3), 2.761 ppm (CH2D).
A
[PH]
[PD]
CH3
(PIE)obsd
)
)
(2)
1.5A
CH2D
1
Figure 1. Partial H NMR spectrum (recorded in CDCl3) at 500 MHz of
H-3 formed by lyonium ion catalyzed hydrolysis of H-1 in 50/50 (v/v)
HOH/DOD (I ) 1.0, KCl) at 25 °C. The same spectrum is shown at two
different resolutions. The small peaks on either side of the singlet at 2.614
ppm are 13C satellites from coupling of the R-CH3 protons to the neighboring
carbonyl carbon.28 The peak assignments are given in the text.
2.4. Kinetic Studies. The hydrolysis of X-1 in 50/50 (v/v) HOH/
DOD at 25 °C (I ) 1.0 KCl) was monitored by UV spectroscopy.24
The observed first-order reaction rate constants and second-order
rate constants for Brønsted acid catalysis were determined as
described in earlier work.24
2.4.1. Deuterium Exchange Reactions of X-3. The exchange
of the R-CH3 hydrogen of X-3 for deuterium in 50/50 (v/v) HOH/
DOD (I ) 1.0 KCl) was monitored at 25 °C. The exchange reactions
were initiated by making a 100-fold dilution of X-3 in acetonitrile
into 50/50 (v/v) HOH/DOD (I ) 1.0 KCl) to give the following
final substrate concentrations and reaction volumes: 4-NO2-3, 0.09
mM in 250 mL solvent; 3,5-diNO2-3, 0.08 mM in 250 mL solvent.
At timed intervals, 50 mL of the reaction mixture were withdrawn,
the organic material was extracted into 1-2 mL of CDCl3, and the
organic layer was dried as described above.
3) and alkene (4-NO2-1) reaction products were separated by HPLC,
and the product ratio was determined from the ratio of the HPLC
peak areas Aalk/Aket and using ꢀKet/ꢀalk ) 0.17 for the ratio of the
extinction coefficients of 4-NO2-3 and 4-NO2-1. The product ratio
[alkene]/[ketone] decreased slowly with time, due to acid-catalyzed
conversion of 4-NO2-1 to 4-NO2-3. The initial ratio of product
yields was determined by making a small (<20%) linear extrapola-
tion to zero time of a plot of Aalk/Aket against time.
3. Results
ACH D
A second-order rate constant of kL ) 500 M-1 s-1 for
hydrolysis of 4-MeO-1 in 50/50 (v/v) HOH/DOD (I ) 1.0, KCl)
2
) (kobs)t
(3)
A
+ 1.5A
CH2D
CH3
at 25 °C was estimated as the average of the values of kH
)
24
30
870 M-1 s-1 and kD ) 170 M-1 s-1 for the reactions in
HOH and DOD, respectively. The hydrolysis reaction of
4-MeO-1 was examined at lyonium ion concentrations ranging
from 3 to 11 mM, where the estimated half times for hydrolysis
are between 0.5 and 0.12 s. These acidic solutions of 50/50
(v/v) HOH/DOD were vigorously vortexed during addition of
substrate 4-MeO-1 to ensure rapid mixing of the reactant.
Figure 1 shows the partial 500 MHz NMR spectrum, using
two different scales for the y-axis, of H-3 that forms as the
product of the lyonium ion catalyzed reaction of H-1 in 50/50
(v/v) HOH/DOD (I ) 1.0, KCl) at 25 °C. These spectra are
similar to those reported in earlier determinations of deuterium
enrichment of carbon acids using 1H NMR.28,29,31-39 The major
peak is the singlet for the R-CH3 group of H-3 formed by
kA ) kobs/[A-]
(4)
The first-order rate constant, kobs (s-1), for the deuterium exchange
reaction of the R-CH3 group of X-3 to form the R-CH2D group
was determined as the slope of a plot of reaction progress against
time over the first 5-10% of the reaction (eq 3), where ACH is the
area of the singlet due to the CH3 group of the reactant and ACH D
is the area for the downfield shifted triplet due to the CH2D group
of the product. The second-order rate constant for the carboxylate
anion-catalyzed exchange reaction was determined according to eq
4, where [A-] is the concentration of the buffer base for the
particular experiment.
2.5. Products of Solvolysis of 4-Nitroacetophenone Dimethyl
Ketal. This ketal was prepared as a 0.25 M solution in acetonitrile
that contained 0.5 mM of the internal standard fluorene. Solvolysis
was initiated by making a 100-fold dilution of the ketal into water
buffered with potassium phosphate at pH 6.7. The ketone (4-NO2-
3
2
(31) Richard, J. P.; Nagorski, R. W. J. Am. Chem. Soc. 1999, 121, 4763–
4770.
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Primary Deuterium Isotope Effects on Protonation
A R T I C L E S
Table 1. Product Isotope Effects and Derived Kinetic Isotope
Effects on Hydron Transfer from L3O+ and Substituted Carboxylic
Acids to X-1 in 50/50 (v/v) HOH/DOD at 25°C and I ) 1.0 (KCl)
product isotope effect
a
c
c
pKHa2
4-OMe b
-H b
4-NO2
3,5-di-NO2
O
L+
-1.76 PIEb 8.1 ( 0.1 8.2 ( 0.2 7.8 ( 0.1 7.3 ( 0.2
KIEe
5.6
5.7
5.4
5.0
Cl2CHCOOL
CNCHCOOL
ClCH2COOL
1.03 PIE 8.7 ( 0.2 7.7 ( 0.1 7.4 ( 0.2d 6.4 ( 0.1
2.23 PIE 8.7 ( 0.3 8.0 ( 0.2 6.7 ( 0.1 5.7 ( 0.1
2.65 PIE 8.6 ( 0.1 7.7 ( 0.1 6.4 ( 0.1 5.3 ( 0.1
MeOCH2COOL 3.33 PIE 8.4 ( 0.1 7.6 ( 0.1 6.5 ( 0.1 5.1 ( 0.1
CH3COOL 4.60 PIE 8.1 ( 0.2 7.0 ( 0.1 6.0 ( 0.1
f
KIE
7.3
6.3
5.4
a pKa’s determined in H2O: Fox, J. P.; Jencks, W. P. J. Am. Chem.
Soc. 1974, 96, 1436-1449. b Calculated as the average of the values of
(PIE)obs determined at several different concentrations of the catalyzing
acid. c Unless noted otherwise, the values of (PIE)AL for the carboxylic
acid-catalyzed reactions were obtained from a nonlinear least-squares fit
of the data in Figure 4A and B to eq 8 (see text). d Calculated as the
average of the values of (PIE)obs determined for reactions at 0.40, 0.60,
and 0.80 M buffer. e KIE ) ΦL(PIE)L, where ΦL ) 0.69.43,44 f KIE )
Figure 2. Product deuterium isotope effects for lyonium ion-catalyzed
protonation of X-1 in 50/50 (v/v) HOH/DOD (I ) 1.0, KCl). Key: (b)
4-MeO-1; (1) 3,5-di-NO2-1.
Φ
AL(PIE)AL, where ΦAL ) 0.9.45
Scheme 2
the apparent PIE for hydrolysis of X-1 in 50/50 (v/v) HOH/
DOD would depend upon the true PIE on protonation of X-1
and a second isotope effect on the partitioning of -CH3 and
-CH2D labeled X-2+ between addition of water and deproto-
nation to reform X-1.41 We have therefore examined the effect
of increasing [AcO-] on the yield of the products of solvolysis
of 4-nitroacetophenone dimethyl ketal in water that contains
10 mM phosphate buffer at pH 6.7 and 25 °C. The solvolysis
gives very low yields of alkene 4-NO2-1 (>0.1%). This shows
that >99.9% of the 4-NO2-2+ intermediate of hydrolysis of
4-NO2-1 would partition forward to product under these
conditions. The rate constant ratio kAcO/ks ) 0.0011 M was
determined as the slope of a plot (not shown) of product yields
([4-NO2-1]/[4-NO2-3]) against [AcO-] (Scheme 3).
reaction with L2OH+, and the smaller peaks are the 0.016 ppm
upfield-shifted triplet for the R-CH2D group of H-3 formed by
reaction with L2OD+. The observed product isotope effect
(PIE)obs for protonation of H-1 is equal to the ratio of the
integrated areas of the peaks for the -CH3 and -CH2D groups
(eq 2). A small 0.3%/D isotope effect has been reported for
partitioning of -H and -D labeled alkanes between methanol/
water mixtures and the solid support of a C18 reverse phase
HPLC column, with the -H labeled alkanes showing a slight
preference for the hydrophobic environment.40 A similar isotope
effect on partitioning of the -H and -D labeled X-3 between
CDCl3 and water would have been too small to be detected by
these experiments, and so this partitioning isotope effect is
assumed to be negligible.
Carboxylic acids are very effective catalysts of the protonation
of X-1, which is the rate-determining step for hydrolysis of X-1
to form X-3 (Scheme 1). The values of (PIE)obs for the reactions
of X-1 in the presence of carboxylic acid catalysts in 50/50
(v/v) HOH/DOD (I ) 1.0, KCl) at 25 °C, determined by H
NMR analysis, are reported in Table S2 of the Supporting
Information.
Figure 3A shows that there is only a small change in the
value of (PIE)obs for protonation of 4-MeO-1 as [LA]T is
increased from 0.20 to 0.80 M. This is because the PIEs on the
lyonium ion and buffer catalyzed reactions are similar. The
buffer catalyzed reaction is the major pathway even when
1
concentrations of buffer are low ([PH]LA . [PH]L and [PD]LA
.
[PD]L, eq 7, Scheme 2). The product isotope effects on
The values of (PIE)obs for the L3O+-catalyzed reactions of
X-1 in 50/50 (v/v) HOH/DOD (I ) 1.0, KCl) at 25 °C are
reported in Table S1 of the Supporting Information. Figure 2
shows the values of (PIE)obs determined for hydrolysis of
4-MeO-1 and 3,5-di-NO2-1 in the presence of different [L3O+].
In all cases, the variation in the values (PIE)obs for the reaction
of X-1 (X ) 4-OMe, 4-H, 4-NO2, 3,5-di-NO2) at different
[L3O+] is less than (2%. The product isotope effects on
protonation of X-1 by lyonium ion [(PIE)L, eq 5 and Scheme
2], calculated as the average of the (PIE)obs determined for
reactions at five different [L3O+], are reported in Table 1.
The interpretation of these data would become problematic,
if the first-order rate constants for addition of solvent to X-2+
and for deprotonation to form X-1 were similar. This is because
(32) Rios, A.; Amyes, T. L.; Richard, J. P. J. Am. Chem. Soc. 2000, 122,
9373–9385.
(33) Rios, A.; Crugeiras, J.; Amyes, T. L.; Richard, J. P. J. Am. Chem.
Soc. 2001, 123, 7949–7950.
(34) Richard, J. P.; Williams, G.; O’Donoghue, A. C.; Amyes, T. L. J. Am.
Chem. Soc. 2002, 124, 2957–2968.
(35) Rios, A.; Richard, J. P.; Amyes, T. L. J. Am. Chem. Soc. 2002, 124,
8251–8259.
(36) Crugeiras, J.; Rios, A.; Amyes, T. L.; Richard, J. P. Org. Biomol.
Chem. 2005, 3, 2145–2149.
(37) Crugeiras, J.; Rios, A.; Riveiros, E.; Amyes, T. L.; Richard, J. P. J. Am.
Chem. Soc. 2008, 130, 2041–2050.
(38) Nagorski, R. W.; Richard, J. P. J. Am. Chem. Soc. 2001, 123, 794–
802.
(39) Rios, A.; Richard, J. P. J. Am. Chem. Soc. 1997, 119, 8375–8376.
(40) Tanaka, N.; Thornton, E. R. J. Am. Chem. Soc. 1976, 98, 1617–1619.
(41) Thibblin, A. Chem. Soc. ReV. 1989, 18, 209–224.
9
J. AM. CHEM. SOC. VOL. 131, NO. 39, 2009 13955

A R T I C L E S
Tsang and Richard
Figure 4. Effect of increasing [RCO2H] on the PIE for the reactions of
X-1 in 50/50 (v/v) HOH/DOD at 25 °C and I ) 1.0 (KCl). (A) Data for
4-NO2-1. Key: (9) acetic acid buffer ([AH]/[A-] ) 1.0); (2) methoxyacetic
acid buffer ([AH]/[A-] ) 1/9); (b) chloroacetic acid buffer ([AH]/[A-] )
1/9); ([) cyanoacetic acid buffer ([AH]/[A-] ) 1/9); (1) dichloroacetic
acid buffer ([AH]/[A-] ) 1/9). The lines showing the fit of data for the
chloroacetic and methoxyacetic acid catalyzed reactions are nearly super-
imposible. (B) Data for 3,5-di-NO2-1. Key: (2) methoxyacetic acid buffer
([AH]/[A-] ) 7/3); (b) chloroacetic acid buffer ([AH]/[A-] ) 1/9); ([)
cyanoacetic acid buffer ([AH]/[A-] ) 1/9); (1) dichloroacetic buffer ([AH]/
[A-] ) 1/9).
Figure 3. Effect of increasing [RCO2H] on the observed PIE for the
reactions of X-1 in 50/50 (v/v) HOH/DOD at 25 °C and I ) 1.0 (KCl). (A)
Data for 4-MeO-1. Key: (9) acetic acid buffer ([AH]/[A-] ) 1/9); (2)
methoxyacetic acid buffer ([AH]/[A-] ) 1/9); (b) chloroacetic acid buffer
([AH]/[A-] ) 1/9V; ([) cyanoacetic acid buffer ([AH]/[A-] ) 1/9); (1)
dichloroacetic acid buffer ([AH]/[A-] ) 1/9). (B) Data for 4-H-1. Key:
(9) acetic acid buffer ([AH]/[A-] ) 1.0); (2) methoxyacetic acid buffer
([AH]/[A-] ) 1/9); (b) chloroacetic acid buffer ([AH]/[A-] ) 1/9); ([)
cyanoacetic acid buffer ([AH]/[A-] ) 1/9); (1) dichloroacetic acid buffer
([AH]/[A-] ) 1/9).
protonation of 4-MeO-1 by carboxylic acids [(PIE)LA, eq 6)]
in 50/50 (v/v) HOH/DOD, determined as the average of the
values of (PIE)obs observed at the three highest concentrations
of the carboxylic acid catalyst, are reported in Table 1.
increased by ca. 20% during CH3CO2L catalyzed hydrolysis in
50/50 (v/v) HOH/DOD. We attribute the additional -D labeled
product at later reaction times to a competing acetate anion
catalyzed deuterium exchange reaction of 3,5-di-NO2-3. We
have therefore directly compared the rate constants for car-
boxylate anion catalyzed deuterium exchange reactions of
4-NO2-3 and 3,5-di-NO2-3 and for carboxylic acid catalyzed
protonation of 4-NO2-1 and 3,5-di-NO2-1 in 50/50 (v/v) HOH/
DOD (Table 3). This comparison shows that the ketone product
of hydrolysis of 3,5-di-NO2-1 catalyzed by Brønsted acids more
reactiVe than CH3CO2L or of hydrolysis of aryl vinyl ethers
more reactiVe than 3,5-di-NO2-1 is stable to exchange over
several half times of the vinyl ether hydrolysis reaction. For
example, kHA ) 2.8 × 10-4 M-1 s-1 for methoxyacetic acid
catalyzed hydrolysis of 3,5-NO2-1 in 50/50 (v/v) HOH/DOD
at 25 °C is 230-fold larger than kA ≈ 1.2 × 10-6 M-1 s-1 for
the methoxyacetate anion catalyzed deuterium exchange reaction
of 3,5-NO2-3.
The ratio of -H and -D labeled ketone products for the
methoxyacetic acid catalyzed hydrolysis of 3,5-NO2-1 (Table
S2) were determined after ca. one reaction half time, where
there can be no significant methoxyacetate acetate anion
catalyzed deuterium exchange reaction of the ketone product.
For example, only a 24 min reaction time was used for
hydrolysis of 3,5-NO2-1 in 50/50 (v/v) HOH/DOD that con-
tained 0.80 M MeOAcOH buffer ([HA]/[A-] ) 7/3) at 25 °C
(Table S2). A control experiment with 0.80 M MeOAcOH
buffer, at an even higher pL ([HA] ) 0.08 M, [A-] ) 0.72 M),
showed that only 12% of the R-CH3 groups of 3,5-NO2-3
underwent deuterium exchange after 2400 min. A second control
showed that identical values (PIE)obs ) 5.5 ( 0.1 were
determined for protonation of 3,5-NO2-1 in 0.80 M methoxy-
acetic acid buffer ([HA]/[A-] ) 9) at several times up 1230
min, which is 35 half times for the hydrolysis reaction (Table
S2).
[PH]L
(PIE)L )
(5)
(6)
(7)
[PD]L
[PH]LA
[PD]LA
(PIE)LA
)
[PH]L + [PH]LA
[PD]L + [PD]LA
(PIE)obs
)
Figure 3B shows that the value of (PIE)obs for protonation of
H-1 does not change significantly as [LA]T is increased from 0.16
to 0.64 M. This reflects the strong buffer catalysis of protonation
of H-1.24 PIEs on protonation of H-1 by carboxylic acids [(PIE)LA]
in 50/50 (v/v) HOH/DOD, determined as the average of the values
of (PIE)obs observed at the three highest concentrations of the
carboxylic acid catalyst, are reported in Table 1.
The general base catalyzed deuterium exchange reaction of
X-3 is normally much slower than the hydrolysis of X-1. For
42
example kA ) 7.9 × 10-7 M-1 s-1
for deprotonation of
acetophenone (H-3) by acetate anion in water, and the rate
constant for the deuterium exchange reaction of H-3 in 50/50
(v/v) HOH/DOD will be 4-5-fold smaller, because of the
discrimination isotope effect against protonation of the ac-
etophenone enolate by LOD in the mixed solvent. By compari-
son, rate constants kHA g 6.6 × 10-5 M-1 s-1 were reported for
protonation of X-1 in water.24
It would have been difficult to obtain a reliable value of
(PIE)LA for the relatively slow protonation of 3,5-di-NO2-1 by
CH3CO2L, because the apparent yield of the -D labeled product
(42) Hegarty, A.; Dowling, J.; Eustace, S.; McGarraghy, M. J. Am. Chem.
Soc. 1998, 120, 2290–2296.
Figure 4 shows the change in (PIE)obs with increasing
concentrations of carboxylic acid buffers for the hydrolysis of
4-NO2-1 (Figure 4A) and 3,5-di-NO2-1 (Figure 4B) in 50/50
(v/v) HOH/DOD at 25 °C. The second-order rate constants for
(43) Kresge, A. J.; Allred, A. L. J. Am. Chem. Soc. 1963, 85, 1541–1541.
(44) Gold, V. Proc. Chem. Soc., London 1963, 141–143.
(45) Jarret, R. M.; Saunders, M. J. Am. Chem. Soc. 1986, 108, 7549–7553.
9
13956 J. AM. CHEM. SOC. VOL. 131, NO. 39, 2009

Primary Deuterium Isotope Effects on Protonation
A R T I C L E S
Table 2. Second-Order Rate Constants for Acid-Catalyzed
Hydrolysis of X-1 and for the Base-Catalyzed Exchange of the
First R-CH3 Hydrogen of X-3 for Deuterium from Solventa
Table 3. Product Isotope Effects on Proton Transfer from Lyonium
Ion and Methoxyacetic Acid to Ring-Substituted
R-Methoxystyrenes in 50/50 (v/v) HOH/DOD at I ) 1.0 (KCl)
Determined for Reactions at Several Different Temperatures
b
c
kLA (M-1 s-1
)
kA (M-1 s-1
)
X-1
T (K)
acid
(PIE)La
acid
4-NO2
3,5-di-NO2
4-NO2
3,5-di-NO2
MeO-1
278
320
343
313
328
343
359
L3O+
L3O+
L3O+
L3O+
L3O+
L3O+
L3O+
9.1 ( 0.2b
6.9 ( 0.1c
5.9 ( 0.1c
6.5 ( 0.2b
6.0 ( 0.1b
5.6 ( 0.1b
5.2 ( 0.1b
L+
1.1
7.1 × 10-2
Cl2CHCOOL
CNCHCOOL
ClCH2COOL
2.0 × 10-2
2.3 × 10-2 1.4 × 10-3
3,5-di-NO2-1
1.7 × 10-2 9.45 × 10-4
d
g
e
MeOCH2COOL 4.6 × 10-3 2.8 × 10-4 3.7 × 10-7
1.2 × 10-6
f
CH3COOL
6.7 × 10-4 2.4 × 10-5 1.5 × 10-6
a For reactions in 50/50 (v/v) HOH/DOD at 25 °C and I ) 1.0 (KCl).
b Second-order rate constants for Brønsted acid catalyzed hydrolysis of
X-1 in 50/50 (v/v) HOH/DOD determined as the slope of a plot of 4-5
values of kobs against the concentration of the buffer acid catalyst, unless
noted otherwise. c Second-order rate constant for Brønsted base
catalyzed deprotonation of X-3 in 50/50 (v/v) HOH/DOD determined by
monitoring incorporation of deuterium into the R-CH3 group of the
ketone by 1H NMR. d Estimated from kobs ) 2.6 × 10-7 s-1 for the
reaction catalyzed by 0.80 M methoxyacetic acid buffer ([A-]/[AH] )
9). e Estimated from kobs ) 8.8 × 10-7 s-1 for the reaction catalyzed by
d
X-1
T (K)
acid
(PIE)AL
H-1
277
321
343
MeOCH2COOL
MeOCH2COOL
MeOCH2COOL
8.8 ( 0.3
6.4 ( 0.2
5.9 ( 0.1
a The PIE on lyonium ion catalyzed protonation of X-1 (eq 5). b The
average of the values of (PIE)obs (eq 2) determined for reactions at
several different [L3O+]. c Determined as described in text. d The
product isotope effect on methoxyacetic acid catalyzed protonation of
X-1 (eq 6), calculated as the average of four buffer independent values
0.80
M )
methoxyacetic acid buffer ([A-]/[AH] 9). f Calculated
assuming kAcO/kMeOAc ) 11 for protonation of 3,5-di-NO2 by acetic and
methoxyacetic acid is the same for reactions in HOH24 and in 50/50 (v/
v) HOH/DOD. g Calculated from kobs ) 1.1 × 10-6 s-1 ) kA/[A-] for
the reaction catalyzed by 0.80 M acetic acid buffer ([A-]/[AH] ) 9).
of (PIE)obs
.
(70% free base) between 3 and 12 mM. The increase in kobs for
hydrolysis, from 0.011 to 0.021 s-1 as the concentration of the
buffer is increased from 3 to 12 mM (Table S3), corresponds
to an increase from 30% to 65% in the contribution of the buffer
catalyzed pathway of the total reaction. The value of (PIE)obs
) (PIE)L ) 5.87 ( 0.03 determined for these reactions is
independent of buffer concentration (Table S3), so that the PIEs
on the lyonium ion and buffer catalyzed reaction are identical
within experimental error. A control experiment at 343 K with
the ketone 4-MeO-3 in 50/50 (v/v) HOH/DOD that contains
12 mM acetate buffer (70% free base) showed that there was
no detectable deuterium exchange over a period of 10 min,
which is 60 half times for the hydrolysis of 4-MeO-1 under
these conditions.
the lyonium ion and buffer catalyzed reactions in the same
solvent are reported in Table 2. The data in Table 2 show that
for many of these hydrolysis reactions both the lyonium ion
and buffer catalyzed pathways contribute to the observed
reaction rate constants. Now, the value of (PIE)obs decreases
with increasing concentrations of buffer, because (PIE)LA
<
(PIE)L. Table 1 reports the values of (PIE)LA for protonation of
4-NO2-1 and 3,5-di-NO2-1 by carboxylic acids that were
determined from the nonlinear least-squares fit of the data from
Figure 4A and 4B to eq 8, using the values of kL and kLA (M-1
s-1) from Table 2 and (PIE)L from Table 1, and treating (PIE)LA
as a variable parameter. The four terms in eq 8 correspond to
the normalized velocities for product formation by the four
pathways in eq 7 ([PH]L, [PD]L, [PH]LA, and [PD]LA, Scheme 2).
Product isotope effects on the reactions of 3,5-di-NO2-1 at
313, 328, 343, and 359 K at different [L3O+] are summarized
in Table S3. In all cases (PIE)obs is independent of [L3O+]. The
value of (PIE)L for lyonium ion protonation of 3,5-di-NO2-1 at
each temperature was calculated as the average of the values
(PIE)obs determined at four different [L3O+] (Table 3).
(PIE)L
(PIE)LA
kL[L+]
kL[L+]
+ kLA[LA]
(
)
)
(
)
)
1 + (PIE)L
1 + (PIE)LA
(PIE)obs
)
1
1
+ kLA[LA]
(
(
1 + (PIE)L
1 + (PIE)LA
The yields of the -H and -D labeled products formed after
ca. 10 half times of methoxyacetic acid catalyzed hydrolysis
of H-1 in 50/50 (v/v) HOH/DOD (I ) 1.0, KCl) and at several
different temperatures were determined by 1H NMR. The values
of (PIE)obs for experiments at 277 K ([MeOCH2CO2-]/
[MeOCH2CO2H] ) 9) are summarized in Table S4. The
experiments at 321 and 343 K were carried out at [A-]/[AH]
) 99 and using a constant concentration of 10 mM acetic acid
buffer to maintain pH. There is more than a doubling in kobs for
hydrolysis of H-1 at 321 and 343 K as ([MeOCH2CO2-] +
[MeOCH2CO2H]) is increased from 0.10 to 0.45 M but no
change in (PIE)obs ((3%) (Table S4). Therefore, there is no
detectable difference in the PIE for reactions catalyzed by the
different acids present in solution. The values of (PIE)AL reported
in Table 3 for methoxyacetic acid catalyzed hydrolysis of H-1
were calculated as the average of the values (PIE)obs determined
at four different ([MeOCH2CO2-] + [MeOCH2CO2H]) (Table S4).
Short reaction times of <5 min were used for the reaction at 343
K to guarantee that there was no base catalyzed exchange of
deuterium from solvent into product H-3.
(8)
The product isotope effect on protonation of 4-MeO-1 by
lyonium ion at 278 K, calculated as the average of the (PIE)obs
(Table S3) determined for reactions at four different [L3O+], is
reported in Table 3. The reactions of 4-MeO-1 at 319 K were
examined at four different low concentrations of acetic acid
buffer (40% free base) between 3 and 12 mM. The increase in
kobs for hydrolysis of 4-MeO-1, from 0.0104 to 0.0165 s-1 as
the buffer concentration is increased from 3 to 12 mM (Table
S3), corresponds to an increase from 20% to 50% in the
contribution of the buffer catalyzed pathway of the total reaction
with the remaining reaction being due to catalysis by L3O+.
The value of (PIE)obs ) (PIE)L ) 6.9 ( 0.1 was found to be
independent of buffer concentration (Table S3).We conclude
that the PIEs on the lyonium ion and buffer catalyzed reaction
are essentially identical, as was also observed for the acetic acid
catalyzed reaction at 298 K (Table 3).
The reactions of 4-MeO-1 at 343 K were examined in the
presence of four different concentrations of acetic acid buffer
9
J. AM. CHEM. SOC. VOL. 131, NO. 39, 2009 13957

A R T I C L E S
Tsang and Richard
Scheme 3
Scheme 4
4. Discussion
There is good evidence that protonation of X-1 to form X-2+
is effectiVely irreversible and the rate-determining step for the
hydrolysis of X-1 to form X-3.23,46-48 If so, then the PIEs
determined for the hydrolysis of X-1 are equal to the primary
isotope effects on protonation of these carbon bases. We have
examined the partitioning of X-2+ (Scheme 3) to quantify the
irreVersibility of protonation of these vinyl ethers. The value
of kAcO/ks ) 0.0011 M reported here for partitioning of 4-NO2-
2+ between deprotonation and addition of water (Scheme 3)
shows that 4-NO2-2+ formed as an intermediate of protonation
of 4-NO2-1 by acetic acid rarely returns to 4-NO2-1. A value
of kAcO/ks ) 0.0034 M has been reported for the partitioning of
H-2+,24 and kAcO/ks ) 0.0057 M for partitioning of 4-MeO-
By comparison, the values of (PIE)obs for protonation of X-1
determined by 1H NMR analysis are generally reproducible to better
than (2%. The precision of the measurements of the ratio of 1H
NMR peak areas is potentially better than (2%.50
2+may be calculated from ks ) 7 × 106 s-1 and kAcO ) 4.0 ×
24,48,49
104 M-1 s-1
.
The partitioning of 3,5-NO2-3+ was not
examined, because changes from electron-donating to electron-
withdrawing ring substituents at X-2+ cause kAcO/ks to decrease
(Vida infra), so that kAcO/ks < 0.0011 M for partitioning of this
oxocarbenium ion.
These data show that hydrolysis of 4-MeO-1 has the greatest
tendency toward reversibility. Return to alkene becomes more
significant with decreasing acidity of the acid catalyst, because
of a corresponding increase in the basicity of its conjugate base.
Even in the most unfavorable case for catalysis by acetic acid,
4-MeO-2+ returns to reactant only ∼3/1000 times that it is
generated by protonation of 4-MeO-1 by 1.0 M acetic acid
([AH]/A-] ) 1.0).
Isotope effects on hydron transfer from solvent or from Brønsted
acids that undergo fast hydron exchange with solvent can be
determined either as the ratio of rate constants (kH/kD) for reactions
in HOH and DOD (a KIE)23 or as the ratio of the hydrogen and
deuterium labeled products (eq 2) of reaction in 50/50 (v/v) HOH/
DOD (a PIE). The KIE on hydron transfer is generally simpler to
measure than the PIE, because the kinetic determination does not
require analytical methods to distinguish between -H and -D
labeled products. On the other hand, the uncertainty in second-
order rate constants kL is generally (5% so that the uncertainty in
the KIE determined from a rate constant ratio will be ca. (10%.
The interpretation of the PIEs determined in this work is simpler
than interpretation of earlier KIEs on the protonation of vinyl
ethers.23 The primary deuterium isotope effect and the secondary
solvent deuterium isotope effect both contribute to the magnitude
of the KIE determined from the rate constant ratio kH/kD for
reactions in HOH and DOD.51 By comparison, the PIE is obtained
from the yields of -H and -D labeled products from a reaction
in 50/50 (v/v) HOH/DOD and provides a direct measure of the
relative reactivity of these two isotopes in a common solvent.51
4.1. Catalysis by Lyonium Ion and by Brønsted Acids. The
value of (PIE)L or (PIE)AL (Table 1) for these Brønsted acid
catalyzed reactions is equal to the equilibrium constant for
exchange of -H and -D at the transition state for hydron
transfer in 50/50 (v/v) HOH/DOD (1/φTS, where φTS is referred
to as the fractionation factor) when x ) 0.50 for the mole
fraction of -D in solvent (eq 9).52,53 The value of 1/φTS defines
the relative stability of the -H and -D labeled transition states
compared to a common ground state of 50/50 (v/v) HOH/DOD.
The kinetic isotope effect (kAH/kAD) is defined by Eyring theory
as the ratio of equilibrium constants for conversion of the -H
and -D labeled Brønsted acids to the corresponding transition
(50) Singleton, D. A.; Thomas, A. A. J. Am. Chem. Soc. 1995, 117, 9357–
9358.
(46) Kresge, A. J.; Chen, H.-L.; Chiang, Y.; Murrill, E.; Payne, M. A.;
Sagatys, D. S. J. Am. Chem. Soc. 1971, 93, 413–423.
(47) Loudon, G. M.; Smith, C. K.; Zimmerman, S. E. J. Am. Chem. Soc.
1974, 96.
(51) Jencks, W. P. Catalysis in Chemistry and Enzymology; Dover
Publications: New York, 1987; pp 268-272.
(52) Kresge, A. J.; O’Ferrall, R. A. M.; Powell, M. F. In Isotopes in
Organic Chemistry; Buncel, E., Ed.; Elsevier: Amsterdam, 1987; pp
178-275.
(48) Richard, J. P.; Williams, K. B.; Amyes, T. L. J. Am. Chem. Soc. 1999,
121, 8403–8404.
(49) Young, P. R.; Jencks, W. P. J. Am. Chem. Soc. 1977, 99, 8238–8248.
(53) Schowen, R. L. Prog. Phys. Org. Chem. 1972, 9, 275–332.
9
13958 J. AM. CHEM. SOC. VOL. 131, NO. 39, 2009

Primary Deuterium Isotope Effects on Protonation
A R T I C L E S
states for protonation of X-1 (KA(H /KA(D, Scheme 4). Equation
10, derived from Scheme 4, shows that the KIE and the PIE
are simply related by the equilibrium constant 1/φAL for
exchange of -H and -D at the Brønsted acid (eq 11).52,53
[SH]((x)
[SD]((1 - x)
1/ΦTS ) (PIE)AL
)
(9)
kAH
kAD
K(AH
ΦAL
(KIE)AL
)
)
)
) ΦAL(PIE)AL
(10)
(11)
(
)
(
(
)
ΦTS
KAD
[AH](x)
[AD](1 - x)
1/ΦAL
)
Figure 5. (A) Arrhenius-type plots of (PIE)L for the protonation of
4-MeO-1 (9) and 3,5-di-NO2-1 (b) by lyonium ion in 50/50 HOH/DOD
at I ) 1.0 (KCl). (B) Arrhenius-type plot of (PIE)AL for protonation of H-1
by methoxyacetic acid in 50/50 HOH/DOD at I ) 1.0 (KCl).
Equations 9 and 10 show that the PIE is directly related to
the partitioning of -H and -D between a common ground state
of 50/50 (v/v) HOH/DOD and the transition state for hydron
transfer, while the KIE measures the relative barriers to moving
from -H and -D labeled Brønsted acids to the transition state.
The PIE and the KIE are different when the H/D enrichment of
the Brønsted acid catalyst is different from the enrichment of
solvent (φAL * 1.0, eq 10), as is the case for L3O+ catalyzed
state can be obtained using eq 12, where (φL O)2 ) 0.4843,44 is
the maximum SDIE for a product-like tran3sition state (R )
1.0).51,54 Substitution of SDIE ) 0.70 and (φL O+)2 ) 0.48 into
3
eq 12 gives R ) 0.48. This corresponds to a transition state
that is roughly at the midpoint between reactant L2O-L+ and
product L-O-L with respect to changes in the hydrogen-
bonding interactions between the solvent and the nonreacting
reactions (φAL ) φ ) 0.69).43,44 The value of (KIE)L for the
L3O
L3O+ catalyzed reaction provides a measure of the change in
the fractionation of -H compared with -D between 50/50 (v/
v) HOH/DOD at the reactant compared with the transition state.
Correction of the values of (PIE)L in Table 1 for the preferential
hydrons of L2O-L+
.
log(SDIE)
fractionation of -H from solvent to lyonium ion catalyst (φL O
3
R )
(12)
2
) 0.69) gives the values of (KIE)L reported in this table. Table
1 also reports values of (KIE)AL for protonation of X-1 by acetic
acid, calculated from the (PIE)AL and φAL ) 0.90 (eq 10).45
We will focus in this paper on the product isotope effects
(PIE)L and (PIE)AL, because their changes with changing reaction
driving force are due solely to changes in transition state
structure, as measured by 1/φTS. By comparison, the KIE
depends upon φAL for the reactant and φTS for the transition
state, so that changes in reactant φAL with changing driving force
will affect the KIE (eq 10). Note, for example, that the difference
between the KIEs for the lyonium ion catalyzed and the acetic
acid catalyzed reactions (Table 1) are partly due to the difference
in the fractionation factors for the two Brønsted acid catalysts.
4.2. Secondary Solvent Deuterium Isotope Effects. The rate
log(φL O
)
+
3
4.3. Temperature Dependence of PIEs. Figure 5A shows
Arrhenius-type plots of the PIEs for protonation of 4-MeO-1
and 3,5-di-NO2-1 in 50/50 (v/v) HOH/DOD. The following
slopes and intercepts were determined by linear least-squares
analysis of the data from Figure 5A: 4-MeO-1, slope of -[(Ea)H
- (Ea)D]/R ) 630 ( 30 K and intercept ln(AH/AD) ) -0.048 (
0.11; 3,5-di-NO2-1, slope of 590 ( 19 K and intercept -0.001
( 0.06 (the quoted errors are standard deviations). These give
values of [(Ea)H - (Ea)D] ) -1.25 and -1.17 kcal/mol and
(AH/AD) ) 1.00 and 0.95, respectively, for protonation of
4-MeO-1 and 3,5-di-NO2-1 by L2OH+ and L2OD+. Figure 5B
shows the linear Arrhenius-type plot of (PIE)AL for protonation
of H-1 by methoxyacetic acid in 50/50 (v/v) HOH/DOD,
constructed using data from Table 3. The slope of this plot is
-[(Ea)H - (Ea)D]/R ) 595 K ( 30, and the intercept is ln(AH/
AD) ) 0.02 ( 0.10. These give values of [(Ea)H - (Ea)D] )
-1.18 kcal/mol and (AH/AD) ) 1.02 for protonation of 4-H-1
by methoxyacetic acid.
constant ratio kH/kD ) 4.0 for L+ catalyzed hydrolysis of H-1
24
in pure HOH (kH ) 85 M-1 s-1
)
and in pure DOD (kH ) 21
M-1 s-1)30 at 25 °C and I ) 1.0 (KCl) reflects the total changes
in bonding at the transferred -L and the two “stationary” -L
of L3O+. The primary (KIE)L ) 5.7 for protonation of H-1 in
50/50 HOH/DOD (Table 1) shows that the zero-point energy
of the transferred -L is largely lost at this transition state (see
below), and, when combined with kH/kD ) 4.0, gives a value
of 4.0/5.7 ) 0.70 for the secondary solvent deuterium isotope
effect (SDIE) on this reaction. This solvent isotope effect
represents the contributions of bonding changes at the nonre-
acting hydrons to the ratio kH/kD ) 4.0. The isotope effect is
due to a tightening of the O-L bonds at these “nonreacting”
hydrons on proceeding from L2O-L+, where these O-L bonds
are weakened by strong hydrogen bonds to solvent, to a
transition state that has advanced toward product L-O-L that
forms weaker hydrogen bonds to solvent.51,54 A rough estimate
of the fractional progress R of the reactants toward the transition
The average value of [(Ea)H - (Ea)D] ) -1.2 kcal/mol
determined from these Arrhenius-type plots is remarkably close
to the value -1.21 kcal/mol for the difference in zero-point
energy for ground state hydrons at LO-H and LO-D (∆zpe),
calculated from “first principles” using eq 13,55 where νΗ
)
3400 is the IR stretching frequency for the LO-H bond56 and
νΗ/νD ) 1/1.35 is the ratio of stretching frequencies for LO-H
and LO-D bonds.55 This provides good evidence that most or
all of the zero-point energy of the solvent LO-L bond is lost
at the transition state for protonation of X-1 by Brønsted acids.
(55) Lowrey, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry; Harper & Row: New York, 1987; pp 233-236.
(56) O’Ferrall, R. A. M.; Koeppl, G. W.; Kresge, A. J. J. Am. Chem. Soc.
1971, 93, 1–9.
(54) Kreevoy, M. M.; Steinwand, P. J.; Kayser, W. V. J. Am. Chem. Soc.
1966, 88, 124–131.
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A R T I C L E S
Tsang and Richard
∆zpe ) -1/2hc(VH - VD) ) -1/2hc(1 - 1/1.35)VH (13)
4.4. PIE and Reaction Driving Force. Figures 3B, 4A, and
4B for the reactions of H-1, 4-NO2-1, and 3,5-di-NO2-1,
respectively, provide the following insight into the relationship
between the magnitude of the PIE and the reaction driving force.
The value of (PIE)L for catalysis by lyonium ion (y-intercept,
Figures 3 and 4) is generally equal to or larger than the value
of (PIE)obs ) (PIE)AL for reactions in the presence of large
concentrations of carboxylic acid catalysis, and the values of
(PIE)AL decrease with increasing catalyst pKa. This shows that
these PIEs generally decrease as the proton transfer reaction
becomes more unfavorable thermodynamically. On the other
hand, the difference between (PIE)L for catalysis by L3O+ and
(PIE)AL for catalysis by methoxyacetic acid increases as the
reactivity of the vinyl ether substrate is decreased by electron-
withdrawing ring substituents. For example, (PIE)L ) 8.2 and
(PIE)AL ) 7.6, respectively, for protonation of H-1 by L3O+
and methoxyacetic acid, while (PIE)L ) 7.3 and (PIE)AL ) 5.1
for protonation of 3,5-di-NO2-1 by the same two acids.
These trends are also shown in the logarithmic plot (Figure
6) of isotope effects against the change in the reaction standard
Gibbs free energy (∆G° ) -RT ln Keq, Scheme 5),24 where
the range of values of ∆G° on the x-axis is 16 kcal/mol.24 The
solid symbols in Figure 6 are PIEs, and the open symbols are
KIEs that were calculated from the PIE using eq 10. Note that
similar PIEs for reactions in 50/50 HOH/DOD are observed
for L+ and carboxylic acid catalyzed reactions of similar driving
force. This confirms that the difference in the KIEs determined
for protonation of X-1 by L+ and carboxylic acids in pure HOH
and DOD is due essentially entirely to the difference in
secondary solvent deuterium isotope effects on proton transfer
(see above).
Figure 6. Effect of changing thermodynamic driving force on the product
isotope effects (PIEs) and the kinetic isotope effects (KIEs) for protonation
of X-1 in 50/50 HOH/DOD at I ) 1.0 (KCl) to form the corresponding
oxocarbenium ion X-2+. The solid symbols show PIEs. Key: (b) protonation
of 4-MeO-1; (9) protonation of H-1; (1) protonation of 4-NO2-1; ([)
protonation of 3,5-di-NO2-1. The open symbols show the values of the
KIE for protonation of X-1 by lyonium ion.
Scheme 5
Scheme 6
Figure 6 shows that the maximum PIE of ca. 8.7 is observed
for the nearly thermoneutral (∆G° ) 1.0 kcal/mol) protonation
of 4-MeO-1 by Cl2CHCOOH. There is a falloff in this isotope
effect to 8.1 for thermodynamically favorable protonation of
4-MeO-1 by L3O+ and a falloff to 8.0 for protonation of H-1
by CNCH2COOH as the reaction becomes thermodynamically
favorable (∆G° ) 5.1 kcal/mol). The result is a broad region
that runs from ∆G° ) -2.8 kcal/mol to ∆G° ) 5.1 kcal/mol
where the change in PIE with changing reaction driving force
is relatively small (0.7 units). There is then a steeper change in
PIE with changing driving force, as shown by the decrease in
the (PIE)L ) 8.0 for protonation of H-1 by cyanoacetic acid to
(PIE)AL ) 5.1 for protonation of 3,5-di-NO2-1 by methoxyacetic
acid (Figure 4B) as ∆G° increases from 5.1 to 13.1 kcal/mol.
An isotope effect maximum at ∆G° ≈ 0 kcal/mol similar to
that shown in Figure 6 has been reported in earlier studies of
the KIEs on Brønsted base catalyzed deprotonation of -H and
-D labeled R-carbonyl carbon acids.57 The rate constant ratio
kH/kD for lyonium ion catalyzed hydrolysis of substituted vinyl
ethers in HOH and DOD also show a maximum at intermediate
reactivity.23 However, the values of ∆G° for these reactions
were not determined. The scatter in the earlier experimental data
is much greater than that for Figure 6, and this resulted in very
poorly defined isotope effect maxima. For example, nearly the
same value of kH/kD ) 2.6 is observed for specific acid catalyzed
hydrolysis of 4-methylene-1,3-dioxane (kH ) 6.5 M-1 s-1) and
methyl trans-propenyl ether (kH ) 0.072 M-1 s-1), despite the
ca. 100-fold difference in the second-order rate constants for
these reactions.23 The extensive scatter in these earlier plots of
KIE against reaction driving force represents partly or entirely
the very large structural diversity of reactants in comparison
with structurally homologous substrates X-1.
The complete equations for kinetic isotope effects published
by Bigeleisen and Mayer58 can be used to rationalize both small
and large kinetic isotope effects and changes in these isotope
effects.59 Two explanations have been proposed to explain the
changes in the primary kinetic isotope effect responsible for
bell-shaped plots of primary isotope effects against reaction
driving force and the centering of the isotope effect maximum
on ∆G° ) 0.25
(1) The change in the primary isotope effect may reflect a
change in the fraction of the zero-point energy of the reactant
A-H bond that is maintained in the symmetrical stretching
vibration at the transition state (Scheme 6), as described by
Melander and Westheimer.26,27 Equal force constants for the
partial bonds of A and B to -L are expected at the transition
state for thermoneutral proton transfer (∆G° ) 0, Scheme 6),
so that there should be no net movement of -L associated with
this symmetrical stretch and no effect of -H for -D substitution
on this stretching frequency. Hammond-type movement of
hydron -L toward the acid catalyst or base acceptor will be
observed,60 respectively, for a change to thermodynamically
(58) Bigeleisen, J.; Mayer, M. G. J. Chem. Phys. 1947, 15.
(59) Bigeleisen, J.; Wolfsberg, M. AdV. Chem. Phys. 1958, 1, 15–76.
(60) Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334–338.
(57) Bell, R. P. The Proton in Chemistry, 2nd ed.; Cornell University Press:
Ithaca, NY, 1973; p 265.
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Primary Deuterium Isotope Effects on Protonation
A R T I C L E S
Figure 7. A reaction, where proton transfer from the carboxylic acid to the carbon base to form an ion pair, is followed by full solvation of the anion with
a value of Rsolv ) -0.20.64 The effective negative charge at the product complex (1 - Rsolv ) 1.2) is used to obtain a normalized Brønsted parameter Rnor
;
Rnor ) Robs/(1 - Rsol) which provides a more realistic measure of the position of the transition state relative to the ion-pair product complex. This scale has
been constructed so the overall change in charge at the carboxylic acid on proceeding from reactants to the fully solvated product carboxylate anion is Req
) 1.0.
Scheme 7
favorable hydron transfer (∆G° , 0, Scheme 6), where the
hydron is bonded most tightly to A, or to thermodynamically
unfavorable transfer (∆G° . 0) where the hydron is bonded
most tightly to B. In both cases, a part of the zero-point energy
of the reactant A-L bond is maintained at the symmetrical
stretching vibration, which will show a larger frequency for the
light isotope -H compared with -D.
There is a Hammond effect on protonation of X-1 by
substituted carboxylic acids. This results in a 0.10 unit increase
in the Brønsted parameter R for catalysis by carboxylic acids
as the thermodynamic barrier for proton transfer is increased
by 9 kcal/mol by changing the substituent at X-1 from 4-MeO-
to 3,5 di-NO2.24 This Hammond-type shift in the position of
the reaction transition state provides a simple explanation for
the decrease in the PIE with the increasing thermodynamic
barrier to proton transfer.
extrapolation of ln PIE to 1/T ) 0 would give a positiVe
y-intercept.61-63 We conclude that protonation of X-1 by
Brønsted acids in water appears to proceed mainly by a
mechanism where the reactions of both -H and -D pass over
a maximum on the potential energy surface, instead of tunneling
through the energy barrier.
(2) It has been proposed that the contribution of tunneling
increases with the size of the tunneling cross section and that
this cross section is a maximum for thermoneutral hydron
transfer, but decreases in size as ∆G° for proton transfer
becomes either positive or negative.25 This would cause the
isotope effect to change from a large tunneling-enhanced value
for thermoneutral proton transfer to the smaller values for wholly
activation-limited thermodynamically favorable or unfavorable
proton transfer.
The value of [(Ea)H - (Ea)D] ) -1.2 kcal/mol calculated from
the slopes of the Arrhenius-type plots shown in Figure 5 is
roughly equal to the difference in the zero-point energy of the
ground-state LO-L bond. This is consistent with a reaction in
which the zpe of the hydron is lost at the potential energy
maximum for the transition state. The ratio of (AH/AD) ) 1.0
for the preexponential factors is also consistent with a semiclas-
sical model for proton transfer, where the rate constants for
reaction of A-H and A-D approach the same limiting value
at very high temperatures. The ratio of (AH/AD) ) 1.0 is
inconsistent with a reaction in which there is significant quantum
mechanical tunneling of the light, but not the heavy isotope.61-63
In this case, there should be a sharp increase, with increasing
T, in the rate of the activation-limited reaction of A-D relative
to the rate of the (partly) tunneling-limited reaction of A-H.
This would give rise to a sharp decrease in the PIE with
increasing T, so that extrapolation of the ln PIE to 1/T ) 0
would show a negatiVe y-intercept. A unit ratio for the
preexponential term is also inconsistent with significant tun-
neling for the reactions of both -H and -D. The isotope effect
on a reaction where both isotopes tunnel through the barrier
will show a small or negligible temperature dependence, so that
4.5. Structure-Reactivity Relationships. The primary deu-
terium isotope effect maximum observed for thermoneutral
protonation of X-1 is consistent with a transition state for proton
transfer in which the hydron remains stationary during the
symmetrical stretch shown in Scheme 6.26,27 This corresponds
to a transition state in which bond cleavage at the carboxylic
acid and bond formation to carbon are each ca. 50% of that
observed for the overall proton transfer reaction (Figure 7).
By comparison, the structure reactivity parameters R ) 0.66
and ꢀ ) 0.58 (Scheme 7)24 estimated for thermoneutral
protonation of X-1 by substituted carboxylic acids are signifi-
cantly greater than the values of R ) ꢀ ) 0.50 predicted by
simple Marcus theory.6,65 These Brønsted parameters are
consistent with the development of an effective transition state
charge of -0.66 at the carboxylic acid catalyst and of +0.58 at
the carbon acid base,66,67 where the charges are normalized
relative to values of -1 for the ionization substituted carboxylic
acid and +1 for protonation of X-1 to form the oxocarbenium
ion X-2+.
(61) Kohen, A. In Isotope Effects in Chemistry and Biology; Kohen, A.,
Limbach, H.-H., Eds.; Taylor & Francis: New York, 2006; pp 743-
764.
(62) Kohen, A.; Klinman, J. P. Acc. Chem. Res. 1998, 31, 397–404.
(63) Kwart, H. Acc. Chem. Res. 1982, 15, 401–408.
(64) Jencks, W. P.; Haber, M. T.; Herschlag, D.; Nazaretian, K. L. J. Am.
Chem. Soc. 1986, 108, 479–483.
(65) Marcus, R. A. J. Phys. Chem. 1968, 72, 891–899.
(66) Hupe, D. J.; Jencks, W. P. J. Am. Chem. Soc. 1977, 99, 451–464.
(67) Williams, A. AdV. Phys. Org. Chem. 1992, 27, 1–55.
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A R T I C L E S
Tsang and Richard
We propose that there is a balanced transition state for proton
transfer, as suggested by the position of the isotope effect
maximum, and that the Brønsted structure-reactivity parameter
R (Scheme 7) overestimates the fractional proton transfer from
the acid catalyst. This would be the case if the total change in
effectiVe charge on proceeding from free reactants to the ion
pair product complex is greater than the change of -1.0 assumed
for ionization of carboxylic acids in water,64 and if solvation
of the developing carboxylate anion (Ksol, Figure 7) lags behind
proton transfer to the carbon base.4,5,68 This is shown in Figure
7, where formation of hydrogen bonds between solvent and the
carboxylate anion reduces the charge at the oxygen anion, so
that Ksol for anion solvation increases with increasing pKa of
the carboxylic acid catalyst. A value of Rsol ) -0.20 has been
estimated for conversion of complexes between substituted
quinuclidines and activated phosphate monoesters (e.g., 2,4-
(R ) 0.66, Scheme 7) would be only slightly greater than 50%
of the total charge of 1.2 at the product complex: Rnor ) Robs/(1
- Rsol) ) 0.66/1.20 ) 0.55. This is closer to the value 0.50
predicted by Marcus theory for a thermoneutral proton transfer
reaction.
4.6. Computational Studies. We have compared these ex-
perimentally determined isotope effects with isotope effects
calculated using a novel approach based on Kleinert’s variational
perturbation theory within the framework of Feynman path
integrals.20-22 There is generally good agreement between the
results of experiments and calculations, and the computational
results provide additional deeper insight into the origin of these
primary isotope effects.
Acknowledgment. This paper is dedicated to Yvonne Chiang
and A. Jerry Kresge. We acknowledge the National Institutes of
Health (GM 39754) for generous support of this work.
dinitrophenyl phosphate) to the free solvated quinuclidine.64
A
similar value of Rsol ) -0.20 for formation of hydrogen bonds
Supporting Information Available: Table S1-S4 of observed
product isotope effects, (PIE)obs, for reactions of X-1 in 50/50
(v/v) HOH/DOD that contains different concentrations of
lyonium ion or Brønsted acid catalysts, and at different reaction
temperatures. This material is available free of charge via the
Internet at http://pubs.acs.org.
to the carboxylate anion would give a total absolute effectiVe
-
charge of (1 - Rsol) ) 1.20 at RCO2 in the ion-pair complex
(Figure 7).65 In this case, the effectiVe change in charge at the
carboxyl(ate) oxygen on moving from reactant to transition state
(68) Bernasconi, C. F.; Wiersema, D.; Stronach, M. W. J. Org. Chem. 1993,
58, 217–223.
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