δ-deuterium isotope effects as probes for transition-state structures of isoprenoid substrates

Article abstract of DOI:10.1021/jo500394u

The biosynthetic pathways to isoprenoid compounds involve transfer of the prenyl moiety in allylic diphosphates to electron-rich (nucleophilic) acceptors. The acceptors can be many types of nucleophiles, while the allylic diphosphates only differ in the number of isoprene units and stereochemistry of the double bonds in the hydrocarbon moieties. Because of the wide range of nucleophilicities of naturally occurring acceptors, the mechanism for prenyltransfer reactions may be dissociative or associative with early to late transition states. We have measured δ-secondary kinetic isotope effects operating through four bonds for substitution reactions with dimethylallyl derivatives bearing deuterated methyl groups at the distal (C3) carbon atom in the double bond under dissociative and associative conditions. Computational studies with density functional theory indicate that the magnitudes of the isotope effects correlate with the extent of bond formation between the allylic moiety and the electron-rich acceptor in the transition state for alkylation and provide insights into the structures of the transition states for associative and dissociative alkylation reactions.

Full text of DOI:10.1021/jo500394u

Article
pubs.acs.org/joc
δ‑Deuterium Isotope Effects as Probes for Transition-State Structures
of Isoprenoid Substrates
Seoung-ryoung Choi,† Martin Breugst,‡,§ Kendall N. Houk,‡,* and C. Dale Poulter*,†
†Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
‡Department of Chemistry & Biochemistry, University of California, 607 Charles E. Young Drive East, Los Angeles, California 90095,
United States
S
* Supporting Information
ABSTRACT: The biosynthetic pathways to isoprenoid
compounds involve transfer of the prenyl moiety in allylic
diphosphates to electron-rich (nucleophilic) acceptors. The
acceptors can be many types of nucleophiles, while the allylic
diphosphates only differ in the number of isoprene units and
stereochemistry of the double bonds in the hydrocarbon
moieties. Because of the wide range of nucleophilicities of
naturally occurring acceptors, the mechanism for prenyltrans-
fer reactions may be dissociative or associative with early to
late transition states. We have measured δ-secondary kinetic
isotope effects operating through four bonds for substitution
reactions with dimethylallyl derivatives bearing deuterated
methyl groups at the distal (C3) carbon atom in the double
bond under dissociative and associative conditions. Computational studies with density functional theory indicate that the
magnitudes of the isotope effects correlate with the extent of bond formation between the allylic moiety and the electron-rich
acceptor in the transition state for alkylation and provide insights into the structures of the transition states for associative and
dissociative alkylation reactions.
of a proton and inorganic pyrophosphate (PPi).3−5 The allylic
substrates belong to a series of isoprenoid homologues, where n
INTRODUCTION
■
Isoprenoid compounds form the largest and most structurally
diverse family of molecules found in nature. Currently, over
= 0−4 is most common. The acceptors can be carbon−carbon
double bonds, aromatic rings, hydroxyl groups, carboxylate
60000 isoprenoid metabolites have been discovered and
characterized.1 They perform numerous important biological
groups, amines, and thiols/thiolates. While the allylic moiety is
normally attached to the acceptor through C1 as shown in
functions in cells, including electron transport during redox
Scheme 1 (normal prenylation), attachment through C3
reactions (respiratory quinones), defense by plants and animals
(reverse prenylation) is sometimes observed.6,7 Isoprenoid
(sesquiterpenes, diterpenes, monoterpenes, isoprenoid thiols),
cyclases catalyze intramolecular versions of the prenyltransfer
development and reproduction (juvenile hormones, sterols,
reaction, where the electron-rich partner is a distal double bond
pheromones), photoprotection and vision (carotenoids),
membrane structure (cholesterol, farnesylated proteins), and
cell signaling (farnesylated and geranylgeranylated proteins).
in the allylic substrate.
A variety of approaches have been used to investigate the
mechanisms for prenyl transfer. The most extensively studied
Isoprenoid molecules are deeply integrated into cellular
reactions are chain elongations and cyclizations, where the
function and are apparently required for life by all organisms
except for a small family of highly symbiotic bacteria.2
electron-rich acceptor is a carbon−carbon double bond. Early
on, chemists recognized that the biosynthetic reactions leading
to the large variety of acyclic and cyclic isoprenoid carbon
skeletons found in nature could most easily be rationalized as
alkylations of carbon−carbon double bonds by allylic
carbocations.8−10 Initially, associative reactions were proposed
to account for the high degree of stereoselectivity typically
observed for prenyltransfer reactions,11,12 although it is now
recognized that stereoselectivity is a poor tool for distinguishing
Prenyltransfer reactions are the key building steps for
biosynthesis of isoprenoid metabolites. They involve addition
of an electrophilic allylic isoprenoid diphosphate to an electron-
rich acceptor (A, see Scheme 1) with concomitant elimination
Scheme 1. Prenyltransfer Reaction
Received: February 19, 2014
Published: March 25, 2014
© 2014 American Chemical Society
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between concerted and stepwise mechanisms for enzyme-
catalyzed reactions because the positions and conformations of
substrates are highly ordered within an enzyme−substrate
complex.
RESULTS
■
Kinetic and Product Studies. Dissociative Nucleophilic
Substitution. Secondary δ-deuterium KIEs (δ-DKIE) were
determined for solvolysis of (E)-crotyl 2,4-dimethoxybenzene-
sulfonates (1H-ODBS, 1D-ODBS), (E)-crotyl bromides (1H-
Br, 1D-Br), and 3,3-dimethylallyl bromides (2H-Br, 2D-Br,
2D2Br) in ionizing solvents under dissociative conditions
(Figure 1). Rates were measured in triplicate by monitoring
Linear free energy (LFE) correlations and product studies
with alternate substrates for chain elongation prenyltransferases
indicate that the reactions are dissociative.13,14 While the LFE
approach can provide important insights about mechanism, the
technique requires the use of substrate analogues whose
structures and binding interactions are different from those of
the normal substrates. It is sometimes difficult to disentangle
the effects of changing the structure of a substrate on binding
and release of products from those on the chemical step. In the
case of dimethylallyl tryptophan synthase, which catalyzes
alkylation of the weakly nucleophilic indole nucleus in
tryptophan by dimethylallyl diphosphate, LFE studies were
consistent with an associative mechanism with a late transition
state where substantial positive charge has developed in the
dimethylallyl unit.15 However, Tanner and co-workers recently
reported secondary α-deuterium kinetic isotope effect (α-
DKIE) and positional isotope exchange experiments with
labeled dimethylallyl diphosphate that support a dissociative
mechanism with formation of a dimethylallyl/pyrophosphate
ion pair in the active site of the enzyme.16 Protein farnesyl
transferase (PFTase) catalyzes alkylation of a cysteine thiol in
C-terminal four amino acid recognition motifs. Mechanistic
studies suggest an associative reaction with a late transition
state. Evidence for an associative process includes inversion of
configuration at C1 of FPP and sensitivity to the nature of the
thiolate nucleophile.17,18 LFE studies with fluorinated analogues
of FPP provide evidence for an electrophilic alkylation but do
not distinguish between associative and dissociative transition
states.19 More recently, Fierke and co-workers20 and Distefano
and co-workers21 reported primary 13C−O and secondary α-
deuterium KIEs for labeled farnesyl diphosphate that support
an associative reaction with a late transition state.
The electron-rich acceptors in prenyltransfer reactions range
from weakly nucleophilic carbon−carbon double bonds to
powerfully nucleophilic thiolates. As the nucleophilicity of the
acceptor increases, one would anticipate that the prenyltransfer
reaction shifts from a dissociative to an associative mechanism
with a concomitant decrease in the development of positive
charge in the allylic moiety as the nucleophilicity of the
acceptor increases.22 The allylic diphosphate substrates for all
prenyltransfers have a methyl group at C3, which we thought
could be used as a useful probe for evaluating the structures of
the transition states of the reactions. Substitution of the distal
CH3 group in (E)-2-chloro-3-pentene by CD3 results in a 13%
KIE during solvolysis in 95% aqueous ethanol.23 This δ-
secondary KIE is in accord with a transition state with
substantial development of positive charge at the distal allylic
carbon in the developing carbocation in a dissociative solvolysis
reaction. In the dimethylallyl cation the magnitude of the KIE
should scale with the amount of positive charge that develops at
C3 in an associative reaction and approach 0 as the transition
state shifts from late to early. The remote location of the
isotope and the magnitude of the KIE suggest that CD3-
substituted allylic diphosphates should be excellent probes of
transition state structures in prenyltransfer reactions. We now
report kinetic and computational studies of δ-deuterium KIEs
for allylic systems under dissociative and associative reaction
conditions that confirm the predictive value of this approach.
Figure 1. Allylic dimethoxybenzenesulfonates and bromides.
changes in UV absorbance for the dimethoxybenzenesulfonates
and in conductivity for the bromides. First-order rate constants
were determined by fitting the data to a simple exponential
decay, A = A0e−kt, where A is UV absorbance or conductivity, t
is time (seconds), and k is the first-order rate constant. The
kinetic data are summarized in Table 1.
An average δ-DKIE of 1.127 was determined for solvolysis of
1H/D-ODBS in six different solvents. These results are
consistent with an increase in hyperconjugation of the methyl
hydrogens with the π system as positive charge develops at C3
in the transition state for heterolysis of the C1−leaving group
bond. In contrast δ-DKIE = 1.055 was determined for solvolysis
of (E)-crotyl bromide in 80/20 H2O/acetonitrile (v/v). Thus,
the magnitude of the isotope effect decreased by 57% when the
dimethoxybenzenesulfonyl leaving group in 1-ODBS was
replaced by bromide. Average δ-DKIEs of 1.081 for 2H/D-Br
and 1.206 for 2H/D2-Br were determined in five different
solvents. Small variations were seen for the KIEs measured in
different highly ionizing solvents.
Associative Nucleophilic Substitution. δ-DKIEs were
determined for nucleophilic substitution with 1H/D-ODBS
and tetraethylammonium cyanide in DMF. Rates were
measured under pseudo-first-order conditions at fixed concen-
trations of 1H/D-ODBS and different concentrations of
cyanide. Values for the pseudo-first-order rate constants are
given in Table 2. The average δ-DKIE for kobs determined at six
different cyanide concentrations was 1.013. Second-order rate
constants kH = (7.32 0.05) × 10−2 M−1 s−1 and kD
=
CN
CN
(7.23 0.05) × 10−2 M−1 s−1 were determined from the slopes
of plots of kobs versus [CN−] according to eq 1. Values for the y
intercepts (kH0 and kD ) were essentially zero, as expected for a
0
strongly associative reaction.
kobs = k0 + kCN[CN−]
(1)
A single substitution product, (E)-pent-3-enenitrile, indicated
that nucleophilic attack by CN− occurred at C1.
Computational Studies. In order to understand the
observed isotope effects, density functional theory calculations
were conducted employing three different dispersion-corrected
functionals, B3LYP-D2,24−26 M06-2X,27 and ωB97X-D.28 As
solvent mixtures cannot be adequately modeled with
Gaussian09, we used the major component of the mixtures,
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Table 1. Secondary δ-Deuterium Isotope Effects for Dissociative Solvolysis of Allylic Derivatives
a
b
substrate
solvent
T (°C)
kH (10−3 s−1
)
kD (10−3 s−1
)
kH/kD
1H/D-ODBS
30W70AN
40W60AN
50W50AN
TFE
22.5
22.5
22.5
22.5
22.5
22.5
2.011 0.095
4.569 0.179
14.22 0.30
6.384 0.368
7.184 0.386
2.186 0.196
1.794 0.072
4.015 0.137
12.96 0.03
5.573 0.286
6.432 0.354
1.914 0.204
1.121 0.011
1.138 0.010
1.097 0.006
1.146 0.007
1.117 0.007
1.142 0.010
5W95TFE
20W80ET
1H/D-Br
2H/D-Br
80W20AN
25
1.651 0.012
1.566 0.006
1.055 0.003
30W70AN
40W60AN
30W70ET
5W95TFE
30W70TFE
25
25
25
25
10
15.39 0.29
72.39 1.37
17.59 0.02
39.88 0.66
35.01 0.59
14.21 0.01
65.93 0.73
16.22 0.10
37.06 0.38
32.98 0.12
1.084 0.007
1.098 0.008
1.084 0.002
1.076 0.007
1.061 0.006
2H/D2-Br
30W70AN
40W60AN
30W70ET
5W95TFE
30W70TFE
25
25
25
25
10
15.39 0.29
72.39 1.37
17.59 0.02
3.88 0.66
12.77 0.03
57.68 0.63
14.85 0.22
33.43 0.20
29.42 0.20
1.205 0.008
1.255 0.009
1.185 0.006
1.193 0.007
1.190 0.007
35.01 0.59
a
b
Abbreviations: AN, acetonitrile; W, water, ET, ethanol; TFE: 2,2,2-trifluoroethanol. Errors were propagated from standard deviations for the rate
constants according to ref 64.
Table 2. Pseudo-First-Order Rate Constants for Associative
Reactions of 1H/D-ODBS in DMF at 22.5 °C
Scheme 2. Dissociative Nucleophilic Substitution of 1H/D-
ODBS, 1H/D-Br, and 2H/D/D2-Br
Et4NCN (mM) kH (10−3 s−1
)
kD (10−3 s−1
)
kH/kD
obs
obs
100
120
140
160
180
240
6.579 0.123
6.607 0.105
8.519 0.104
9.673 0.161
10.90 0.27
12.56 0.21
16.92 0.06
0.996 0.004
1.016 0.003
1.005 0.005
1.036 0.005
1.023 0.003
1.005 0.003
1.013 0.004 (av)
8.654 0.103
9.724 0.216
11.29 0.22
12.86 0.07
17.01 0.09
i.e., acetonitrile and dimethylformamide for the SN2-type
reactions and acetonitrile, ethanol, and trifluoroethanol as
well as water for the SN1-type reactions, for these calculations.
Regardless of the computational method employed, almost
identical isotope effects have been calculated in all cases. The
same isotope effects were calculated from scaled and unscaled
harmonic frequencies, and (for SN2 reactions) they were
identical within rounding errors with those determined with the
QUIVER program.29 The Bell tunneling correction predicts
that tunneling is not important for these transformations, all of
which involve only secondary isotope effects. Additionally,
variation of the solvent (26.7 < ε < 78.4) resulted in the same
barriers and isotope effects. For the sake of clarity, we only
discuss values obtained with B3LYP-D2 in the following, as
those numbers were closest to the experimental data (see the
Supporting Information for other data).
Dissociative Nucleophilic Substitution. To better under-
stand the experimentally observed kinetic isotope effects, we
investigated the dissociation reactions of 1H-ODBS, 1H-Br,
and 2H-Br computationally (Scheme 2). The dissociations
were calculated to be endergonic (21.8 kcal mol−1 for 1H-
ODBS, 25.8 kcal mol−1 for 1H-Br, and 19.7 kcal mol−1 for 2H-
Br in pure acetonitrile). While the 4 kcal mol−1 difference
between the crotyl sulfonate (1H-ODBS) and bromide (1H-
Br) can be attributed to the better stabilization of the negative
charge in the sulfonate anion in comparison to bromide, the
smaller endergonicity for the dissociation of 3H can be
rationalized by the greater stability of the dimethylallyl cation
4H in comparison to the crotyl analogue 3H.
In general, the calculated bond lengths within the allyl
cations 3H and 4H were very similar. The slightly elongated
C−H bonds within the methyl groups (1.103 vs 1.090 for 3H
and 1.106 vs 1.093 for 4H; see Figure S27 in the Supporting
Information) reflect the stabilization of the allyl cations via
hyperconjugation. According to a natural population analysis,
the overall stabilizing contribution arising from all C−H−π*
interactions in the dimethylallyl cation 4H is twice the value
found for the crotyl cation 3H (4H, 40 kcal mol−1; 3H, 21 kcal
mol−1).
Additionally, we calculated the charge distribution within the
allyl cations 3H and 4H with a variety of methods (ChelpG,
Merz−Singh−Kollman, Hirshfeld, natural bond order (NBO),
and atoms in molecules (AIM); see the Supporting Information
for all numbers) as well as an electrostatic potential (Figure 2).
While the absolute values deviate, all methods employed in this
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isotope effects for the dissociative nucleophilic substitution of
crotyl sulfonates (1H/D-ODBS) are compared in Table 3.
Table 3. Calculated Equilibrium Isotope Effects for the
a
Dissociation of 1H/D-ODBS
Solvent
KH/KD (calcd)
kH/kD (exptl)
b
acetonitrile
ethanol
TFE
1.18
1.18
1.18
1.19
1.121 0.011
1.142 0.010
1.146 0.007
c
water
a
b
B3LYP-D2/6-31+G(d,p)/IEFPCM, various solvents, 25 °C. In
c
30W70AN. In 20W80ET.
Both values are in qualitative agreement and reflect the change
in hybridization and hyperconjugation of the cation occurring
in the reactions. The slight overestimation of the isotope effects
can be rationalized by the fact that the transition state for the
dissociation is close to but not identical with the free crotyl
cation.
Figure 2. Calculated electrostatic potentials for the cations 3H and 4H
(B3LYP-D2/6-31+G(d,p)/IEFPCM(acetonitrile)).
Tables 4 and 5 summarize the calculated equilibrium isotope
effects and the experimentally determined δ-DKIEs for the
study show that a large positive charge is located on the carbon
atoms 1 and 3 in both allyl cations 3H and 4H. The calculated
electrostatic potential as well as charges calculated with the
ChelpG and Merz−Singh−Kollman formalism reveal that a
larger positive charge is present at the C-3 atom for both
cations. Both the optimized geometries and the charges are
consistent with the predominance of resonance structures with
the positive charge located on the more substituted allylic
terminus.
Table 4. Calculated Equilibrium Isotope Effects for the
Dissociation of 1H/D-Br
a
solvent
KH/KD (calcd)
kH/kD (exptl)
acetonitrile
water
1.17
1.17
b
1.055 0.003
a
b
B3LYP-D2/6-31+G(d,p)/IEFPCM, various solvents, 25 °C. In
Regardless of the type of computation employed, no SN1-
type transition states could be located on the potential energy
surfaces for the C−O/Br bond cleavages in 1H-ODBS, 1H-Br,
and 2H-Br. Relaxed potential energy surface scans resulted in
barrierless combinations of the sulfonates or bromides and the
allylic cations in all cases, which can be attributed to the high
electrophilicities of the allylic cations 3H and 4H.30,31 As the
dissociation of 1H-ODBS, 1H-Br, and 2H-Br should occur
with very late transition states according to the Leffler−
Hammond postulate,32,33 the free allylic cations 3H and 4H
were considered as transition state analogues. The calculated
reaction free energy (ΔG = 21.8 kcal mol−1 in pure acetonitrile)
for the dissociation of the crotyl sulfonate 1H-ODBS is almost
identical with the experimental activation free energy (k1 = 2.01
× 10−3 s−1; ΔG⧧ = 21.1 kcal mol−1 in 30% aqueous
acetonitrile). The same agreement is also found for prenyl
bromide (2H-Br). In contrast, the reaction free energy for the
dissociation of crotyl bromide (1H-Br) was calculated to be
slightly higher (ΔG⧧ = 23.8 kcal mol−1 in pure water) in
comparison to the experimental value (ΔG⧧ = 21.3 kcal mol−1
in 80% aqueous acetonitrile), which could indicate a partial SN2
contribution in these reactions. However, in all cases, the
calculated equilibrium isotope effects should constitute an
upper limit for the kinetic isotope effects determined
experimentally.
80W20AN.
Table 5. Calculated Equilibrium Isotope Effects for the
a
Dissociation of 2H/D/D2-Br
KH/KD (calcd)
kH/kD (exptl)
solvent
2D-Br 2D2-Br
2D-Br
2D2-Br
b
b
c
acetonitrile
trifluoroethanol
ethanol
1.12
1.13
1.14
1.13
1.26
1.27
1.28
1.28
1.084 0.007
1.076 0.007
1.084 0.002
1.205 0.008
1.193 0.007
1.185 0.006
c
d
d
water
a
b
B3LYP-D2/6-31+G(d,p)/IEFPCM, various solvents, 25 °C. In
c
d
30W70AN. In 5W95TFE. In 30W70ET.
dissociative nucleophilic substitution of the crotyl and
dimethylallyl bromides. Similar equilibrium isotope effects
have been calculated for crotyl bromide (Table 4) and crotyl
sulfonate (Table 3), while slightly smaller values have been
obtained for dimethylallyl bromide. The experimentally
determined kinetic isotope effect for 1H/D-Br is only 32% of
that for the corresponding sulfonate, indicating that the free
allylic cation is no longer a good approximation for the bromide
The equilibrium isotope effects calculated from the free
crotyl cation 3H and the experimentally determined kinetic
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Figure 3. Calculated transition state, selected bond lengths (in Å), and calculated electrostatic potential for the SN2 reaction of cyanide and 1H-
ODBS [B3LYP-D2/6-31+G(d,p)/IEFPCM(DMF), 25 °C].
transition state. Differences between experimental and
calculated KIEs for 2H/D-Br and 2H/D2-Br of approximately
63% and 72%, respectively, reflect a later transition state for
dissociation of the dimethylallyl bromides.
DISCUSSION
■
Structures of transition states for enzyme-catalyzed reactions
can provide important clues for the rational design of potent
inhibitors.34 Kinetic isotope effects give information about the
reorganization of bonds as substrates are transformed into
products and, in combination with ab initio computations,
provide estimates of charge densities and bond lengths at the
transition state. Typically, KIE experiments measure primary
(bond breaking) and α-secondary (bond bending), or β-
secondary (hyperconjugation) effects. In 1968, Jewett and
Dunlop23 observed an unusually large 13% δ-DKIE for
solvolysis of (E)-2-chloro-3-pentene, where the heavy isotope
was separated from the reaction center by four bonds. They
attributed the KIE to hyperconjugation of developing positive
charge at C3 with hydrogen/deuterium atoms in the attached
methyl group. For electrophilic reactions, their results suggest
that a maximal δ-DKIE will be observed for a dissociative
reaction, which proceeds through a carbocationic intermediate,
and a minimal value, for an associative reaction with an early
transition state.
We measured δ-DKIEs for dissociative and associative
displacement reactions of (E)-crotyl and dimethylallyl deriva-
tives (see Table 1). The dissociative reactions exhibited simple
first-order kinetic behavior, and the associative reactions
showed simple pseudo-first-order behavior when run in a
large excess of added nucleophile. Replacing a single CD3 group
at C3 gave δ-DKIEs from 5.5% to 14.7% for (E)-crotyl and
dimethylallyl derivatives. In contrast, the δ-DKIE for
nucleophilic substitution of (E)-crotyl dimethoxybenzenesulfo-
nate by cynanide in DMF was ∼1%. These observations are
consistent with the original proposal by Jewett and Dunlap23
that the δ-DKIE arises from hyperconjugation between the
methyl hydrogens and the electron-deficient allylic carbon at
C3. In addition, the inverse β-DKIE for the solvolysis of 3-
methyl- and 3-deuteriomethyl-4-chloro-2-pentene supports
positive charge accumulations at the terminal carbon atoms
of the allylic system in the transition state.35 Density functional
theory calculations indicated substantial stabilization of
carbocations 3 and 4 from hyperconjugation with the methyl
groups at C3, with contributions from C−H−π* for the
dimethylallyl cation 4 being twice those for the crotyl cation 3.
Correspondingly, the δ-DKIEs measured for (CD3)2-dimethy-
lallyl bromide were ∼twice those for (E)-CD3-dimethylallyl
bromide.
Associative Nucleophilic Substitution. The associative
nucleophilic substitution of dimethoxybenzenesulfonate by
cyanide proceeds through the typical SN2-type transition state
TS-1 (Figure 3). In the transition state, the cleaving C−O and
the forming C−C bond lengths were found to be 2.01 and 2.51
Å, respectively. The calculated charge distribution (see the
Supporting Information for details) as well as the electrostatic
potential predicts that the negative charge is mainly located on
both the sulfonate and the cyanide (ChelpG: −0.68 and −0.74,
respectively), while a positive charge remains on the butenyl
system (ChelpG: +0.42). These findings are in perfect
agreement with the SN2-type transition state for that reaction.
For the pentavalent carbon atom, a partial charge of +0.27 has
been calculated, which is significantly smaller than the partial
charges for the reactive carbon atoms in the allylic cations 3H
and 4H (3H, +0.38; 4H, +0.35; see Tables S1 and S2 in the
Supporting Information).
The calculated free energy of activation (ΔG⧧ = 18.8 kcal
mol−1) for the associative nucleophilic substitution of
dimethoxybenzenesulfonate by cyanide is in excellent agree-
ment with the experimentally determined second-order rate
constant in dimethylformamide (kH = 7.32 × 10−2 L mol−1
CN
s−1, ΔG⧧ = 19.0 kcal mol−1). Very small normal δ-DKIEs were
calculated for the substitution reaction in both dimethylforma-
mide and acetonitrile (Table 6). These results are in perfect
agreement with the experimental observations and reflect the
long distance between the reaction center and the place of
isotopic exchange.
Table 6. Calculated Kinetic Isotope Effects for the SN2
a
Reaction of Cyanide and 1H/D-ODBS
solvent
acetonitrile
dimethylformamide
kH/kD (calcd)
kH/kD (exptl)
1.01
1.01
1.013 0.004
a
B3LYP-D2/6-31+G(d,p)/IEFPCM, various solvents, 25 °C.
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472 mg) in THF (5 mL) was added dropwise at −78 °C. The mixture
was stirred at −78 °C for 2 days and quenched by ice-cold saturated
NaHCO3. The mixture was extracted with cold ether and the extract
washed with cold brine. The combined organic layers were dried over
MgSO4 and carefully concentrated in vacuo. Purification by flash
column chromatography (silica gel, ether) gave the sulfonate ester as a
colorless oil (311 mg, 63%), which was stored in ethyl ether at −78 °C
until used: 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 9 Hz, 1H), 6.52
(m, 2H), 5.74 (m, 1H), 5.51 (m, 1H), 4.51 (dd, J = 6.0, J = 0.9 Hz,
2H), 3.90 (s, 3H), 3.84 (s, 3H), 1.65 (dd, J = 6.0, J = 0.9 Hz, 3H); 13C
NMR (CDCl3) 165.8, 159.2, 133.6, 133.3, 123.9, 116.8, 104.5, 99.6,
71.6, 56.4, 56.0, 17.9; HRMS (M + Na) calcd for C12H16O5SNa
295.0616, found 295.0623.
Relaxed potential energy surface scans gave barrierless
combinations of the sulfonates or bromides with the highly
electrophilic allylic cations. Since the dissociative substitutions
should occur with very late transition states, the free cations 3
and 4 were considered as transition state analogues in the
computational studies. Thus, the calculated δ-DKIEs should be
upper limits for the experimental values. We found the
experimental δ-DKIEs for the solvolysis reactions were lower
than the calculated values and appeared to correlate with
structural changes expected for an earlier transition state due to
a nucleophilic component from solvent.33,36 For example,
experimental δ-DKIEs for 1H/D-ODBS (for example, kH/kD =
1.097 in 50W50AN) were ∼65% of the calculated values, while
the isotope effect for 1H/D-Br (kH/kD = 1.055 in 80W20AN)
with a poorer leaving group was only 35% of the calculated
value. In contrast, experimental δ-DKIEs for dimethylallyl
bromide were substantially higher than those for crotyl bromide
and the differences between experimental and computed δ-
DKIEs were smaller for the dimethylallyl system.
tert-Butyldiphenyl(prop-2-yn-1-yloxy)silane (4-
OTBDPS).46,47 A solution of propargyl alcohol (1.79 g, 32.0 mmol)
in CH2Cl2 (10 mL) was added to a solution of TBDPSCl (9.68 g, 35.2
mmol) and imidazole (2.39 g, 35.2 mmol) in CH2Cl2 (30 mL) at
room temperature. The mixture was stirred for 5 h and diluted with
ether and extracted with ether, and the extract was washed with brine,
dried over MgSO4, filtered, and concentrated in vacuo. The resulting
crude solid was purified by flash column chromatography (95/5
1
hexane/ethyl acetate) to give 9.48 g (100%) of a colorless oil: H
The δ-DKIE, kH/kD = 1.013, measured for nucleophilic
substitution of 1H/D-ODBS by cyanide under pseudo-first-
order conditions, was in excellent agreement with the isotope
effect determined by computation. The very small values for k0
relative to kCN for unlabeled and labeled substrates indicate that
the reaction is highly associative. A partial charge of +0.08 at C3
calculated for the associative transition state is substantially
smaller than value of +0.45 computed for C3 in carbocation 3.
There are many instances where computational tools have
been used to determine structures of transition states and the
underlying mechanisms for nucleophilic substitution reactions
from primary and secondary kinetic isotope effects.37−41
Notable exceptions are those based on α-DKIEs.42−45 There
is no simple linear correlation between α-DKIEs and structures
of different transition states because of variations in the relative
contributions from C−H/D stretching and bending modes
when the reaction center is changing hybridization. In contrast,
the proposed origin of the δ-DKIEs we observed involves
differences in hyperconjugation that reflect changes in charge
density at the distal allylic carbon, where the tetrahedral
character of the directly attached CH3/CD3 group is basically
unaltered during the substitution reaction.
NMR (300 MHz, CDCl3) δ 7.78 (m, 4H), 7.42 (m, 6H), 4.35 (s, 2H),
2.4 (t, 1H), 1.09 (s, 9H); 13C NMR (CDCl3) 135.8, 133.1, 130.1,
128.0, 82.2, 73.2, 52.7, 26.9, 19.4; LCMS (M + Na) calcd for
C19H22OSiNa 317.46, found 317.1.
[2H3]Methyl p-Toluenesulfonate (3).48 To a solution of p-
toluenesulfonyl chloride (26.4 g, 0.138 mol) in THF (100 mL) were
added CD3OD (10 g, 0.277 mol) and 20% NaOH (70 mL) at °C.
After 4 h, the mixture was diluted with water and extracted with ether.
The combined organic layers were washed with saturated aqueous
NH4Cl and brine. The organic layer was dried over MgSO4, filtered,
and concentrated in vacuo to give 23.7 g (91%) of a colorless residue,
which was stored at −78 °C until used: 1H NMR (300 MHz, CDCl3):
δ 7.76 (d, J = 6 Hz, 2H), 7.33 (d, J = 6 Hz, 2H), 2.42 (s, 3H); 13C
NMR 145.1, 132.3, 130.2, 128.2, 21.8.
([4-2H3]2-Butyn-1-yloxy)tert-butyldiphenylsilane (5D-
OTBDPS).47 To a solution of 4-OTBDPS (6.51 g, 22.1 mmol) in
THF (40 mL) was slowly added n-BuLi (10.6 mL, 26.5 mmol, 2.5 M
solution in hexane) at 0 °C. After 10 min, [2H3]methyl tosylate 3 (5.02
g, 26.5 mmol) was slowly added and the resulting mixture was stirred
at room temperature overnight. The mixture was diluted with ethyl
acetate and washed with saturated aqueous NH4Cl solution and brine.
The organic layer was dried over MgSO4 and concentrated under
vacuum. The residue was purified by flash column chromatography on
silica gel (10/1 hexane/ether) to give 6.4 g (93%) of a pale yellow oil:
1H NMR (300 MHz, CDCl3) δ 7.78 (m, 4H), 7.4 (m, 6H), 4.34 (s,
2H), 1.09 (s, 9H); 13C NMR (CDCl3) 135.8, 133.5, 129.9, 127.9, 81.4,
77.8, 53.1, 26.9, 19.4; LCMS (M + Na) calcd C20H21D3OSiNa 334.5,
found 334.1.
CONCLUSIONS
■
Our studies indicate that δ-DKIEs provide an excellent tool for
studying the transition state structures of prenyltransfer
reactions. One anticipates that these transition states depend
to a significant extent on the strength of the nucleophile in the
nearby acceptor substrate, which can range from weakly
nucleophilic carbon−carbon double bonds to powerfully
nucleophilic thiolates. δ-DKIE measurements with deuterium-
labeled substrates, along with an ab initio analysis of the data,
should provide important information about bonding in the
transition state. Since the magnitude of the isotope depends on
the number of δ-deuterium atoms, using allylic substrates that
are perdeuterated in these positions can enhance the sensitivity
of the method.
[4-2H3]But-2-yn-1-ol (5D-OH).47,49 To a solution of 5D-
OTBDPS (6.4 g, 20.6 mmol) in THF (100 mL) was added TBAF
hydrate (16.1 g, 61.7 mmol) at room temperature. The mixture was
stirred for 4.5 h, diluted with water, and extracted with ether. The
combined organic layers were washed with brine and dried over
Mg2SO4. Solvent was carefully removed under vacuum. The residue
was purified by flash column chromatography on silica gel (2/1
pentane/diethyl ether) to give 727 mg (78%) of a colorless liquid: 1H
NMR (300 MHz, CDCl3) δ 4.21 (s, 2H), 1.53 (s, OH); 13C NMR
(CDCl3) 81.6, 77.8, 50.8 (deuterated C4 was not detected); GCMS
(m/z, [M − H]+) calcd C4H2D3O 72.05, found 72.08; GCMS (m/z,
[M − OH]+) calcd for C4H2D3 56.06, found 56.10.
(E)-[4-2H3]2-Buten-1-ol (1D-OH).47 To a suspension of lithium
aluminum hydride (95%, 350 mg, 9.2 mmol) in dry THF (20 mL) was
slowly added deuterated butynol 5D-OH (518 mg, 7 mmol) in dry
THF (5 mL) at 0 °C. The ice bath was removed, and the reaction
mixture was stirred at room temperature for 22 h. The reaction was
quenched by the sequential addition of water (1 mL), 30% NaOH (1
mL), and water (1 mL). The resulting suspension was filtered and
washed with diethyl ether. The ether layer was dried over MgSO4. The
EXPERIMENTAL SECTION
■
(E)-But-2-en-1-yl 2,4-Dimethoxybenzenesulfonate (1H-
ODBS). To a solution of KH (60% in oil, 2.4 mmol, washed with n-
hexane) in THF (10 mL) was added (E)-crotyl alcohol (2.00 mmol,
144 mg) in THF (2 mL) dropwise at −78 °C. After evolution of H2
ceased, a solution of 2,4-methoxybenzenesulfonyl chloride (2 mmol,
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Article
solvent was removed through a distilling column. Distillation of the
residue gave 208 mg (40%) of a colorless liquid: 1H NMR (300 MHz,
CDCl3) δ 5.65 (m, CHCH), 4.05 (d, J = 4.8 Hz, 2H); 13C NMR
(CDCl3) 130.4, 128.1, 63.8 (deuterated C4 was not detected); GCMS
(m/z) calcd for C4H5D3O 75.08, found 74.9.
stirred at 35−40 °C overnight. The solution of CD3ZnI was separated
from the remaining zinc dust and added to a solution of 6-OTBDPS
(6.80 g, 15.6 mmol) and Pd(Ph3)4 (1 mol %) in THF (50 mL) at
room temperature. The mixture was stirred at room temperature for 6
h and quenched by adding saturated aqueous NH4Cl. The quenched
mixture was extracted with ether, and the extract was washed with
brine and dried over MgSO4. The crude residue was purified by
column chromatography (hexane) to yield a colorless oil (4.83 g,
(E)-[4-2H3]But-2-en-1-yl 2,4-Dimethoxybenzenesulfonate
(1D-ODBS). The colorless oil (218 mg, 63%) was synthesized as
described above for 1H-ODBS: 1H NMR (300 MHz, CDCl3) δ 7.8 (d,
J = 9 Hz, 1H), 6.5 (m, 2H), 5.7 (m, 1H), 5.29 (m, 1H), 4.5 (dd, J =
6.6, J = 1.2, 2H), 3.9 (s, 3H), 3.84 (s, 3H); 13C NMR (CDCl3) 165.7,
159.2, 133.5, 133.3, 123.9, 116.8, 104.4, 99.6, 71.6, 56.4, 55.9; HRMS
(M+Na): calcd for C12H13D3O5SNa 298.0804, found 298.0801.
(E)-1-Bromo-2-butene (1H-Br).50 To a solution of (E)-crotyl
alchol (721 mg, 10 mmol) in dry ether (25 mL) was added PBr3 (0.47
mL, 5 mmol) via a syringe at 0 °C. The mixture was stirred for 30 min
at 0 °C and for additional 30 min at room temperature. Ice was added
to quench the reaction. The ether layer was washed with brine, dried
over MgSO4 and evaporated. The crude residue was purified by a
vacuum distillation (50 mmHg) at rt (bp lit. 97−99 °C50) to afford a
1
94.7%): H NMR (300 MHz, CDCl3) δ 7.76 (m, 4H), 7.44 (m, 6H),
5.45 (dq, J = 6.3, J = 1.5 Hz, 1H), 4.42 (dq, J = 6.4, J = 1.2 Hz, 2H),
1.75 (dd, J = 1.2 Hz, 3H), 1.12 (s, 9H); 13C NMR (CDCl3) 135.9,
134.3, 129.7, 127.8, 124.5, 61.4, 27.1, 25.9, 19.4; GCMS (m/z, [M −
C4H9]+) calcd for C17H16D3OSi 270.14, found 270.10.
(Z)-[4′-2H3]-3-Methyl-2-butenol (2D-OH). The deprotection was
performed as described in the synthesis of 5D-OH. To a solution of
2D-OTBDPS (4.6 g, 14 mmol) in THF (90 mL) was added TBAF
(18 mmol, 1 M in THF) at room temperature. The resulting residue
was purified by flash column chromatography (3/1 pentane/ether) to
yield a colorless oil (1.15 g, 92%): 1H NMR (300 MHz, CDCl3) δ 5.32
(tq, J = 6.0, J = 1.5 Hz, 1H), 4.03 (d, J = 7.2 Hz, 2H), 2.56 (s, OH),
1.67 (dd, J = 1.2 Hz, 3H); 13C NMR (CDCl3) 135.8, 123.9, 59.2, 25.8;
GCMS (m/z) calcd for C5H7D3O 89.09, found 89.1.
1
colorless oil (0.76 g, 90%); H NMR (300 MHz, CDCl3) δ 5.74 (m,
2H), 3.93 (ddq, J = 0.6, J = 3.6, J = 6.6 Hz, 2H), 1.72 (ddt, J = 0.9, J =
1.8, J = 5.7 Hz, 3H); 13C NMR (CDCl3) 131.5, 127.7, 33.7, 17.8;
GCMS (m/z): calcd for C4H7Br 133.97, found 134.06.
(Z)-[4′-2H3]-1-Bromo-3-methyl-2-butene (2D-Br).53 To a sol-
ution of 2D-OH (0.59 g, 6.6 mmol) in dry ether (15 mL) was added
PBr3 (0.31 mL, 3.3 mmol) via a syringe at 0 °C. The mixture was
stirred for 30 min at 0 °C and for an additional 30 min at room
temperature. Ice was added to quench the reaction. The ether layer
was washed with brine, dried over MgSO4, and evaporated. The crude
product was purified by vacuum distillation to give a colorless oil (0.66
g, 66%): 1H NMR (300 MHz, CDCl3) δ 5.51 (tq, J = 8.5, J = 1.5 Hz,
1H), 4.00 (dq, J = 8.7, J = 0.6 Hz, 2H), 1.76 (dt, J = 1.5, J = 0.6 Hz,
3H); 13C NMR (CDCl3) 140.2, 121.0, 29.9, 25.9; GCMS (m/z) calcd
for C5H6D3Br 151.1, found 151.1.
(E)-[4-2H3]-1-Bromo-2-butene (1D-Br). To a solution of (E)-
butenol 1D-OH (0.6 g, 7.98 mmol) in dry ether (5 mL) was added
PBr3 (0.38 mL, 3.99 mmol) via a syringe at 0 °C. The mixture was
stirred for 30 min at 0 °C and for an additional 30 min at room
temperature. Ice was added to quench the reaction. The ether layer
was washed with brine, dried over MgSO4, and evaporated. The crude
residue was purified by vacuum distillation to afford a colorless oil
(0.66 g, 60%): 1H NMR (300 MHz, CDCl3) δ 5.72 (m, 2H), 3.94 (d, J
= 6.6 Hz, 2H); 13C NMR (CDCl3) 131.5, 127.8, 33.7; GCMS (m/z)
calcd for C4H4D3Br 136.99, found 137.1.
[4,4′-2H6]-Ethyl 3-Methyl-2-butenoate (7).54 To a solution of
triethylphosphonoacetate (26.2 g, 117 mmol) in THF (200 mL) was
slowly added n-BuLi (109 mmol, 2.5 M in hexane) at 0 °C. After the
mixture was stirred until bubbling ceased at room temperature,
acetone-d6 (5 g, 77.98 mmol) in THF (50 mL) was added to the anion
of the phosphonate. The mixture was stirred for 3 h at room
temperature and quenched by adding saturated aqueous NH4Cl. The
aqueous layer was extracted with diethyl ether. The combined organic
layers were washed with brine and dried over MgSO4. The product
was purified by flash column chromatography (2/1 pentane/ether) to
give a light yellow oil (8.29 g, 79.3%): 1H NMR (300 MHz, CDCl3) δ
5.64 (s, 1H), 4.12 (q, J = 7.14 Hz, 2H), 1.24 (t, J = 7.14 Hz, 3H); 13C
NMR (CDCl3) 166.8, 156.3, 116.3, 59.5, 14.4; GCMS (m/z) calcd for
C7H6D6O2 134.12, found 134.0.
(Z)-3-Iodo-2-butenol (6-OH).51 To a solution of 2-butyn-1-ol
(5.8 g, 82.7 mmol) in 90 mL of ether was added dropwise Red-Al
(41.8 mL, 124 mmol, 60 wt % in toluene) at −78 °C. The reaction
mixture was warmed to room temperature and stirred overnight. The
reaction mixture was cooled to −78 °C and quenched with a solution
of I2 (63 g, 248 mmol) in THF (200 mL). The mixture was warmed to
room temperature and stirred for 2 h. Saturated aqueous Na2S2O3 was
added to the mixture, and the layers were separated. The aqueous layer
was extracted with ether (×3), and the combined ether layers were
washed with brine, dried over MgSO4, and evaporated. The crude
product was purified by flash column chromatography (2/3 ethyl
1
acetate/hexane) to give a light yellow oil (12.9 g, 78.8%): H NMR
(300 MHz, CDCl3) δ 5.68 (tq, J = 5.85, J = 1.5, 1H), 4.06 (dq, J =
5.85, J = 1.2, 2H), 3.46 (s, OH), 2.48 (dd, J = 2.85, J = 1.5, 3H); 13C
NMR (CDCl3) 134.5, 101.8, 67.4, 33.9; GCMS (m/z) calcd for
C4H7IO 197.95, found 198.0.
[4,4′-2H6]-3-Methyl-2-butenol (2D2-OH).55 To a suspension of
LAH (2.67 g, 70.5 mmol) in THF (100 mL) was added a solution of
butenoate 7 (9.3 g, 47 mmol) in THF (30 mL) at 0 °C. The mixture
was stirred at 0 °C and at room temperature for 30 min. Ether (50
mL) was added to dilute the mixture, and Na2SO4 (80 g) mixed with
water (20 mL) was added in portions at 0 °C. After the mixture was
stirred for 1 h at room temperature, additional Na2SO4 was added to
remove water. The solid was filtered off and washed with ether.
Purification by flash column chromatography (1/2 ether/pentane)
afforded a colorless oil (2.73 g, 63%): 1H NMR (300 MHz, CDCl3) δ
5.31 (t, J = 6.9, 1H), 4.02 (d, J = 6.9 Hz, 2H), 2.73 (s, OH); 13C NMR
(CDCl3) 135.6, 123.9, 59.1; GCMS (m/z) calcd for C5H4D6O 92.11,
found 92.18.
(Z)-tert-Butyl((3-iodobut-2-en-1-yl)oxy)diphenylsilane (6-
OTBDPS). The protection was performed as described in the
synthesis of 4-OTBDPS. Butenol 6-OH (4.2 g, 21.2 mmol) in
CH2Cl2 (20 mL) was added to a solution of TBDPSCl (6.99 g, 25.4
mmol) and imidazole (1.73 g, 25.4 mmol) in CH2Cl2 (50 mL) at
room temperature. The resulting crude product was purified by flash
column chromatography (12/1 hexane/ethyl acetate) to give 8.9 g
1
(96.2%) of a colorless oil: H NMR (300 MHz, CDCl3) δ 7.72 (m,
4H), 7.42 (m, 6H), 5.81 (tq, J = 5.4, J = 1.5 Hz, 1H), 4.26 (dq, J = 5.4,
J = 1.5 Hz, 2H), 2.50 (dd, J = 3.0, J = 1.5 Hz, 3H), 1.09 (s, 9H); 13C
NMR (CDCl3) 135.8, 135.2, 133.7, 129.9, 127.9, 99.4, 69.4, 33.7, 27.0,
19.4; GCMS (m/z, [M − C4H9]+) calcd for C16H16IOSi 379.00, found
379.1.
[4,4′-2H6]-1-Bromo-3-methyl-2-butene (2D2-Br). The bromi-
nation was performed as described in the synthesis of 2D-Br. To a
solution of 2D2-OH (0.5 g, 5.42 mmol) in dry ether (25 mL) was
added PBr3 (0.26 mL) via a syringe at 0 °C. The crude residue was
purified by vacuum distillation to afford a colorless oil (0.76 g, 90%):
1H NMR (300 MHz, CDCl3) δ 5.50 (t, J = 8.4 Hz, 1H), 3.98 (d, J =
8.4 Hz, 2H); 13C NMR (CDCl3) 140.1, 121.0, 29.9; GCMS (m/z)
calcd for C5H3D6Br 154.03, found 154.06.
(Z)-[4′-2H3]-tert-Butyl((3-methylbut-2-en-1-yl)oxy)diphenyl-
silane (2D-OTBDPS).52 LiCl (30 mmol) was placed in an N2-flushed
flask and dried for 20 min at 150−170 °C under vacuum. Zinc dust
(30 mmol) was added, and the heterogeneous mixture of Zn and LiCl
was dried again for 20 min at 150−170 °C under vacuum. THF (5
mL) was added, and the Zn was activated with BrCH2CH2Br (5 mol
%) and TMSCl (1 mol %). A solution of CD3I (4.35 g, 30 mmol) in
THF (30 mL) was then added at room temperature. The mixture was
Kinetic Measurements. Rates for dissociative nucleophilic
substitution reactions of 2,4-dimethoxybenzenesulfonate esters (0.1
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mM) and bromides (0.6 or 1 mM) were measured in 30/70−80/20
H2O/AcCN (v/v), TFE, 95/5 TFE/H2O (v/v), or 60/40−80/20
EtOH/H2O (v/v)). Rates for associative nucleophilic substitution
reactions for were measured in 100−240 mM tetraethylammonium
cyanide in dry DMF. Time courses for reactions of sulfonate esters
were determined from UV absorbance measured at 30 s intervals at six
different wavelengths between 225 and 290 nm. Time courses for
bromides were determined from changes in conductivity measured at
1 s intervals. Measurements were in triplicate at 10, 22.5, or 25 °C.
Product Studies: (E)-Pent-3-enenitrile. To 0.3 g (1.19 mmol) of
1 in diethyl ether (10 mL) was added tetraethylammonium cyanide
(224 mg, 1.42 mmol) in acetonitrile (5 mL) at room temperature, and
the progress of the reaction was monitored by TLC. Upon completion,
the mixture was diluted with diethyl ether and passed through a short
plug of silica gel. Solvent was removed by careful distillation to give 35
Engineering Discovery Environment (XSEDE), which is
supported by National Science Foundation Grant No. OCI-
1053575 and resources from the UCLA Institute for Digital
Research and Education (IDRE). We thank Dr. Matthew
Janczak for help with error analysis.
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■
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ASSOCIATED CONTENT
* Supporting Information
■
(22) Mayr, H.; Forner, W.; Schleyer, P. v. R. J. Am. Chem. Soc. 1979,
̈
S
101, 6032.
Text, figures, and tables giving additional experimental
methods, characterization data, monitored kinetic data, and
computational details. This material is available free of charge
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AUTHOR INFORMATION
Corresponding Authors
*E-mail for K.N.H.: houk@chem.ucla.edu.
*E-mail for C.D.P.: poulter@chem.utah.edu.
■
Present Address
§Department fur Chemie, Universitat zu Koln, Greinstraße 4,
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the Alexander von Humboldt Foundation
(Feodor Lynen scholarship to M.B.), the National Institutes of
Health (GM-21328 to C.D.P.), and the National Science
Foundation (CHE-0548209 to K.N.H.) for financial support of
this research. This work used the Extreme Science and
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