Leaving group effects in gas-phase substitutions and eliminations

Article abstract of DOI:10.1021/ja047002u

Using a methodology recently developed for studying the product distributions of gas-phase S_N2 and E2 reactions, the effect of the leaving group on the reaction rate and branching ratio was investigated. Using a dianion as the nucleophile, reactions with a series of alkyl bromides, iodides, and trifluoroacetates were examined. The alkyl groups in the study are ethyl, n-propyl, n-butyl, isobutyl, isopropyl, sec-butyl, and tert-butyl. The data indicate that leaving group abilities are directly related to the exothermicities of the reaction processes in both the gas phase and the condensed phase. Gas-phase data give a reactivity order of iodide > trifluoroacetate > bromide for S_N2 and E2 reactions. Previous condensed phase data indicate a reactivity order of iodide > bromide > trifluoroacetate for substitution reactions; however, the basicities of bromide and trifluoroacetate are reversed in the condensed phase so this reactivity pattern does reflect the relative reaction exothermicities. Aside from this variation, the gas-phase data parallel condensed phase data indicating that the substituent effects are rooted in the nature of the alkyl substrate rather than in differences in solvation. The experimental data are supported by calculations at the MP2/6-311+G(d,p)//MP2/6-31+(d) level.

Full text of DOI:10.1021/ja047002u

Published on Web 09/15/2004
Leaving Group Effects in Gas-Phase Substitutions and
Eliminations
Scott Gronert,*,† Adelaide E. Fagin,† Keiko Okamoto,† Sudha Mogali,‡ and
Lawrence M. Pratt‡
Contribution from the Department of Chemistry and Biochemistry, San Francisco State
UniVersity, San Francisco, California 94132 and Department of Chemistry, Fisk UniVersity,
NashVille, Tennessee 37208
Received May 21, 2004; E-mail: sgronert@sfsu.edu
Abstract: Using a methodology recently developed for studying the product distributions of gas-phase
SN2 and E2 reactions, the effect of the leaving group on the reaction rate and branching ratio was
investigated. Using a dianion as the nucleophile, reactions with a series of alkyl bromides, iodides, and
trifluoroacetates were examined. The alkyl groups in the study are ethyl, n-propyl, n-butyl, isobutyl, isopropyl,
sec-butyl, and tert-butyl. The data indicate that leaving group abilities are directly related to the exothermicities
of the reaction processes in both the gas phase and the condensed phase. Gas-phase data give a reactivity
order of iodide > trifluoroacetate > bromide for SN2 and E2 reactions. Previous condensed phase data
indicate a reactivity order of iodide > bromide > trifluoroacetate for substitution reactions; however, the
basicities of bromide and trifluoroacetate are reversed in the condensed phase so this reactivity pattern
does reflect the relative reaction exothermicities. Aside from this variation, the gas-phase data parallel
condensed phase data indicating that the substituent effects are rooted in the nature of the alkyl substrate
rather than in differences in solvation. The experimental data are supported by calculations at the MP2/
6-311+G(d,p)//MP2/6-31+(d) level.
Scheme 1
Introduction
Substitution and elimination reactions have had a central role
in the development of modern mechanistic organic chemistry.1-5
They share the same reactants, a nucleophile and substrate with
a good leaving group, and often compete (for example, see
Scheme 1). A tremendous amount of data is available for these
reactions and generalizations have been put forward to explain
the effects of the substrate’s structure, the nucleophile, the
leaving group, and the solvent on the absolute and relative rates
of these processes.
Scheme 2
More recently, these reactions have been studied in the gas
phase by several research groups in an effort to simplify the
systems and eliminate solvation effects.6 A major complication
in the gas-phase study of substitution and elimination reactions
is that they generally lead to the same ionic product (Scheme
1) and therefore cannot be distinguished directly by mass
spectrometry. Novel approaches to deal with this issue have
been developed in the past but did not prove to be general.7,8
To allow for the direct detection of reaction products, we have
turned to dianions as nucleophiles because their reactions lead
to two ionic products, one of which is diagnostic of the
mechanism.9 An example is shown in Scheme 2 using a dianion,
I, with a carboxylate as the nucleophile and a sulfonate as a
spectator ionic site. Only the carboxylate is reactive under these
conditions and the second charge has a limited effect on the
potential energy surfaces of substitution reactions.10-12 We have
† San Francisco State University.
‡ Fisk University.
(1) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry, 3rd ed.; Harper Collins Publishers: New York, 1987.
(2) Saunders, W. H., Jr.; Cockerill, A. F. Mechanisms of Elimination Reactions;
John Wiley & Sons: New York, 1973.
(3) Streitwieser, A., Jr. SolVolytic Displacement Reactions; McGraw-Hill: New
York, 1962.
(4) Ingold, C. K. Structure and Mechanism in Organic Chemistry; Cornell
University Press: Ithaca, NY, 1969.
(7) Lieder, C. A.; Brauman, J. I. Int. J. Mass Spectrom. Ion Phys. 1975, 16,
307.
(8) Jones, M. E.; Ellison, G. B. J. Am. Chem. Soc. 1989, 111, 1645.
(9) Gronert, S. Acc. Chem. Res. 2003, 36, 848.
(5) Hammett, L. P. Physical Organic Chemistry, 2nd ed.; McGraw-Hill: New
York, 1970.
(6) The following recent review highlights the accomplishments of many
workers in the study of gas-phase substitution and elimination reactions:
Gronert, S. Chem. ReV. 2001, 101, 329.
(10) Gronert, S.; Fong, L.-M. Int. J. Mass Spectrom. 1999, 192, 185.
(11) Gronert, S. J. Mass Spectrum. 1999, 34, 787.
(12) Gronert, S. Int. J. Mass Spectrom. 1999, 185, 351.
9
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J. AM. CHEM. SOC. 2004, 126, 12977-12983
12977

A R T I C L E S
Gronert et al.
ratio correction). The equation describing the reagent pressure (Torr)
is given below:
used this approach to study several factors that influence the
competition between substitution and elimination including the
structure of the alkyl halide substrate and the nature of the
nucleophilic center.13,14 Here, we explore the effect of the
leaving group on the rates of the reactions and the competition
between the mechanisms. Three leaving groups have been
investigated, bromide, iodide, and trifluoroacetate.15 The gas-
phase proton affinity (PA)16 of iodide (314 kcal/mol) is 9 kcal/
mol less than bromide so it is expected to be a better leaving
group and to lead to faster reactions. Trifluoroacetate has
essentially the same PA (323 kcal/mol) as bromide so similar
rates might be expected; however, trifluoroacetate relies on
resonance delocalization for some of its stability and this factor
may not be fully realized in the transition states. Moreover, the
reactions of alkyl trifluoroacetates tend to be more exothermic
than those of the bromides.16-18 For the alkyl component of
the substrates, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,
isobutyl, and tert-butyl groups have been used. To support the
experimental work, the reactions also have been studied
computationally using acetate as a simplified model for the
dianion nucleophile
1/2
PRX ) 1.75 × 10-3 × FRX × dRX/MWRX/FHe × (MWRX/MWHe
)
(1)
where FRX is the reagent flow rate (liquid, mL/min), dRX is the reagent
density, MWRX is the reagent molecular weight, FHe is the helium flow
rate (gas, moles/min), and MWHe is the atomic weight of He. Typical
reagent pressures were between 10-5 and 10-7 Torr.
Once an appropriate flow of the neutral reagent was established,
the system was given several minutes for the reagent pressure to
equilibrate to a steady state. Kinetic measurements were completed by
varying the time delay between dianion isolation and the expulsion of
all ions to obtain a mass spectrum. During the delay time, the dianion
was held in the trap with a qz value of 0.5 to ensure that the expected
products would experience stable trapping fields. In most cases, 13
different time delays were used in each run. Time delays and reagent
flows were adjusted to obtain plots that covered two to three half-lives
of the reactant ion. Reported rates are the average of at least six kinetic
runs using at least three different reagent flow rates and were obtained
on at least two different days. Kinetic plots showed good linearity and
gave correlation coefficients (r2) greater than 0.98. To evaluate the
absolute accuracy of the rate constant measurements, we previously
have compared our data with results from flowing afterglow work and
seen good correspondence.13,14 Other work from our laboratory indicates
that the ion trap provides an environment that is effectively at ambient
temperature (∼300 K).19 Finally, product distributions were determined
by integrating the areas under the appropriate peaks. No evidence for
secondary reactions was observed and the product distributions varied
little as a function of reaction extent.
All the neutral reagents were obtained in the highest purity
commercially available and used without further purification with
exception of the trifluoroacetates. The commercial samples were
contaminated with traces of trifluoroacetic acid and required purifica-
tion. Just before use, they were added to an aqueous NaHCO3/
cyclohexane mixture, the organic layer was removed and then used
for the mass spectrometric studies. The cyclohexane (and any trace
H2O) has no effect on the experiment and appropriate dilution factors
were used in the analysis of the kinetic data. The dianion precursor
salt was available from a previous study.14
Methods
Mass Spectrometry. All experiments were completed in a modified
Finnigan LCQ quadrupole ion trap mass spectrometer equipped with
electrospray ionization (ESI). The tetrabutylammonium salt of I was
dissolved in HPLC-grade acetonitrile or methanol (10-4-10-5 M) and
pumped through the electrospray interface at flow rates from 3 to 10
µL/min. Typical ESI conditions involved needle potentials from 3.5 to
4.5 kV and heated capillary temperatures from 125 to 200 °C. In some
cases, triethylamine (10-3-10-2 M) was added as a base to enhance
the dianion signal. A notched waveform was applied to isolate the
dianion in the ion trap. Once a steady signal was obtained, the neutral
reagent was introduced into the helium system via a custom gas-
handling system. The system has been described previously,9,13 but a
brief overview is given here. The liquid reagent was delivered to a
measured flow of helium (1-2 L/min) by a syringe pump. With reagent
flows of 30-300 µL/hr, rapid evaporation occurs at the syringe needle
to give mixing ratios of ∼102-104 (He/reagent). For less volatile
substrates, the mixing region was heated to 50-75 °C. Most of the
gas mixture is diverted to an exhaust system and ∼0.25 mL/min is
carried through the LCQ’s restriction capillary to the ion trap to establish
a helium pressure of 1.75 ( 0.2 × 10-3 Torr. At these pressures, the
mean free path of the molecules is considerably longer than the
dimensions of the trap and the loss of gases out of the end cap holes
of the trap can be treated as an effusion process. The lighter helium
atoms effuse more quickly than the reagent molecules and the mixing
ratio must be corrected for differential effusion (square root of the mass
Computational. Calculations were completed with the GAUSSI-
AN9820 or GAUSSIAN0321 quantum mechanical packages on a Digital
(19) Gronert, S. J. Am. Soc. Mass Spectrom. 1998, 9, 845.
(20) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi,
R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.;
Challacombe, M.; Gill, P. M. W.; Johnson, B. G.; Chen, W.; Wong, M.
W.; Andres, J. L.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian
98, Revision A.7; Gaussian, Inc.: Pittsburgh, PA, 1998.
(13) Gronert, S.; Pratt, L. M.; Mogali, S. J. Am. Chem. Soc. 2001, 123, 3081.
(14) Flores, A. E.; Gronert, S. J. Am. Chem. Soc. 1999, 121, 2627.
(15) Although alkyl trifluoroacetates are known to undergo nucleophilic acyl
substitution reactions in the gas phase, that process would be endothermic
with a carboxylate as the nucleophile and therefore is not competitive in
this system: McDonald, R. N.; Chowdhury, A. K. J. Am. Chem. Soc. 1982,
104, 901.
(16) Bartmess, J. E. Negative Ion Energetics Data. In NIST Standard Reference
Database Number 69; Mallard, W. G., Linstrom, P. J., Eds.; National
Institute of Standards and Technology: Gaithersburg, MD, 2004; http://
webbook.nist.gov.
(17) Trifluoroacetate has lower alkyl cation affinities than bromide (i.e., it
requires less energy to heterolytically cleave a C-OC(O)CF3 bond than a
C-Br bond).
(18) Afeefy, H. Y.; Liebman, J. F.; Stein, S. E. Neutral Thermochemical Data.
In NIST Chemistry WebBook, NIST Standard Reference Database Number
69; Mallard, W. G., Linstrom, P. J., Eds.; National Institute of Standards
and Technology: Gaithersburg, MD, 2004; http://webbook.nist.gov.
(21) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa,
J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.;
Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo,
J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Revision B04; Gaussian, Inc.: Pittsburgh, PA, 2003.
9
12978 J. AM. CHEM. SOC. VOL. 126, NO. 40, 2004

Leaving Group Effects
A R T I C L E S
Table 1. Rate Constants for Reactions with Ia
leaving group
alkyl group
Br
TFAb
I
ethyl
0.44
0.67
1.39
0.32
0.12
0.56
0.48
1.3
28
41
59
26
7.2
47
93
n-propyl
n-butyl
isobutyl
isopropyl
s-butyl
1.6
0.4
tert-butyl
a Units ) 10-11 cm3 molecule-1 sec-1. Expected absolute uncertainty is
(20% but realtive values have smaller uncertainies, (5%. b TFA )
trifluoroacetate.
to maximize the trapping efficiency of the higher mass products
(301 and 349) at the expense of the low mass ions (i.e., iodide).
A kinetic plot for this reaction is shown in Figure 1b and it has
good linearity over more than two half-lives. In Table 1, overall
rate constants are given for the reactions of I with the alkyl
bromides, iodides, and trifluoroacetates. The rate constants range
from as low as ∼1 × 10-12 cm3 molecule-1 sec-1 up to ∼9 ×
10-10 cm3 molecule-1 sec-1. It is not straightforward to estimate
collision rates for dianions such as I,9 but one expects values
of about 2-5 × 10-9 cm3 molecule-1 sec-1 27
. Therefore, these
rate constants correspond to efficiencies (reaction rate/collision
rate) ranging from less than 0.001 to greater than 0.1. The rate
constant data in Table 1 point to a clear pattern in leaving group
ability: iodide > trifluoroacetate > bromide. This pattern does
not match the gas-phase proton affinities of the leaving groups
(iodide < bromide ∼ trifluoroacetate) but does parallel the
expected exothermicities of the reactions. For example, NIST
data indicate that the gas-phase SN2 reactions of methyl iodide
are 2.2 kcal/mol more exothermic than those of methyl
trifluoroacetate and 6.4 kcal/mol more exothermic than those
of methyl bromide.16,18 Our computational work also indicates
that the alkyl trifluoroacetate reactions generally are about 4
kcal/mol more exothermic than the alkyl bromide reactions.
Therefore, the higher gas-phase reactivity of the trifluoroacetates
compared to the bromides is reasonable given the reaction
thermodynamics. However, a different pattern is found in
solution. For example, Noyce reported a relative reactivity
ranking of 1:7:43 for the series trifluoroacetate/bromide/iodide
in solvolysis reactions.28 An important difference is that in water,
trifluoroacetate is a much stronger base than bromide (or iodide),
so it is expected to be a poorer leaving group in that medium.
The large shift in relative basicity between the media is easily
rationalized. The resonance delocalization and diffuse nature
of trifluoroacetate reduces its solvation energy relative to the
halides and makes it a less stable anion in solution (i.e., more
basic). The key point, however, is that leaving group ability
appears to be controlled by the same factor in both phases, the
exothermicity of the reaction process.
Figure 1. (a) Spectrum from the reaction of I with isopropyl iodide. The
dianion, I, is at m/z ) 150 and the E2 and SN2 products appear at m/z )
301 and 343, respectively. (b) Kinetic plot for the reaction of I with isopropyl
iodide.
Alpha, an HP/Convex Exemplar, or a Pentium 4 computer. Geometries
were initially optimized at the HF/6-31+G* level and frequency
calculations were also completed at this level. All of the species in the
study exhibited the proper number of imaginary frequencies. In addition,
optimizations were completed at the MP2/6-31+G(d) level. Energies
reported in the text are at the MP2/6-311+G(d,p) level corrected for
zero-point vibrational energies (ZPE, scaled by 0.9135).22 For iodide,
an all-electron basis set reported by Radom and co-workers was
employed.23 In some cases, larger basis sets and higher levels of
correlation were employed to test the accuracy of the computed values.
Given that the computational work on the model systems is to
provide qualitative comparisons to the experiments, no thermal cor-
rections were made. Multiple rotamers were considered and data for
only the most stable ones are listed in the tables. For the E2 reactions,
only anti orientations were considered because there is ample evidence
that they are preferred in the gas-phase eliminations of simple
halides.24-26
Results and Discussion
Figure 1a provides a sample mass spectrum for the reaction
of I with isopropyl iodide. Dianion I appears at m/z ) 150 and
the SN2 and E2 products appear at m/z ) 343 and 301,
respectively. A rather small signal is observed for iodide under
these conditions because the qz value of the trap had been set
Product distributions from the reactions are presented in Table
2. The data are in accord with expectations from previous
condensed- and gas-phase work.1,6 Substitution dominates with
primary alkyl groups and a mixture of substitution and elimina-
tion is observed with secondary alkyl groups. Elimination is
the only pathway with the tertiary alkyl group. Table 2 also
(22) Pople, J. A.; Scott, A. P.; Wong, M. W.; Radom, L. Isr. J. Chem. 1993,
33, 345.
(23) Glukhovtsev, M.; Pross, A.; Mcgrath, M.; Radom, L. J. Chem. Phys. 1995,
103, 1878.
(24) Gronert, S. J. Am. Chem. Soc. 1991, 113, 6041.
(25) Gronert, S. J. Am. Chem. Soc. 1993, 115, 652.
(26) Gronert, S. J. Org. Chem. 1994, 59, 7046.
(27) Su, T.; Bowers, M. T. In Gas-Phase Ion Chemistry; Bowers, M. T., Ed.;
Academic Press: New York, 1979; pp 1, 83.
(28) Noyce, D. S.; Virgilo, J. A. J. Org. Chem. 1972, 37, 2643.
9
J. AM. CHEM. SOC. VOL. 126, NO. 40, 2004 12979

A R T I C L E S
Gronert et al.
Table 2. Partial Rate Constants for Reactions with Ia
directly interfere with the incoming nucleophile (not just with
its solvation shell).
leaving group
TFAb
E2c
I
In secondary systems, the SN2 rate constants naturally drop
because of crowding in the transition states. The effect is most
dramatic for isopropyl bromide where almost no SN2 products
are observed. For sec-butyl bromide and iodide, the SN2 rate
reduction in the gas phase is not nearly as large as in the
isopropyl system; however, in solution, isopropyl and sec-butyl
halides tend to give similar rates. The enhanced reactivity of
the sec-butyl group relative to isopropyl in the gas phase can
partially be explained by its greater polarizability. The compu-
tational modeling (see below) also suggests that sec-butyl has
a significantly lower SN2 barrier than isopropyl bromide.
Comparing the substituent effects across the series of leaving
groups, it is clear that similar factors are at work but that the
bromides are more sensitive to them. Bromide is the worst
leaving group in the gas phase and therefore the alkyl bromides
suffer the largest transition-state barriers. The barriers for the
bromides may be close to the limit of energy available in the
gas-phase collision complexes (see below), and therefore the
rate constants could be very sensitive to small changes in the
barriers. Aside from this difference, the data in Figure 2 and
Table 2 show a remarkable consistency across the three leaving
groups and the two media (gas phase and condensed phase). It
does appear that the addition of methyl groups at the R- or
â-carbons causes somewhat larger SN2 rate reductions in
solution. This effect is probably related to the fact that a solvated
nucleophile is effectively larger and is more prone to steric
crowding.
E2 Rates. For all the leaving groups, a clear trend is seen in
the E2 rate constants (Table 2). The elimination rates are low
for the straight-chain, primary alkyl groups, but much higher
for the secondary and tertiary groups. However, the isobutyl
substrates are much more reactive than the other primary
substrates, and on a per â-hydrogen basis, are the most reactive
of all. Because the E2 rate constants are very low for some of
the primary bromides, the iodides are more useful for making
quantitative comparisons. With the primary iodides, it is clear
that addition of methyl groups at the â-carbon has a dramatic
effect on the E2 rate constant. Almost no E2 products are seen
with ethyl, low rate constants are observed with n-propyl and
n-butyl, and a very high rate constant is observed with isobutyl.
The rate constant ratio for this series (ethyl, n-propyl, isobutyl)
is 1:5.2:240 on a per â-hydrogen basis. Moreover, the E2 rate
for sec-butyl is nearly 15 times greater than that for isopropyl.
Addition of methyl groups at the R-carbon also enhances the
E2 rates. Going across the series ethyl/isopropyl/tert-butyl, the
relative E2 rates (per â-hydrogen basis) increase sharply, 1:3.9:
110. As with the â-methyl groups, it appears that the second
addition of a methyl group has the greatest impact on the rate.32
In Figure 3, the gas-phase data for the iodides are compared to
data obtained in ethanol for alkyl bromides.33 The same order
of reactivities is observed in both phases (propyl < isopropyl
< isobutyl < sec-butyl < tert-butyl) and therefore it appears
that similar factors are at work in determining the relative rates.
Br
alkyl Group SN2
E2c
%SN2 SN2
%SN2 SN2
E2c
%SN2
ethyl
n-propyl 0.67
n-butyl 1.39
0.43
0.00
0.00
0.00
99 1.3
100
99 1.6
0.0
100 28 0.3 (0.1) 99
39 1.6 (0.8) 96
100 56 3.0 (1.5) 95
3.7 23 (23) 14
0.0
isobutyl 0.04 0.28 (0.28) 11
isopropyl 0.004 0.12 (0.02)
0.20 0.36 (0.18) 36 13 34 (17) 27
tert-butyl 0.00 0.48 (0.05)
3
0.1 0.3 (0.05) 22 5.0 2.2 (0.4) 69
s-butyl
0
0.0 92 (10)
0
a Units ) 10-11 cm3 molecule-1 sec-1
c Parenthetic data is on per â-hydrogen basis.
.
b TFA ) trifluoroacetate.
Figure 2. Relative rate data for the SN2 reactions. Br and I refer to gas-
phase data with I as the nucleophile. Solution data is for iodide exchange
reactions in ethanol.3 All values relative to ethyl (represented by dashed
horizontal line).
provides data on the partial rate constants for the SN2 and E2
pathways and is useful for analyzing substituent effects.
SN2 Rates. The bromides provide a good illustration of the
effect of the alkyl group on the SN2 rates. For the primary
bromides, there is a general increase in the SN2 rate as the chain
length increases from ethyl to n-propyl and then to n-butyl. This
pattern has been observed before and been attributed to the
greater polarizability of the longer alkyl chains, which can
stabilize the anionic SN2 transition states.9,24,25,29-31 A similar
effect is observed in the trifluoroacetates where n-butyl trifluo-
roacetate reacts slightly faster than ethyl trifluoroacetate. In the
iodides, the same order of reactivity also is observed (n-butyl
> n-propyl > ethyl). In Figure 2, the rate data for the gas-
phase SN2 reactions are presented along with representative data
from solution.3 The rates in the figure are relative to the ethyl
representative of each series (the rate constants for the ethyl
systems are represented by the dashed line). It can be seen in
the figure that chain lengthening retards the SN2 reaction in
solution (i.e., ethyl faster than n-propyl and n-butyl). In the
condensed phase, polarizability effects are less important and
apparently the longer alkyl chains interfere with the solvation
of the transition state. In the isobutyl system, there is a sharp
drop in the SN2 rate constant for the gas-phase (bromide and
iodide) and the condensed-phase systems. Kebarle and co-
workers29 had also noted this effect in early gas-phase work.
Branching at the â-carbon is believed to cause steric crowding
in the SN2 transition state, and this factor appears to be nearly
as important in the gas phase as in solution. This result suggests
that the two additional methyl groups on the â-carbon can
(32) The low E2 rate for ethyl iodide adds some uncertainty to the ratios. It is
possible that some of the observed proton-transfer products with ethyl iodide
result from reaction with a small HI impurity rather than from an E2 reaction
with ethyl iodide. Therefore, the true E2 rate with ethyl iodide could be
smaller and thus all of the rate ratios proportionally larger.
(33) Biale, G.; Cook, D.; Lloyd, D. J.; Parker, A. J.; Stevens, I. D. R.; Takahashi,
J.; Winstein, S. J. Am. Chem. Soc. 1971, 93, 4735.
(29) Caldwell, G.; Magnera, T. F.; Kebarle, P. J. Am. Chem. Soc. 1984, 106,
959.
(30) Li, C.; Ross, P.; Szulejko, J. E.; McMahon, T. B. J. Am. Chem. Soc. 1996,
118, 9360.
(31) DePuy, C. H.; Gronert, S.; Mullin, A.; Bierbaum, V. M. J. Am. Chem.
Soc. 1990, 112, 8650.
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12980 J. AM. CHEM. SOC. VOL. 126, NO. 40, 2004

Leaving Group Effects
A R T I C L E S
Table 4. Energies of Transition States for the Reactions of
Acetate with Alkyl Bromides and Trifluoroacetates
(MP2/6-311+G(d,p)//MP2/6-31+G(d))a
speciesb
SN2
E2
SN2 preference
EtBr
n-PrBr
1.4
4.6
1.6
0.8
-1.8
3.0
0.1
1.3
3.1
1.1
1.0
0.1
2.4
-1.0
-1.1
3.2
1.7
1.8
-2.8
-0.5
-1.2
-8.2
4.6
4.0
4.5
2.2
0.7
-0.1
-1.0
1.0
3.5
1.3
n-BuBr
iBuBr
iPrBr
s-BuBr
t-BuBr
EtTFA
n-PrTFA
n-BuTFA
iBuTFA
iPrTFA
s-BuTFA
t-BuTFA
9.5
-1.5
-2.9
-3.6
-2.1
1.8
Figure 3. Relative rate data for the E2 reactions (relative to ethyl). Gas
phase refers to the reactions of I with alkyl iodides. Solution data refers to
the reactions of ethoxide/ethanol with alkyl bromides.33 Condensed-phase
data originally were reported at 25 and 55 °C but were converted to a single
temperature of 40 °C using an assumed Ea of 22.9 kcal/mol (the average
value from systems measured at multiple temperatures). This conversion
adds relatively little uncertainty to the plot.
-2.0
4.7
1.0
-5.8
a kcal/mol. b TFA ) trifluoroacetate.
Table 3. Energies of Transition States for the Reactions of
study, MP4 calculations on all the systems with the 6-311+G-
(d,p) basis set were not practical. As a result, the computational
data is limited to the bromides and trifluoroacetates at the MP2/
6-311+G(d,p) level. Because we are examining model systems,
the limited quantitative accuracy of this level is not a major
concern and we are only seeking qualitative trends in the
computational data.
Acetate with Ethyl Bromide and Ethyl Iodidea
level
species
MP2 6-31+G(d,p) MP4 6-31+G(d,p) MP2 6-311+G(d,p) MP4 6-311+G(d,p)
EtI/SN2
EtI/E2
SN2 prefer-
ence (I)
3.7
5.2
1.4
1.6
5.0
3.3
-0.7
-2.4
-0.5
1.9
-0.4
0.2
EtBr/SN2
EtBr/E2
SN2 prefer-
ence (Br)
SN2 (I vs Br)b
-3.1
2.9
6.0
-5.4
3.1
8.5
1.5
4.8
3.4
-0.9
5.0
5.9
In Table 4, transition-state energies are presented for the alkyl
bromides and trifluoroacetates reacting with acetate. In some
cases, negative transition-state energies have been obtained. This
is common in gas-phase reactions and implies that the transition
state is more stable than the separated reactants. This does not
always lead to a collision-controlled reaction rate because
entropic bottlenecks are possible, especially with tight transition
states such as that of an SN2 process.35 With a negative
transition-state energy, a barrier can still exist on the potential
energy surface because the reaction initially passes through a
stabilized ion/dipole complex on the way to the transition state.
These complexes are generally 10-15 kcal/mol more stable than
the reactants30 so a significant barrier on the surface could still
lead to a transition state that is more stable than the reactants.
If the transition state is considerably less stable than the
separated reactants (3-5 kcal/mol), very low rate constants are
expected in the gas phase.6
A comparison of the data in Tables 2 and 4 indicates that
the computational barriers are in reasonable accord with the
observed rate constants for the SN2 and E2 reactions. For
example, the computed reactivity order for the SN2 reactions
of the bromides is n-butyl > n-propyl > isobutyl > sec-butyl
∼ ethyl > isopropyl. Experimentally, the order is n-butyl >
n-propyl > ethyl > sec-butyl > isobutyl > isopropyl. The only
significant difference involves isobutyl bromide, which is
predicted to be relatively more reactive than it is experimentally.
This discrepancy may be related to an underestimation of steric
effects because of the small size of the model nucleophile
(acetate). We have much less experimental data for the
trifluoroacetates, but the data are also in good accord with the
computations. For the E2 reactions, there again is reasonable
consistency between the experimental and computational data,
but only if one uses rates that are on a per â-hydrogen basis
(the appropriate comparison).
6.8
7.0
-2.1
-1.5
a kcal/mol. b Iodide SN2 transition-state energy - bromide SN2 transition-
state energy.
The major difference is that the gas-phase data are more
sensitive to substituents and greater rate effects are observed.
Because steric crowding is not especially important in E2
reactions, it appears that the added polarizability of the additional
methyl groups is the key to enhancing the rates. Polarizability
effects are less important in solution so smaller substituent
effects are observed.
Computational Modeling. To gain greater insight into the
reactions, ab initio calculations were used to model the transition
states. As in our previous work, acetate was used as a simple
model for the dianion nucleophile. In these studies, the iodides
proved to be problematic. Initial attempts at the MP2/6-31+G-
(d,p) level suggested that the iodides had higher barriers than
the bromides (Table 3). After several trials with various basis
sets, we concluded that the all-electron basis set that we had
chosen for iodide was sufficient,23 but that at least a triple-ú
basis set was needed for the other atoms (6-311+G(d,p)). With
this basis set, the barriers for ethyl iodide are lower than those
of ethyl bromide; however, the SN2 and E2 barriers were nearly
the same for ethyl iodide, which is inconsistent with the
experimental data.34,35 Ethyl iodide required a shift to the MP4
level to resolve this inconsistency.36 Given the scope of this
(34) Because SN2 reactions are expected to have large entropic barriers, an SN2
reaction must have a lower enthalpic barrier to dominate over an E2
reaction. In fact, one expects E2 to dominate in systems where the SN2
barrier is marginally smaller (1-2 kcal/mol) than the E2 barrier. See ref
35.
(35) Olmstead, W. N.; Brauman, J. I. J. Am. Chem. Soc. 1977, 99, 4219.
(36) We were not able to test this level thoroughly in these systems. It may be
satisfactory, but it is possible that higher levels would be needed to obtain
data that is consistent with all the iodide experiments.
It is interesting to evaluate the effect of substituents on the
E2 transition-state structures. It is well-known that E2 transition
9
J. AM. CHEM. SOC. VOL. 126, NO. 40, 2004 12981

A R T I C L E S
Gronert et al.
ter).2 The E2 transition states for ethyl, isopropyl, and tert-butyl
bromide are shown in Figure 4. Across this series, there is a
consistent elongation of the CR-Br distance in the transition
state as methyl groups are added to the R-carbon. Also, the O-H
distance (transferring proton) becomes longer and the Câ-H
distance becomes shorter in the tert-butyl system. These changes
imply that the leaving group expulsion component of the
reaction progresses to a greater extent and the proton-transfer
component to a lesser extent when methyl groups are added to
the R-carbon (i.e., more E1-like). Despite these subtle geometric
shifts across the series, proton transfer and leaving group
expulsion are both well advanced in all of the transition states
in Figure 4 and therefore they are best classified as prototypical
E2 transition states. The isopropyl and tert-butyl systems prefer
a conformation where the acetate carbonyl is above the breaking
C-Br bond. This conformation suggests a weak, stabilizing
interaction between the nucleophile and the R-carbon in the more
E1-like systems and has some of the characteristics of the E2C
transition state proposed by Winstein;37 however, the energetic
impact is less than 1 kcal/mol (relative to a conformation similar
to that found for ethyl). In terms of energies, the addition of
methyl groups at the R-carbon reduces the E2 barrier by 1.4
kcal/mol for the first addition and 1.9 kcal/mol for the second
addition.
A less pronounced pattern is observed in the transition-state
geometries when methyl groups are added to the â-carbon
(Figure 5). However, from ethyl to n-propyl and then isobutyl,
there is a shift toward a less advanced proton-transfer component
and a slightly more advanced leaving group expulsion compo-
nent in the transition state. Despite the smaller impact on the
geometries, the addition of methyl groups to the â-carbon has
a larger effect on the transition-state energies. The first addition
reduces the E2 barrier by 3 kcal/mol and the second by 3.4
kcal/mol. The larger energetic impact of â-methyl groups is also
seen in the reaction exothermicities. For example, the elimination
reaction of n-propyl bromide is 3 kcal/mol more exothermic
than that of ethyl bromide whereas the elimination reaction of
isopropyl bromide has essentially the same exothermicity as that
of ethyl bromide.18 These data point out that the methyl groups
have a twofold effect on the transition-state energies. For
R-methylation, the charged transition state benefits from the
added polarizability of the substrate even though the methylation
has little effect on the exothermicity of the process. For
â-methylation, the transition state benefits from the added
polarizability as well as from a portion of the additional
exothermicity of the reaction. This combination creates a
situation where the energetic effect of the substituent on the
transition state can be equal to or greater than its effect on the
reaction product. The strong influence of polarizability on the
methyl substituent effect is in accord with the larger rate
enhancements observed in the gas-phase experiments (Figure
3).
In all cases, the trifluoroacetates are computed to have lower
SN2 barriers than the bromides. This is consistent with the rate
data. For the E2 reactions, the computed barriers are generally
lower for the trifluoroacetates, which is in accord with the
observation that isopropyl trifluoroacetate has a higher E2 rate
constant than isopropyl bromide. The other difference between
Figure 4. E2 transition states (MP2/6-31+G(d)) for the E2 reactions of
acetate with (a) ethyl, (b) isopropyl, and (c) tert-butyl bromide. In all cases,
acetate is on the upper right and bromide is on the lower left.
states can span a range of profiles from E1CB-like (high
â-carbanion character) to E1-like (high R-carbocation charac-
(37) Beltrame, P.; Biale, G.; Lloyd, D. J.; Parker, A. J.; Winstein, S. J. Am.
Chem. Soc. 1972, 94, 2240.
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12982 J. AM. CHEM. SOC. VOL. 126, NO. 40, 2004

Leaving Group Effects
A R T I C L E S
bromide. This trend seems to correlate with leaving group ability
and isopropyl iodide gives the most SN2 product in the series
(however, sec-butyl iodide gives somewhat less SN2 product
than sec-butyl bromide). One explanation is that the bond to
the leaving group is cleaved to a greater extent in the SN2
transition state so the process is more sensitive to leaving group
ability. For example, the breaking C-O distances in the SN2
and E2 transition states of ethyl trifluoroacetate are computed
to be 1.912 and 1.885 Å, respectively.
Conclusions
As in solution, gas-phase leaving group abilities correlate with
the exothermicities of SN2 and E2 reactions. In the gas phase,
the observed order of reactivity is iodide > trifluoroacetate >
bromide. This order differs from that found in solution because
the alkyl cation affinities of bromide and trifluoroacetate are
reversed in the two phases. Nonetheless, these results confirm
that variations in reaction energetics play a similar role in
determining the rates of gas-phase and condensed-phase SN2
and E2 reactions. In comparison to condensed-phase data, the
gas-phase SN2 reactions appear to be less sensitive to substituent
effects whereas the gas-phase E2 reactions appear to be more
sensitive to substituent effects. In SN2 reactions, steric crowding
is a key component of the substituent effect (at least with alkyl
substituents) and this will be less important in the gas phase
because the nucelophile does not bring a solvation shell with
it. Steric effects are not particularly important in E2 reactions
so other factors come into play. In particular, polarizability
effects are much more important in the gas phase and are
probably the root of the larger substituent effects observed in
gas-phase E2 reactions. The effect of methylation on the E2
rates is greatest at the â-position, and the computational data
suggest that the energetic effect of methylation on the transition
states can be equal to or greater than its effect on the reaction
products.
As has been noted before,38 the gas phase provides data that
are complementary to that obtained in solution and that reveal
similar reactivity trends. Consequently, it is a very useful
medium for probing the details of fundamental organic reaction
mechanisms and unraveling the origins of reactivity trends
without interference from factors related to solvation effects.
Figure 5. E2 transition states (MP2/6-31+G(d)) for the E2 reactions of
acetate with (a) n-propyl, (b) isobutyl bromide. In both cases, acetate is on
the upper right and bromide is on the lower left.
Acknowledgment. Support from the National Science Foun-
dation (CHE-0348809) is gratefully acknowledged by S.G.
the leaving groups is that the computed SN2 preferences are
greater for the trifluoroacetates. Again, there is limited experi-
mental data for comparison, but in isopropyl, considerably more
SN2 products are observed for the trifluoroacetate than the
JA047002U
(38) DePuy, C. H. J. Org. Chem. 2002, 67, 2393.
9
J. AM. CHEM. SOC. VOL. 126, NO. 40, 2004 12983