Stepwise and concerted solvolytic elimination and substitution reactions: E1 reaction via a primary carbocation

Article abstract of DOI:10.1021/ja970362f

Solvolysis of 9-(X-methyl)fluorene (1-X, X = I, Br, OBs) in 25 vol % acetonitrile in water gives the elimination product 9- methylidenefluorene and the substitution products 9- (hydroxymethyl)fluorene (1-OH) and 9-(acetamidomethyl)fluorene (1- NHCOMe). Kinetic studies of the corresponding ring-substituted compounds 2-X and 3-X show that the rate of elimination increases with increasing acidity of the substrate, Bronsted α > 0. The small kinetic deuterium isotope effects measured for the elimination reactions of the brosylates 1-OBs and 3-OBs, k(H)/k(D) = 2.0 ± 0.1 and 2.8 ± 0.1, respectively, suggest significant amounts of E1 reaction. The bimolecular reactions of the brosylates with added bases may be of irreversible E1cB type in contrast to the reactions of the halides which exhibit E2 reaction with added bases as well as with solvent water.

Full text of DOI:10.1021/ja970362f

4834
J. Am. Chem. Soc. 1997, 119, 4834-4840
Stepwise and Concerted Solvolytic Elimination and Substitution
Reactions: E1 Reaction via a Primary Carbocation
Qingshui Meng and Alf Thibblin*
Contribution from the Institute of Chemistry, UniVersity of Uppsala, P.O. Box 531,
S-751 21 Uppsala, Sweden
ReceiVed February 3, 1997X
Abstract: Solvolysis of 9-(X-methyl)fluorene (1-X, X ) I, Br, OBs) in 25 vol % acetonitrile in water gives the
elimination product 9-methylidenefluorene and the substitution products 9-(hydroxymethyl)fluorene (1-OH) and
9-(acetamidomethyl)fluorene (1-NHCOMe). Kinetic studies of the corresponding ring-substituted compounds 2-X
and 3-X show that the rate of elimination increases with increasing acidity of the substrate, Brønsted R > 0. The
small kinetic deuterium isotope effects measured for the elimination reactions of the brosylates 1-OBs and 3-OBs,
kH/kD ) 2.0 ( 0.1 and 2.8 ( 0.1, respectively, suggest significant amounts of E1 reaction. The bimolecular reactions
of the brosylates with added bases may be of irreversible E1cB type in contrast to the reactions of the halides which
exhibit E2 reaction with added bases as well as with solvent water.
Introduction
Scheme 1
In some recent papers we have reported results on concerted
solvent-promoted elimination reactions.1-5 These E2 reactions
with water as the hydron-abstracting base require relatively
acidic substrates. For example, it was found that 9-(1-X-ethyl)-
fluorene (X ) I, Br) in a highly aqueous solvent reacts by a
solvent-promoted E2 reaction in competition with a minor
reaction through the ion pair.2,3 In contrast, the corresponding
brosylate gives stable alkene mainly via the ion pair as shown
in Scheme 1.
Table 1. Rate Constants for the Solvolyses of 1-X, 2-X, and 3-X
in 25 vol % Acetonitrile in Watera at 70 °C
We now report on a study in which we have decreased the
stability of the putative ion pair by removing the methyl group
of the exocyclic carbon (Scheme 2). Does this primary ion pair
exist, i.e., does it have a significant lifetime, under solvolytic
conditions? Our results indicate that it has a significant lifetime
and that the solvolytic elimination of the brosylates occurs
through the ion pair. There seems to be no precedence for E1
reaction of a primary substrate. The reasons for this surprisingly
high stability of the primary carbocation are discussed. The
paper also addresses the question about the mechanism of the
competing solvent-promoted elimination of the brosylate: is it
of E2 type or of irreversible E1cB type?
substrateb
106kobs, s-1
106kS, s-1
106kE, s-1
1-I
1-Br
1-OBs
2-Br
2-OBs
3-Br
44.5
8.11
32.7
21.7
12.5
68.0
17.3
44.5
7.73
2.77
21.4
3.24
68.0
12.3
0.38
29.9
0.25
9.3
3-OBs
5.0
a [HClO4] ) 1 mM. b Substrate concentration 0.01-0.1 mM.
performance liquid chromatography procedure. The product
compositions are strongly dependent on the nature of the leaving
group. For example, 1-Br and 3-Br yield 95% and almost 100%
elimination, respectively, but 1-OBs and 3-OBs give 8% and
71% elimination, respectively. The measured rate constants and
reaction conditions are shown in Table 1.
Results
The solvolysis of 9-(X-methyl)fluorene (1-X, X ) I, Br, OBs)
in 25 vol % acetonitrile in water provides the alkene 9-meth-
ylidenefluorene and the substitution products 9-(hydroxymeth-
yl)fluorene (1-OH) and 9-(acetamidomethyl)fluorene (1-
NHCOMe, Scheme 2). Solvolysis in mixtures of water with
methanol affords 9-(methoxymethyl)fluorene (1-OMe) instead
of the amide. The solvolyses of 2-bromo-9-(X-methyl)fluorene
(2-X, X ) Br, OBs) and 2,7-dibromo-9-(X-methyl)fluorene (3-
X, X ) Br, OBs) yield analogous products. The kinetics of
the reactions were studied by a sampling-quench high-
Table 2 shows kinetic data for the reactions with added buffer
bases. The fast reactions with strong base at 25 °C were studied
by following the increase in absorbance at 308 nm by UV
spectrophotometry using the stopped-flow technique. The
kinetic data are presented in Table 2.
The deuterated substrates 9-(X-methyl)(9-2H)fluorene (1-X-
d), 2-bromo-9-(X-methyl)(9-2H)fluorene (2-X-d), and 2,7-di-
bromo-9-(X-methyl)(9-2H)fluorene (3-X-d) react slower to give
alkene. The measured kinetic deuterium isotope effects for
solvolysis and base-promoted reactions of these deuterated
substrates are given in Table 3.
X Abstract published in AdVance ACS Abstracts, May 1, 1997.
(1) Meng, Q.; Thibblin, A. J. Am. Chem. Soc. 1995, 117, 1839-1840.
(2) Meng, Q.; Thibblin, A. J. Am. Chem. Soc. 1995, 117, 9399-9407.
(3) Meng, Q.; Gogoll, A.; Thibblin, A. J. Am. Chem. Soc. 1997, 119,
1217-1223.
(4) Meng, Q.; Thibblin, A. J. Am. Chem. Soc. 1997, 119, 1224-1229.
(5) Meng, Q.; Thibblin, A. J. Chem. Soc., Chem. Commun. 1996, 345-
346.
Perchlorate anion has a small rate-enhancing effect on the
solvolysis reaction of 1-OBs which mainly reacts through the
ion pair. Addition of more efficient nucleophiles (Nu-)
S0002-7863(97)00362-4 CCC: $14.00 © 1997 American Chemical Society

SolVolytic Elimination and Substitution Reactions
J. Am. Chem. Soc., Vol. 119, No. 21, 1997 4835
Scheme 2
Table 2. Rate Constants for the Reactions of 1-X, 2-X, and 3-X
with Bases/Nucleophiles
Table 3. Kinetic Deuterium Isotope Effects for the Reactions of
1-X and 3-X
temp,
°C
106kNu
M-1 s-1
,
kE/[base],
temp,
°C
D
D
D
substratea
base
M-1 s-1
substratea
base
kobsH/kobs
kSH/kS
kEH/kE
25 vol % Acetonitrile in Water
1-Brb
1-Brc,d
1-Bre
solvent
AcO-
70
70
25
25
70
70
25
25
70
70
25
25
3.7 ( 0.2
1.12 ( 0.08 4.1 ( 0.3
4.7 ( 0.4
1-Brb,c
1-Brc,d
1-Brc,e
1-Brf
NCCH2COO-
70
70
70
25
70
70
70
25
70
70
25
70
25
70
70
70
70
25
70
70
70
70
25
2.47 × 10-4
8.98 × 10-4
3.34 × 10-3
3.11
MeOCH2COO-
AcO-
HO-
6.0 ( 1.2
1-Brf
MeO- h
solvent
6.9 ( 0.8
HO-
1-OBsb
1.09 ( 0.08 1.05 ( 0.08 2.0 ( 0.1
1-OBsb,c
1-OBsc,d
1-OBsc,e
1-OBsf
2-Brc,d
2-Brc,g
2-Brf
NCCH2COO-
MeOCH2COO-
AcO-
27.5
31.3
44.6
7.02 × 10-6
1.17 × 10-4
5.02 × 10-4
1.16
1-OBsc,d AcO-
3.7 ( 0.2
7.6 ( 0.8
6.6 ( 0.7
1-OBse
1-OBsf
3-OBsb
HO-
MeO- h
solvent
HO-
1.9 ( 0.1
1.04 ( 0.08 2.8 ( 0.1
4.9 ( 0.4
MeOCH2COO-
AcO-
3.77 × 10-3
1.37 × 10-2
8.59
3-OBsd,g AcO-
3-OBse
3-OBsf
HO-
7.5 ( 0.8
5.5 ( 0.6
HO-
MeO- h
2-OBsc,h
2-OBsf
3-Brc,i
AcO-
41.6
3.50 × 10-3
7.91
a Substrate concentration 0.01-0.1 mM. b [HClO4] ) 1 mM. c Mea-
sured with acetate buffer, 0.025-0.20 M ([NaOAc]/[HOAc] ) 4). d The
ionic strength was maintained (0.75 M) with sodium perchlorate.
e Measured with 1-25 mM sodium hydroxide. f Measured with 1-10
mM sodium methoxide. g Measured with acetate buffer, 0.025-0.20
M ([HOAc]/[NaOAc] ) 4). h In methanol.
HO-
CF3COO-
NCCH2COO-
MeOCH2COO-
AcO-
1.40 × 10-4
3.36 × 10-3
1.62 × 10-2
6.60 × 10-2
3-Brb,c
3-Brc,d
3-Brc,g
3-Brf
HO-
36.3
3-OBsc,g
3-OBsb,c
3-OBsc,d
3-OBsc,i
3-OBsf
AcO-
2.39 × 10-2
1.02 × 10-3
4.80 × 10-3
NCCH2COO-
MeOCH2COO-
CF3COO-
HO-
31.6
35.2
Methanol
1-Brf
MeO-
MeO-
MeO-
MeO-
MeO-
MeO-
25
25
25
25
25
25
5.67
3.75
54.6
38.7
368
314
1-OBsf
2-Brf
2-OBsf
3-Brf
3-OBsf
a Substrate concentration 0.01-0.1 mM. b Measured with cyanoac-
etate, 0.025-0.25 M. c The ionic strength was maintained (0.75 M)
with sodium perchlorate. d Measured with methoxyacetate buffer
([MeOCH2COO-]/[MeOCH2COOH] ) 1), 0.025-0.25 M. e Measured
Figure 1. Dependence of the rate constants for solvolysis of 1-OBs
on acetate anion concentration in 25 vol % acetonitrile in water at 70
°C (ionic strength 0.75 M, maintained with sodium perchlorate).
f
with acetate buffer, 0.025-0.20 M ([NaOAc]/[HOAc] ) 4). Base
The observed product ratio of 1-Nu to 1-OH is a measure of
the competition between the nucleophile (Nu-) and water for
reaction with the substrate and/or ion pair. The nucleophilic
selectivities were calculated from the product ratios by treating
the substitution reaction with solvent water as a second-order
reaction. The nucleophilic selectivities were calculated from
the measured product ratios by using eq 1. The nucleophilic
selectivity parameters kNu/kHOH and kMeOH/kHOH are thus dimen-
sionless ratios of second-order rate constants. The measured
values are given in Table 4.
concentration 1-25 mM. g Measured with acetate buffer, 0.025-0.20
M ([HOAc]/[NaOAc] ) 4). h Measured with acetate buffer, 0.05-0.20
M ([NaOAc]/[HOAc] ) 1). i Measured with CF3COO-, 0.10-0.65 M.
significantly increases the overall reaction rate by opening up
a bimolecular reaction route to substitution product 1-Nu
(Scheme 2) as shown with acetate ion in Figure 1. Acetate ion
also functions as a general base catalyst for the elimination
reaction.

4836 J. Am. Chem. Soc., Vol. 119, No. 21, 1997
Meng and Thibblin
Table 4. Nucleophilic Selectivities Expressed as Ratios of
Second-Order Rate Constants for Reactions of 1-OBsa at 70 °C
h
h
nucleophile nMeI
kNu/kHOH
nucleophile nMeI
kNu/kHOH
MeCN
0.20
4.37 81
AcO- d
N3
4.30 73
- e
Cl- b
Br- b
SCN- b
F- c
5.78 1.8 × 103
5.79
6.70
2.7
0.22 × 103 MeOHf
0.98 × 103 H2O
0
1.9
1
-0.27
9.6
CF3CH2OHg -2.8
0.30
a Substrate concentration 0.01-0.1 mM. b Using 0.75 M sodium salt.
c Using 0.32 M NaF ([F-]/[HF] ) 6). d Using 0.50 M NaOAc ([AcO-]/
[HOAc] ) 100). e Using 0.614 M NaN3 ([N3-]/[HN3] ) 9]). f 50 vol
% methanol in water. g 50 vol % 2,2,2-trifluoroethanol in water.
h Pearson, R. G.; Sobel, H.; Songstad, J. J. Am. Chem. Soc. 1968, 90,
319-326. The nucleophilicity of water has been estimated as n )
-0.27: Dietze, P. E.; Jencks, W. P. J. Am. Chem. Soc. 1986, 108,
4549-4555.
Figure 2. Brønsted plots for solvolytic elimination (kE) and substitution
(kS), respectively, in 25 vol % acetonitrile in water at 70 °C: bromides
(squares), brosylates (circles and triangles). The pKa values refer to
those of the parent fluorenes.27
kNu/kHOH ) ([1-Nu]/[1-OH])([H2O]/[Nu-])
(1)
Scheme 3
Discussion
Stepwise Reactions through Ion Pairs. A carbocationic
reaction path for the solvolysis of the bromides and the
brosylates is strongly indicated by the formation of the substitu-
tion product 1-NHCOMe with the acetonitrile component of
the solvent mixture. It reasonably cannot be the result of an
SN2 reaction. The corresponding secondary substrates 9-(1-X-
ethyl)fluorene, and the 2-bromo and the 2,7-dibromo derivatives,
solvolyze to give terminal alkene in addition to amide that was
concluded to be a further support for stepwise reaction through
an ion pair (cf. Scheme 1).1-3 The amides have been suggested
to be formed by nucleophilic substitution with the acetonitrile
component of the solvent. The reaction should occur within a
pool of solvent molecules that are present when the carbocation
is born. We have suggested that the unexpectedly high reactivity
of acetonitrile with very short-lived carbocationic intermediates
reflects the high dipole moment of acetonitrile (11.8 compared
to 5.9 for water).6 Accordingly, charge-dipole interactions
between the carbocation and acetonitrile are assumed to be of
importance in stabilizing the carbocation-acetonitrile pair.
Another indication for carbocation reactions is the gradual
decrease in the solvent substitution rate constant kS with
increasing acidity of the substrate as shown for the brosylates
in Figure 2. The effect, which is quantitatively expressed by a
Brønsted parameter of R ) -0.17, is expected for carbocationic
reactions because an enhanced acidity should decrease the
stability of the carbocation-like transition state of the ionization
step. The fact that the solvent substitution rate constant for
1-OBs is about 80 times larger than that of 1-Br (Table 1) may
be further support for stepwise reactions because brosylates
generally show faster stepwise reactions than bromides.
The small kinetic deuterium isotope effects on the elimination
reactions of 1-OBs and 3-OBs of kEH/kED ) 2.0 ( 0.1 and 2.8
( 0.1, respectively (Table 3), indicate that elimination products
are also formed from the ion pairs. We expect much larger
isotope effects for water-promoted reactions of the E2 type or
of the irreversible E1cB type (Vide infra).7 However, the isotope
effects on the disappearance of the substrates (kobsH/kobsD, Table
3) are too large to attribute the elimination solely to irreversibly
formed ion pairs; a maximum isotope effect kobsH/kobsD of about
1.15 is expected for such a mechanism.8
as the base and E1 through an irreversibly formed ion pair.
However, a closer analysis of the data shows that a branched
ion-pair mechanism in which all or the major part of the
substitution products with the solvent originate from an ir-
reversibly formed intermediate is not consistent with all the
measured isotope effects. The simplest way to account for the
results with the brosylates is therefore a single reaction path to
alkene via an ion-pair mechanism involving branching from a
reversibly formed intermediate (Scheme 3).9
The steady-state approximation applied to Scheme 3 yields
the following rate and isotope effect expressions:
kS ) Kk2
kE ) Kk3
(2)
(3)
(4)
kobs ) kS + kE ) K(k2 + k3)
H
H
D
kS /kSD ) (KH/KD)(k2 /k2 )
(5)
(6)
(7)
kEH/kED ) (KH/KD)(k3 /k3 )
H
D
kobsH/kobsD ) (KH/KD)(k2H + k3 )/(k2D + k3 )
H
D
Let us assume the following reasonable values for the micro-
D
H
scopic isotope effects: KH/KD ) 1.04, k2H/k2 ) 1.0, and k3
/
k3D ) 2.7.9 This gives a good account of the measured isotope
effects for 3-OBs (Table 3); the relative rate constants used for
the calculation of kobsH/kobs are taken from Table 1:
D
H
kS /kSD ) 1.04 × 1.0 ) 1.04
kEH/kED ) 1.04 × 2.7 ) 2.8
kobsH/kobsD ) 1.04(5.0 + 12.3)/(5.0/1.0 + 12.3/2.7) ) 1.9
The small elimination isotope effects may be the consequence
of two competing, parallel reactions: E2 with the solvent acting
The results for the less acidic substrate 1-OBs are also
consistent with the Scheme 3 model if a relatively small isotope
(6) Sidhu, H.; Thibblin, A. J. Phys. Org. Chem. 1994, 7, 578-584.
(7) A reviewer suggests a solvent-promoted E2 reaction with a very E1-
like transition state as an alternative to the carbocation mechanism.
(8) Westaway, K. C. In Isotopes in Organic Chemistry; Buncel, E., Lee,
C. C., Eds.; Elsevier: Amsterdam, 1987; Vol. 7, Chapter 5.
(9) Reaction branching as the cause of unusually large and unusually
small kinetic isotope effects has been reviewed: (a) Thibblin, A.; Ahlberg,
P. Chem. Soc. ReV. 1989, 18, 209-224. (b) Thibblin, A. Chem. Soc. ReV.
1993, 22, 427-433.

SolVolytic Elimination and Substitution Reactions
J. Am. Chem. Soc., Vol. 119, No. 21, 1997 4837
effect is assumed for the dehydronation step. The small
reflects some kind of solvation effect. However, the absence
of a negative charge is favorable in the E2 transition state
because there is an unfavorable electrostatic interaction between
a negatively charged base and the developing partial negative
charge on the â-carbon.
D
elimination isotope effects and the fact that kEH/kE is larger
for the more acidic substrate 3-OBs indicate product-like
transition states with extensive hydron transfer from the
brosylate ion pairs.
Solvent- and Base-Promoted Elimination Reactions. The
solvolytic elimination reactions of 9-(1-X-ethyl)fluorene (X )
Br, I) have been concluded to be of the water-promoted E2
type.1-3 This conclusion is based on the measured large kinetic
deuterium isotope effects, the substantial Brønsted â values, and
the low sensitivity to solvent ionizing power. The solvolytic
elimination reaction of the primary substrate 1-Br shows similar
behavior.
Apparently, the carbocation has a short but significant
lifetime. Thus, the ion pair either undergoes reaction with a
solvent molecule that is present when the carbocation is born
or is dehydronated by the leaving group or by a solvent water
molecule. A reasonable explanation of the stability of the
primary carbocation is that π-orbitals of the fluorenyl moiety
assist the ionization by interaction with the developing p-orbital
on the backside of the reaction center. Theoretical calculations
by MNDO methods support this conclusion. Thus, it has been
reported that the energy level of the HOMO of the fluorenyl-
methyl carbocation is -12.3 eV, which is 3.7 eV below that of
the HOMO of fluorene.10 The lifetime of the carbocation is
further discussed at the end of this paper.
Consistently, the closely related secondary substrates (R,R)-
and (R,S)-9-(1-X-ethyl)fluorene (X ) OBs) solvolyze to give
about 90% retention of configuration with solvent water as the
nucleophile.3 With added nucleophiles the secondary substrates
show bimolecular kinetics with mainly inversion of configura-
tion, but the amount of inversion decreases with the leaving
group in the following order: I > Br > OBs.3
Neighboring-group participation has also been observed for
the solvolysis of (R,R)- and (R,S)-1-(1-X-ethyl)indene (X ) I,
Br, Cl, OBs).5 The result of the homoallylic participation is
that the substitution reaction with solvent water shows a very
high retention of configuration.
The curvature of the log kE plot of the solvolytic elimination
for the brosylates versus pKa of the substrate as shown in Figure
2, the bromides do not show such a behavior, may suggest a
carbocation elimination mechanism. The R value for the
corresponding secondary system is slightly negative in contrast
to the positive R value for the bromides, which has been
concluded to be strong evidence for solvolytic E1 reactions of
the secondary brosylates.3
Further support of the ion-pair mechanism for the solvolytic
elimination is that water shows roughly a 14-fold positive
deviation from the Brønsted plot (â ) 0.79) for 1-OBs with
substituted acetate anions. The positive deviation could be
attributed to a change in mechanism: the reactions with
substituted acetate anions are E2 reactions, but the reaction
without added base is of the E1 type. The E1 reaction of 3-OBs
is slower and the base-promoted E2 reaction of this substrate
is favored by its higher acidity, which give rise to a negative
deviation (10-fold) from the Brønsted plot (â ) 0.64). This is
also the normal behavior of water as a catalyst in E2 reactions
as shown in the Brønsted plots for 1-Br (â ) 0.49) and 3-Br
(â ) 0.60): the catalytic constant for water as a base falls below
the Brønsted line for the substituted acetate anions by factors
of 13 and 6, respectively. Similar negative deviations for E2
reactions have been observed before.2,3 Dehydronation of
carbocation intermediates shows similar behavior.11-13 Negative
deviations of water-catalyzed reactions are well-known for
hydron transfer to and from carbon in which H2O and HO- are
the hydron donor and acceptor, respectively.14 The low catalytic
activity of water as a hydron acceptor in E2 reactions probably
(i) The large isotope effect of kobsH/kobsD ) 3.7 ( 0.2 for the
disappearance of the substrate at 70 °C (Table 3) implies that
the alkene formation does not proceed via an irreversibly formed
carbocationic intermediate, since an isotope effect of kH/kD
e
1.15 at 25 °C is expected for such a mechanism.8 A reversibly
formed intermediate which undergoes rate-limiting hydron
transfer has been ruled out for the secondary bromide since it
is unreasonable that such a short-lived ion pair would undergo
a bimolecular reaction to yield exclusively the stable alkene at
a low concentration of added base.2
(ii) Another, independent, strong indication against a car-
bocation mechanism for the elimination reaction of the primary
substrate 1-Br is the measured Brønsted parameter (â ) 0.49).
A very small â value is expected for a mechanism involving
rate-limiting dehydronation of a very unstable carbocation
intermediate.12 Accordingly, the data exclude reactions through
an ion pair, either coupled with the substitution reactions or as
a separate reaction. However, they indicate the E2 or the
irreversible E1cB mechanism.
(iii) The fact that the fraction of elimination to give the stable
alkene is larger for I- than for Br- as leaving group, the opposite
of what is expected for a stepwise carbocationic mechanism in
which the leaving group of the ion pair acts as the hydron
acceptor, is further support of the E2 mechanism. Thus, the
corresponding tertiary substrates 9-(2-X-propyl)fluorene, which
have been concluded to react stepwise, provide more terminal
alkene from the chloride ion pair than from the bromide ion
I
pair.12,15 The element effect is substantial, kE /kEBr ) 5.8 (Table
1), which may support the E2 mechanism in favor of the
irreversible E1cB mechanism. However, this is not conclusive
evidence because hyperconjugative stabilization from the leaving
group may be important in irreversible E1cB reactions.16
The tertiary bromide only exhibits E2 reaction in the presence
of strong bases.12,15,17 The decreased reactivity of the secondary
substrate 9-(1-X-ethyl)fluorene (X ) Br, I) to ionization shifts
the major reaction pathway from stepwise solvolysis to solvent-
promoted E2 reaction. The presence of bromo substituents in
the 2 and 7 positions of the fluorene ring makes this reaction
even more competitive due to the increased acidity of the
â-hydron.3 The decreased reactivity of the primary substrate
1-Br to ionization should further favor the E2 mechanism.
However, a minor fraction of the alkene may be produced
through the ion pair.
The solvolysis substitution rate constant kS for 1-Br is 27
times smaller than that for the corresponding secondary
substrate.2 The solvolytic elimination rate constants of 1-X (X
) I, Br) are also smaller than those of the corresponding
secondary analogs, e.g., 3 times smaller with bromide as leaving
group. This is reasonable because the secondary system has
(10) Ohwada, T. J. Am. Chem. Soc. 1992, 114, 8818-8827.
(11) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106, 1373-
1383.
(12) Thibblin, A. J. Am. Chem. Soc. 1987, 109, 2071-2076.
(13) Thibblin, A. J. Phys. Org. Chem. 1989, 2, 15-25.
(14) Thibblin, A.; Jencks, W. P. J. Am. Chem. Soc. 1979, 101, 4963-
4973 and references therein.
(15) Thibblin, A.; Sidhu, H. J. Chem. Soc., Perkin Trans. 2 1994, 1423-
1428.
(16) Thibblin, A. Chem. Scr. 1980, 15, 121-127 and references therein.
(17) Thibblin, A. J. Am. Chem. Soc. 1988, 110, 4582-4586.

4838 J. Am. Chem. Soc., Vol. 119, No. 21, 1997
Meng and Thibblin
one more methyl substituent to stabilize the E2 elimination
transition state in which a significant extent of double bond
character has been developed. However, with the stronger base
HO-, the primary bromide reacts 4.6 times faster than the
secondary one, and with acetate anion the ratio is 1.8. This is
consistent with the variable transition state theory which predicts
an E2 transition state having less bond cleavage to the leaving
group with a stronger base (Vide infra). Even less C-X bond
cleavage is expected for OBs-. Accordingly, the primary
brosylate reacts 8.7 times faster with HO- than the correspond-
ing secondary derivative. Rate depression effects of R-methyl
substituents have been observed previously by More O’Ferrall
and co-workers for methoxide-promoted dehydrohalogenation
reactions of fluorene derivatives.18
All the studied substrates show bimolecular kinetics with
added bases as exemplified for 1-OBs in Figure 1. The
Brønsted plots for the general base catalysis of the elimination
reactions all show substantial slopes: the â-values are 0.64 (3-
OBs), 0.79 (1-OBs), 0.60 (3-Br), and 0.49 (1-Br). Consistently,
the primary kinetic isotope effects on the elimination reactions
with added bases are substantial (Table 3). The eliminations
also exhibit significant sensitivity to changes in the acidity of
the â-hydron. The Brønsted parameters for the bromides and
the brosylates with acetate anion at 70 °C of R ) 0.27 and R )
0.36, respectively, are slightly larger than those measured with
hydroxide anion as base at 25 °C, R ) 0.22 (bromides) and R
) 0.32 (brosylates), respectively (plots not shown). Methoxide
ion in methanol at 25 °C gives somewhat larger values, R )
0.39 (bromides) and R ) 0.41 (brosylates).
Figure 3. Reaction coordinate-energy diagram (More O’Ferrall-
Jencks diagram) for alkene-forming 1,2-elimination.17,19 The horizontal
and vertical axes describe the amounts of hydron removal and cleavage
of the bond to the leaving group as measured by the Brønsted â and
C-X bond order, respectively. The energy contour lines are omitted.
The effect of removal of the R-methyl group of the substrate is a raising
of the energy of the upper edge of the diagram. The result for a
predominantly diagonal reaction coordinate is a shift to the right and
an increase in â as indicated.
The corresponding secondary substrates show a lower sen-
sitivity to the acidity of the substrate; e.g., with bromide and
brosylate leaving groups and acetate anion as the base, the R
values are 0.21 and 0.27, respectively.3 This is reasonable
because the primary substrates are expected to react through
transition states involving more hydron transfer.
Figure 4. Swain-Scott plot for the reaction of 1-OBs with nucleo-
philes in 25 vol % acetonitrile in water at 70 °C.
The characteristics of the transition state of â-elimination
reactions are conveniently described by More O’Ferrall-Jencks
diagrams.17,19 For example, the above-discussed change in
transition state caused by the removal of the R-methyl group
can be considered to be the effect of increasing the energy of
the carbocation intermediate in the upper left-hand corner and
the elimination product in the upper right-hand corner of the
diagram. This corresponds to a change in the transition-state
position as shown in Figure 3, resulting in a more carbanion-
like transition state with a larger â value. Accordingly, the
Brønsted parameter for the bromides increases from â ) 0.43
to â ) 0.49. Figure 3 can also be used to describe the effect
of a poorer leaving group: the upper edge will increase in
energy, and the result will be similar.
All the observed changes in the measured â values seem to
be consistent with the changes in the characteristics predicted
by the More O’Ferrall-Jencks diagram for central, diagonal
transition states, with one exception. Thus, the decrease in â
from 0.79 for 1-OBs to 0.64 for 3-OBs may indicate a shift
from an E2 reaction to an irreversible E1cB reaction for the
more acidic brosylate; an increase is predicted for the E2
mechanism with a diagonal transition state. However, an E2
transition state with a large horizontal component, corresponding
to hydron transfer, is an alternative rationalization of the results.
Bimolecular Substitution Reactions (SN2). The presence
of a weak base/nucleophile such as acetate anion gives rise to
competing bimolecular elimination and substitution reactions
as shown for 1-OBs in Figure 1. This substrate exhibits, as
expected, a higher sensitivity to nucleophilicity than the
corresponding secondary brosylate. The Swain-Scott param-
eters are s ) 0.47 (Figure 4) and s ) 0.28,2 respectively. The
transition state formed from the primary substrate requires more
stabilizing interactions with the nucleophile than the secondary
substrate in which the methyl group stabilizes the slightly
carbocationic reaction center. This is reflected in the Swain-
Scott parameters.
The assignment of the E2 mechanism to the base-promoted
elimination reactions of the halides is in accord with the studies
of More O’Ferrall and co-workers who proposed that the
methoxide ion-promoted eliminations of these compounds in
methanol are of the E2 type.18 The main argument was the
observation of elimination rates being larger than the estimated
ionization rates. With less efficient leaving groups, such as
carboxylate anions or tertiary amines, elimination was concluded
to be of the irreversible E1cB type.20
Water, methanol, and 2,2,2-trifluoroethanol show positive
deviations from the Swain-Scott plot (Figure 4). This is
(18) (a) More O'Ferrall, R. A.; Warren, P. J. J. Chem. Soc., Chem.
Commun. 1975, 483-484. (b) More O'Ferrall, R. A.; Warren, P. J.; Ward,
P. M. Acta UniV. Ups., Symp. UniV. Ups. 1978, 12, 209-218.
(19) (a) More O’Ferrall, R. A. J. Chem. Soc. B 1970, 274-277. (b)
Jencks, W. P. Chem. ReV. 1972, 72, 705-718. (c) Jencks, D. A.; Jencks,
W. P. J. Am. Chem. Soc. 1977, 99, 7948-7960. (d) Gandler, J. R.; Jencks,
W. P. J. Am. Chem. Soc. 1982, 104, 1937-1951.
(20) (a) More O’Ferrall, R. A.; Slae, S. J. Chem. Soc. B 1970, 260-
268. (b) More O’Ferrall, R. A.; Warren, P. J. Proc. R. I. Acad. 1977, 77B,
513-521. (c) Kelly, R. P.; More O’Ferrall, R. A.; O'Brien, M. J. Chem.
Soc., Perkin Trans. 2 1982, 211-219. (d) More O’Ferrall, R. A.; Larkin,
F.; Walsh, P. J. Chem. Soc., Perkin Trans. 2 1982, 1573-1579. (e) Larkin,
F.; More O’Ferrall, R. A. Aust. J. Chem. 1983, 36, 1831-1842.

SolVolytic Elimination and Substitution Reactions
J. Am. Chem. Soc., Vol. 119, No. 21, 1997 4839
tography (silica gel) with 25% ethyl acetate-pentane as eluent.
Recrystallization twice from CH2Cl2-pentane (1:2) gave pure mate-
rial: mp 101-102 °C.
2-Bromo-9-(hydroxymethyl)fluorene (2-OH) was prepared from
2-bromofluorene as described above. The crude product was purified
by flash chromatography (silica gel) with 10-20% ethyl acetate in
pentane as eluent. Recrystallization twice from CH2Cl2-pentane (1:
1) gave pure material: mp 115-116 °C.
2,7-Dibromo-9-(hydroxymethyl)fluorene (3-OH) was prepared
from 2,7-dibromofluorene as described above. The crude product was
purified by flash chromatography (silica gel) with ethyl acetate-pentane
(20:80) as eluent. Recrystallization twice from ethyl acetate-pentane
(1:10) gave pure material: mp 168-169 °C (lit.25 mp 154 °C).
9-(Bromomethyl)fluorene (1-Br) was prepared by treatment of the
alcohol 1-OH with ZnBr2-HBr in chloroform. Recrystallization twice
from ethanol-pentane (1:2) gave pure material: mp 65-66 °C.
9-(Iodomethyl)fluorene (1-I) was prepared from 1-OH with ZnI2-
HI in chloroform in a way similar to that described above. Purification
by flash chromatography (silica gel) with ethyl acetate-pentane (3:
97) as eluent, followed by recrystallization from hexane, gave pure
material: mp 93-94 °C.
consistent with, but does not require, nucleophilic assistance
from the solvent. There is a positive deviation of 6-fold for
the reaction of azide ion, consistent with an SN2 transition state
possessing some carbocationic character. Similar deviations
have been observed for the corresponding secondary system as
well as for other systems.2,21,22
The less carbocationic transition state of the primary brosylate
is also reflected in a larger product ratio, [1-SCN]/[1-NCS] )
72, compared with 5 for the secondary derivative.2 A gradual
increase in the reactivity of S relative to N of the thiocyanate
in the order of increasing acidity of the â-hydron has also been
noticed.3
The relative large nucleophilic selectivity ratio of kMeOH/kHOH
) 1.9 for the primary brosylate may reflect SN2 reaction with
methanol. The value measured for the secondary derivative is
1.0,2 and the tertiary chloride, which does not react by an SN2
mechanism with methanol, shows a selectivity value as low as
0.6.12 The very short lifetime of the tertiary chloride ion pair
is also indicated by the selectivity ratio of kN3/kHOH ≈ 5, which
has been used to estimate a lifetime of roughly 1 × 10-11 s.12
The lifetime of the primary carbocation should be, of course,
even shorter. However, it is not possible to semiquantitatively
estimate the lifetime by trapping experiments owing to the
appearance of a second-order reaction with good nucleophiles
as discussed above.
2-Bromo-9-(bromomethyl)fluorene (2-Br) was prepared as de-
scribed above. Recrystallization twice from ethanol-pentane (1:3) gave
pure material: mp 89-90 °C.
2,7-Dibromo-9-(bromomethyl)fluorene (3-Br) was prepared by
following a general bromination procedure.26 To a magnetically stirred
solution of N-bromosuccinimide (0.13 g) in tetrahydrofuran (4 mL)
was added dropwise a solution of triphenyl phosphite (0.23 g) in THF.
This was followed by adding 3-OH (0.15 g). The mixture was stirred
at room temperature for 15 h. The solvent was removed, and the residue
was dissolved in a minimum amount of dichloromethane. Purification
by flash chromatography (silica gel) with 3% ethyl acetate-pentane
as eluent, followed by recrystallization from ethanol-pentane (1:1),
gave pure material: mp 154-156 °C.
9-((((4′-Bromophenyl)sulfonyl)oxy)methyl)fluorene (1-OBs) was
synthesized by stirring a mixture of 1-OH (0.25 g), dry dichloromethane
(5 mL), dry pyridine (2 mL), and p-bromobenzenesulfonyl chloride
(0.75 g) at room temperature. The reaction mixture was quenched after
1 h (ca. 50% reaction) by addition of 2 M hydrochloric acid. The
water phase was extracted with dichloromethane. The combined
organic phases were washed with water and brine, and dried over
sodium sulfate. Evaporation of the solvent and separation with flash
chromatography on silica gel with ethyl acetate-pentane (5:95),
followed by recrystallization from chloroform-ethanol-pentane (1:1:
2), gave pure 1-OBs: mp 143-145 °C.
Experimental Section
General Procedures. NMR spectra were recorded for CDCl3
solutions at 25 °C with a Varian Unity 400 spectrometer, for 1H at 400
MHz and for 13C at 100.6 MHz. Chemical shifts are indirectly
referenced to TMS via the solvent signal (chloroform-d1, 7.26 and 77.0
ppm). The high-performance liquid chromatography analyses were
carried out with a Hewlett-Packard 1090 liquid chromatograph equipped
with a diode-array detector on a C18 (5 µm, 3 × 100 mm) reversed-
phase column. The mobile phase was a solution of acetonitrile in water.
The reactions were studied at constant temperature in a HETO 01 PT
623 thermostat bath. UV spectrophotometry was performed with a
Kontron Uvicon 930 spectrophotometer equipped with an automatic
cell changer kept at constant temperature with water from the thermostat
bath. The fast reactions were studied in the spectrophotometer with
the stopped-flow technique by using an Applied Photophysics RX 1000
rapid kinetics spectrometer accessory. The pH was measured using a
Radiometer PHM82 pH meter with an Ingold micro glass electrode.
Materials. Merck silica gel 60 (240-400 mesh) was used for flash
chromatography. Diethyl ether and tetrahydrofuran were distilled under
nitrogen from sodium and benzophenone. Pyridine and methylene
chloride were distilled under nitrogen from calcium hydride. 9-(Hy-
droxymethyl)fluorene and 2-bromofluorene were purchased from
Lancaster. Methanol and acetonitrile were of HPLC grade. All other
chemicals were of reagent grade and used without further purification.
The deuterium content of all the deuterated compounds was measured
2-Bromo-9-((((4′-bromophenyl)sulfonyl)oxy)methyl)fluorene (2-
OBs) was prepared as described above: mp 149-151 °C.
2,7-Dibromo-9-((((4′-bromophenyl)sulfonyl)oxy)methyl)fluo-
rene (3-OBs) was prepared as described above: mp 173-175 °C.
Kinetics and Product Studies. The reaction solutions were
prepared by mixing acetonitrile or methanol with water at room
temperature, ca. 22 °C. A few microliters of substrate dissolved in
tetrahydrofuran was added. Aliquots of this reaction mixture (∼500
µL) were transferred to several 2 mL HPLC flasks, which were sealed
with gas-tight PTFE septa and placed in an aluminum block in the
water thermostat bath. The concentration of the substrate in the reaction
solution was usually about 0.01-0.1 mM. At appropriate intervals,
samples were taken out and analyzed using the HPLC apparatus. The
rate constants for the disappearance of the substrates were calculated
from plots of substrate peak area versus time by means of a nonlinear
regression computer program. Very good pseudo-first-order behavior
was seen for all the reactions studied. The separate rate constants for
the elimination and substitution reactions were calculated by combina-
tion of product composition data, obtained from the peak areas and
the relative response factors determined in separate experiments, with
the observed rate constants.
1
2
by H NMR to be >99 atom % H in the 9 position of the fluorene
moiety. The deuterated compounds 2-bromo-9-(X-methyl)(9-2H)-
fluorene and 2,7-dibromo-9-(X-methyl)(9-2H)fluorene (X ) OH, Br,
OBs) were synthesized using the same method used for the corre-
sponding nondeuterated analogs.
2-Bromo(9,9-2H2)fluorene and 2,7-Dibromo(9,9-2H2)fluorene were
prepared by the same method as has been used for the synthesis of
(9,9-2H2)fluorene.2,23
9-(Hydroxymethyl)(9-2H)fluorene (1-OH-d) was prepared from
(9,9-2H2)fluorene following Ahlberg’s procedure for the corresponding
indenyl alcohol.24 The crude product was purified by flash chroma-
(21) Richard, J. P.; Jencks, W. P. J. Am. Chem. Soc. 1984, 106, 1383-
1396.
(22) Amyes, T. L.; Jencks, W. P. J. Am. Chem. Soc. 1989, 111, 7900-
7909.
(25) Brown, W. G.; Bluestein, B. A. J. Am. Chem. Soc. 1943, 65, 1235-
1236.
(23) Ek, M. Abstracts Uppsala Dissertations from the Faculty of Sciences;
Acta Universitatis Upsaliensis: Sweden, 1983; 692.
(24) Ahlberg, P. Chem. Scr. 1973, 3, 183-189.
(26) Bose, A. K.; Lal, B. Tetrahedron Lett. 1973, 3937-3940.
(27) Bordwell, F. G.; McCollum, G. J. J. Org. Chem. 1976, 41, 2391-
2395.

4840 J. Am. Chem. Soc., Vol. 119, No. 21, 1997
Meng and Thibblin
The alkene products were found to be stable under the solvolytic
reaction conditions for at least 20 half-lives.
The fast reactions with sodium hydroxide in 25 vol % acetonitrile
in water or sodium methoxide in methanol were studied with the
stopped-flow technique by following the appearance of the elimination
product at 308 nm with UV spectrophotometry.
Determination of Relative HPLC Response Factors. Pure 1-OBs,
1-Br, 2-OBs, 2-Br, 3-OBs, or 3-Br in acetonitrile (1 mM HClO4) was
injected onto the high-performance liquid chromatograph at least five
times. Then, 500 µL of this solution was transferred to a 2 mL
measuring flask and 0.5 M aqueous sodium hydroxide solution (500
µL) was added. After 20 min, 1 M acetic acid (500 µL) was added,
the volume adjusted to 2 mL with acetonitrile, and the sample analyzed
again. The data were used to calculate the relative response factors
for the substrates and the corresponding alkene products.
in acetonitrile (1 mM HClO4). The response factors for 1-OMe, 1-Nu,
and the amides were assumed to be the same as for the corresponding
alcohols.
The estimated errors are considered as maximum errors derived from
maximum systematic errors and random errors.
Acknowledgment. We thank the Swedish Natural Science
Research Council for supporting this work.
Supporting Information Available: Brønsted plots for the
elimination reactions of 1-OBs, 1-Br, 3-OBs, and 3-Br with
substituted acetate anions, Brønsted plots for the acetate anion-
promoted elimination reactions of the bromides and the brosy-
lates, and NMR data of the compounds (5 pages). See any
current masthead page for ordering and Internet access
instructions.
The relative response factors for 1-OBs and 1-OH, 2-OBs and 2-OH,
and 3-Br and 3-OH, respectively, were calculated from HPLC analysis
of a mixture of the two components, prepared by weighing, dissolved
JA970362F