Lack of the neighboring group rate effect in solvolytic reactions that proceed via participation

Article abstract of DOI:10.1002/poc.1290

In order to investigate the influence of solvent polarity on the rate effect of double bonds in reactions that proceed via an extended π-participation mechanism, the solvolysis rates (k_U) of the benzyl chloride derivative 1 and tertiary chlorid

Full text of DOI:10.1002/poc.1290

Research Article
Received: 29 June 2007,
Revised: 19 September 2007,
Accepted: 20 September 2007,
Published online in Wiley InterScience: 19 December 2007
(www.interscience.wiley.com) DOI 10.1002/poc.1290
Lack of the neighboring group rate effect
in solvolytic reactions that proceed
via participation
a
a
*
´
Sandra Juric and Olga Kronja
In order to investigate the influence of solvent polarity on the rate effect of double bonds in reactions that proceed via
an extended p-participation mechanism, the solvolysis rates (kU) of the benzyl chloride derivative 1 and tertiary
chloride 2 that have doubly unsaturated side chains were measured in absolute ethanol, 80% v/v. aq. ethanol and 97%
wt. aq. trifluoroethanol. The rates of the corresponding saturated analogs 1S and 2S (kS) were measured in 80% aq.
ethanol and 97% wt. aq. trifluoroeth‘anol, while those in pure ethanol were calculated according to LFER equation log
k ¼ sf (Ef þ Nf). In solvents with moderate ionizing power (ethanol and 80% aq. ethanol) the expected rate effects were
obtained (kU/kS>1), while in solvent with high ionizing power (2,2,2-trifluoroethanol) absence of the rate effect was
observed (kU/kSꢀ1), indicating that in the kS process the solvation of the transition state is very important, while in kD
process the breaking of the C—Cl bond is not appreciably developed in the transition state and the solvent effect is
marginal. Copyright ß 2007 John Wiley & Sons, Ltd.
Keywords: neighboring group assistance; extended participation; inverse neighboring group rate effect
INTRODUCTION
Neighboring group participation in SN1 reactions occurs when
the group adjacent to the reaction center acts as an intra-
molecular nucleophile. Assistance of the neighboring group may
cause charge delocalization and thus lower the reaction barrier.
The fact that solvolysis of a compound with a suitably located
neighboring group is enhanced in comparison to the solvolysis of
a corresponding compound lacking that group has been taken as
important evidence for the existence of the anchimeric
assistance. Probably the most cited example is the acetolysis
of anti-7-norbornenyl tosylate, which is 1011 faster than the
acetolysis of the saturated analog.[1] Furthermore, the lack of rate
enhancement was often taken as proof that solvolysis follows the
kC route (unassisted process) rather than the kD pathway (assisted
process).[2]
Assistance of the double bond(s) located properly to partici-
pate in forming hexa- or pentacyclic transition states in solvolytic
displacement reactions has been investigated widely.[3] Even
though other kinetic methods indicate that the p-participation of
double bond(s) is operative, solvolysis rates (80% aq. ethanol) of
several substrates with unsaturated side chains (kU) are virtually
equal to the rates of their saturated analogs (kS) or are only
moderately enhanced.[4] In this work, we set out to re-examine
the solvolytic behavior of benzyl and tertiary substrates 1 and 2,
and to find out how the ratio of the rates of a compound that
solvolyses by way of double bond assistance and by the SN1 route
(kU/kS) depends on the solvent. Solvolysis rates of chlorides 1S
and 2S having the same number of carbon atoms in the alkyl side
chains were used as a reference for the unassisted SN1 process.
Compounds 1/1S and 2/2S have been chosen because the
extended p-participation of both double bonds for 1 and 2
were established unambiguously.[5] Thus, both substrates
solvolyse with smaller entropy and enthalpy of activation than
ˇ ´
Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovacica 1, P.O.
*
Box 156, 10000 Zagreb, Croatia.
E-mail: kronja@pharma.hr
a
´
S. Juric, O. Kronja
Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovacica 1,
ˇ ´
10000 Zagreb, Croatia
J. Phys. Org. Chem. 2008, 21 108–111
Copyright ß 2007 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

LACK OF NEIGHBORING GROUP RATE EFFECT
do the corresponding reference compounds that proceed
Table 1. Solvolysis rates of chlorides 1, 2, 1S, and 2S and
kU/kS ratios
by way of one p-bond participation (DDHz ¼ ꢁ36 kJ molꢁ1
,
DDSz ¼ ꢁ95 J Kꢁ1 molꢁ1 for 1; DDHz ¼ ꢁ21 kJ molꢁ1, DDSz ¼
ꢁ88 J Kꢁ1 molꢁ1 for 2; the side chain in the reference compounds
with one neighboring double bond is E-4-methyl-4-hexenyl)
indicating that the second double bond also participates in the
rate determining step. The slope of the Hammett plot obtained
with the series of 1 is considerably smaller (rþ ¼ ꢁ1.76 ꢂ 0.04;
substituents on the phenyl ring were: p-methoxy, p-methyl, H,
m-bromo, and p-bromo) than that obtained with the correspond-
ing reference chlorides with one double bond in the side chain
(rþ ¼ ꢁ3.93 ꢂ 0.10) and saturated side chain 1S (rþ ¼ ꢁ6.28 ꢂ
0.25), supporting considerably less charge at the reaction center.
Similarly, the b-deuterium kinetic isotope effects (KIEs) indicate
pronounced charge delocalization from the reaction center for
chloride 2. Thus, ethanolysis of the hexadeuterated saturated
analog 2S (two deuteromethyl groups adjacent to the reaction
center) produced reference KIE (kH/kD ¼ 1.80 ꢂ 0.03). The effect
was reduced (kH/kD ¼ 1.37 ꢂ 0.03) for the corresponding hex-
adeuterated tertiary chloride with one double bond suggesting a
concerted monocyclization, while the hexadeuterated chloride 2
solvolysed without a significant secondary b-deuterium KIE
(kH/kD ¼ 1.01 ꢂ 0.04).
c
Compound
Solventa
t (8C)
k ꢃ 10ꢁ4 (sꢁ1 b
)
kU/kS
1S
EtOH
80EtOH
25
68
62
58
25
19
25
30
35
25
25
25
25
25
25
70.7
60.8
51.6
25
60
50
35
25
25
3.05 ꢃ 10ꢁ4 d
2.72 (3)
1.36 (2)
94.5 (3)
0.0200e
1.81 (4)
4.16 (1)
7.48 (2)
13.0 (2)
0.626 (3)
2.24f
97TFE
1
EtOH
2050
112
80EtOH
97TFE
EtOH
80EtOH
97TFE
EtOH
4.61g
1.1
2S
2
1.14 ꢃ 10ꢁ3 d
0.123h
8.03 (3)
11.3 (5)
3.97 (5)
1.42 (1)
0.0507e
16.6 (7)
8.74 (5)
3.25 (1)
1.59e
44
80EtOH
97TFE
RESULTS AND DISCUSSION
In order to investigate the influence of solvent ionizing power on
the kU/kS ratio, the solvolysis rates of the unsaturated compounds
1 and 2 were measured by potentiometric titration in absolute
ethanol (EtOH), 80% aq. ethanol (80EtOH) and 97% wt. aq.
2,2,2-trifluorethanol (97TFE), or were taken from the literature
(Table 1). The solvolysis rates of 1S and 2S in 80EtOH and 97TFE
have been measured or taken from literature.[6] However, the
rates of the reference compounds 1S and 2S in pure ethanol are
too slow to be measured by conventional methods at conven-
tional temperatures. In order to get data for solvolysis rates in
pure ethanol, recent findings have been employed to calculate
the solvolysis rates of the substrates that follow an SN1 pathway
(1S and 2S).
13
2.1
17.1 (1)
a EtOH is absolute ethanol, 80EtOH is 80% v/v aqueous ethanol,
97TFE is 97% wt. 2,2,2-trifluoroethanol.
b The uncertainties of the last reported figure (standard devi-
ation of the mean) are shown in parentheses; the rate con-
stants lacking standard errors are extrapolated or taken from
literature.
c kU is the rate of the compound with an unsaturated side
chain, kSꢁ is the rate of the compound with an saturated side
chain.
d Rates calculated according to equation log k ¼ sf (Ef þ Nf).
According to a general reactivity scale developed by studying
the solvolysis rates of a large variety of benzhydryl substrates with
different leaving groups in different solvents, the absolute rate of
the heterolysis reaction (SN1) can be calculated according to the
following equation:[7]
e Extrapolated value.
f Reference [5c].
g Reference [5a].
h Reference [5b].
log k ¼ sfðEf þ NfÞ
(1)
from the nucleofuge specific parameters for chloride (Nf ¼ 1.87
and sf ¼ 1.00), the solvolysis rates of 1S and 2S in pure ethanol
were calculated.
in which: k is the first-order rate constant (sꢁ1); sf is the nucleo-
fuge specific slope parameter; Nf is the nucleofugality parameter;
and Ef is the electrofugality parameter. The nucleofugality (Nf) is
defined for a leaving group and solvent pair, while the
electrofugality parameters Ef are independent variables and
refer to the carbocation generated in heterolysis reaction (SN1). Ef
parameters for the corresponding carbocation of the saturated
model compounds 1S and 2S were easily calculated from the
known reaction rates (kS) for 1S and 2S in 80EtOH and in 97TFE at
258C (Table 1), and from earlier determined nucleofuge specific
parameters for chloride (Nf ¼ 3.28 and sf ¼ 0.98 in 80EtOH and
Nf ¼ 5.56 and sf ¼ 0.82 in TFE). By applying Eqn (1), the following
average electrofugality parameters were obtained: Ef ¼ ꢁ9.38 ꢂ
0.34 for corresponding carbocation of 1S and Ef ¼ ꢁ8.81 ꢂ 0.37
for the corresponding carbocation of 2S. From these Ef values and
Let us discuss the reliability of the calculated rate constants in
pure ethanol obtained for the saturated reference compounds 1S
and 2S by using the Eqn (1). The LFER presented above has been
developed using benzhydryl derivatives.[7a] Because of the
different steric and electronic interactions between the electro-
fuge and the nucleofuge in the substrates 1S and 2S, as well as
the different solvation of differently delocalized carbocations,
deviation from the correlation may occur. The scope of the above
equation has been examined for various electrofuges by calcu-
lating the Efs for a variety of carbocations from the solvolysis rates
of different chlorides or bromides in standard solvents.[7b] It was
demonstrated that for aryl substituted carbocations, as is
generated in solvolysis of 1S, the agreement of Efs are better
J. Phys. Org. Chem. 2008, 21 108–111
Copyright ß 2007 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

´
S. JURIC AND O. KRONJA
than ꢂ 0.3. Therefore, the rate constant calculated for 1S is
reasonably reliable and can be taken as a valid reference value.
The largest scatter in Ef was obtained for tert-butyl cation (Ef ¼
ꢁ8.21 ꢂ 0.68). Since compound 2S produces a tertiary aliphatic
carbocation, it can be predicted that the deviations of Ef in
different solvents is up to ꢂ 0.7. Nevertheless, even though the
calculated rate constant for 2S is less reliable, the error is below
one order of magnitude.
The absolute reaction rates (measured and calculated) and
kU/kS ratios are presented in Table 1. In a solvent with moderate
ionizing power, like absolute ethanol, participation of the double
bonds causes enhancement of the reaction rate in both cases.
However, as the ionizing power of the solvent increases, the kU/kS
ratio decreases, so in 97TFE no rate effects were observed. A
similar observation that the kU/kS ratio is decreased in a solvent
with larger ionizing power was reported for biomimetic
cyclization of substrates with triple bond.[8]
caused by charge delocalization in substrates that proceed via
the neighboring group participation mechanism, then the
enhancement of the reaction rate of the substrates in which
participation occurs is only moderate. Since the transition state
stabilization caused by charge delocalization depends very little
on the solvent used, the existence or absence of the neighboring
rate effect is determined by the efficiency of the carbocation and
leaving group stabilization via an unassisted process. Thus, in
EtOH whose ionizing power is the smallest, the barrier difference
between the nonassisted and assisted process is the largest
because of the least effective stabilization of the transition
structure produced from 1S and 2S, and the kU/kS ratio is the
largest (Table 1). Enhancement of the rate of the saturated
substrates due to solvation causes a less pronounced rate effect
(kU/kS) in 80EtOH. Absence of the rate effect (kU/kS ꢀ 1) is
observed in 97TFE whose ionizing power is the largest among
three solvents used, caused by electrostatic and electrophilic
solvation of the developing chloride ion.[9]
The fact that the kU/kS ratio depends on the solvent can be
rationalized if the manner of stabilization in the kC and kD
processes is considered. In the kC route that 1S and 2S follow,
solvation is the most important variable that influences the rea-
ction rates. Therefore, the solvolysis rates of the saturated
substrates increase with ionizing power of the solvent, because of
the more efficient stabilization of the carbocation and the leaving
group generated in the transition state. On the other hand, even
at the first glance it is obvious that the rate constants of the
substrates that proceed via assistance of the double bonds
depend only marginally on the solvent ionizing power. For
example, solvolysis of benzyl chloride 1 is only about eight times
faster in 97TFE than in EtOH, while the difference of the ionizing
power of those solvents is well above 4 (DY ¼ 4.49, DYOTs ¼ 5.36).
The stabilization of the intermediate carbocation generated from
1 and 2 comes from charge delocalization, which lowers the
energy of the carbocation intermediate. Therefore, according to
the Hammond postulate, the reaction proceeds through an
earlier transition state. In this earlier transition state, the breaking
of the C—Cl bond is less advanced than in the transition state of
solvolysis of the saturated model, and the solvation is less
important. If the charge is delocalized to more atoms, the
transition state is more shifted toward to starting structure. Since
in the carbocation intermediate generated from chloride 1 the
charge is additionally delocalized to the phenyl group by reso-
nance, it is easy to understand why the solvolysis rates of benzyl
chloride 1 are even less influenced by solvent ionizing power
than that of tertiary substrate 2.
The lack of the rate effect or even an inverse rate effect can be
rationalized if the Eyring plots are considered (Fig. 1). The slope of
the unassisted process is much steeper than that of the assisted
process, due to the relatively small DHz of the later caused by
intramolecular bond formation. In Fig. 1 log k of 1 and 1S in 97TFE
and 80EtOH are plotted against 1/T. Intersection of the plots in
97TFE is at 298C, indicating that above this temperature the
saturated reference solvolyses faster than the unsaturated analog
(kU/kS < 1). Even though only a moderate rate effect is obtained
with 1 in 80EtOH, the plot indicates that in all possible experi-
mental conditions kU/kS > 1, since the intercept of the plots is at
1098C, which is above the boiling point of the solvent mixture. As
the barrier between the assisted and unassisted process
increases, the intersection of Eyring plots are shifted to higher
temperatures and normal rate effects can be observed at all
experimental temperatures (kU/kS > 1).
In order to rule out the possibility that the lack of the rate effect
in 97TFE indicates a qualitative change in the mechanism of
solvolysis, we have considered the relevant parameters earlier
measured with benzyl chloride 1. Thus, if the fraction of the
reaction that proceeds by extended participation is considerably
decreased in 97TFE, rþ for 1 would be decreased up to ꢁ4, as is
obtained for a compound that proceeds via simple p-partici-
pation. However, in both solvents measured, 80EtOH and 97TFE,
those parameters are essentially the same (rþ ¼ ꢁ1.45 ꢂ 0.03 in
80EtOH and rþ ¼ ꢁ1.76 ꢂ 0.04 in 97TFE), indicating a similar
amount of the positive charge on the reaction center.
If the energy of stabilization by solvation in the saturated
substrates is close in magnitude to the energy of stabilization
In conclusion, according to the findings above it can be
predicted that for reactions that proceed via distinct neighboring
participation, the kD/kS ratio is sensitive to solvent ionizing power.
Therefore, only a large rate effect (kD/kS : 1) can be taken as
valid proof for neighboring group participation. Moderate or
even inverse rate effects can conceal some considerable
participation, and ambiguous results can be clarified if the
changes in kD/kS are considered after switching to a different
solvent, or by changing the experimental temperature.
EXPERIMENTAL SECTION
Substrate preparation
Substrate 1 was prepared according to known reaction
scheme.[5a,5c]
Figure 1. Eyring plots obtained with 1 and 1S in 97TFE and 80EtOH
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Copyright ß 2007 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2008, 21 108–111

LACK OF NEIGHBORING GROUP RATE EFFECT
2,6,10-trimethyl-6,10-dodecadiene-2-ol
since the solvolysis rates were found to be independent of
contamination.
The Grignard reagent, prepared from Mg (120 mg, 4.9 mmol) and
1-bromo-4,8-dimethyl-4,8-decadiene[5c] (690 mg, 2.82 mmol) in
ether (10 mL) was cooled to 08C and a solution of acetone
(164 mg, 2.82 mmol) in 10 mL ether was added dropwise. Stirring
was continued at room temperature for 1 h. The Grignard comp-
lex was hydrolyzed with saturated aqueous NH4Cl. The water
layer was washed with ether three times and the combined ether
layers were dried over Na2SO4. The crude product was purified by
column chromatography on silica gel. The pure 2,6,10-
trimethyl-6,10-dodecadienol obtained (22.5%) was in the form
of viscous oil.
Kinetic measurements
Solvolysis rates were followed in absolute ethanol (EtOH), 80%
(v/v) aqueous ethanol (80EtOH) and 97% (wt.) aqueous 2,2,2-
trifluoroethanol (97TFE) titrimetrically by means of a pH-stat
(end-point titration, pH ¼ 6.85). Typically, 0.02 mmol of the
chloride was dissolved in 20 mL of the solvent that was thermo-
stated at the required temperature (ꢂ 0.058C), and the liberated
HCl was continuously titrated by using a 0.008 M solution of
NaOH in the same solvent mixture. Individual measurements
could be described by the first-order law from 15% up to at least
85% completion. First-order rate constants were calculated from
about 100 determinations using a nonlinear least-squares
program. Measurements were usually repeated 3–4 times.
1H NMR (CDCl3) ¼ d 1.22 (s, 6H, (CH3)2COH), 1.56–1.62 (m, 9H,
—
—
—
—
C
CCH ), 1.99–2.08 (m, 10H, CCH C), 5.16–5.22 (m, 2H, C CH);
3 2
13C NMR (CDCl3) ¼ d 13.07, 15.36, 15.76, 26.32, 30.33, 34.30, 39.39,
41.67, 70.99, 118.34, 124.39, 135.32, 135.58.
Acknowledgements
2-methyl-tetradecan-2-ol
We gratefully acknowledge the financial support of this research
by the Ministry of Science, Education and Sport of the Republic of
Croatia (Grant No. 006-0982933-2963).
The procedure is the same as described above. From 120 mg
(4.9 mmol) of Mg, 702 mg (2.82 mmol) of 1-bromododecane and
164 mg (2.82 mmol) of acetone was obtained 205 mg (31.8%) of
pure alcohol.
1H NMR (CDCl3) ¼ TM0.96 (t, 3H, CH3CH2), 1.26 (s, 6H,
(CH3)2COH), 1.29–1.40 (m, 22H, CCH2C), 13C NMR (CDCl3) ¼
TM14.09, 21.33, 23.18, 30.33, 32.39, 39.39, 72.11.
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Copyright ß 2007 John Wiley & Sons, Ltd.
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