Reactivity of some tertiary chlorides with olefinic and methoxy neighboring groups. A case of extended π, n-participation

Article abstract of DOI:10.1002/poc.492

Tertiary 2-chloro-2-methyl-5-methoxypentane (2) solvolyzes with a significantly reduced secondary β-deuterium kinetic isotope effect (substrate with two trideuteromethyl groups), and with smaller entropy and enthalpy of activation than the reference saturated analog 4 [k_H/k_D = 1.35±0.01 VS k_H/k_D = 1.79 ± 0.01; ΔΔH^≠ = -11 kJ mol^-1; ΔΔS^≠ = -30 J mol^-1 K^-1, in 80% (v/v) aqueous ethanol], indicating participation of the methoxy group in the rate-determining step. 2-Chloro-2,5-dimethyl-8-methoxy-5(E)-octene (3) solvolyzes with a further reduction of the isotope effect, and drastically smaller activation parameters [k_H/k_D = 1.16 ± 0.01; ΔΔH^≠ = -33 kJ mol^-1; ΔΔS^≠ = -106 J mol^-1 K^-1, in 80% (v/v) aqueous ethanol], suggesting that the solvolysis of 3 proceeds with extended π, n-participation, i.e. the assistance of both neighboring groups occurs in the rate-determining step. Copyright

Full text of DOI:10.1002/poc.492

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2002; 15: 556–560
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.492
Reactivity of some tertiary chlorides with ole®nic and
methoxy neighboring groups. A case of extended p, n-
†
participation
Sandra Juri c and Olga Kronja*
Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovai c a 1, P.O. Box156, 10000 Zagreb, Croatia
Received 19 October 2001; revised 23 January 2002; accepted 4 February 2002
ABSTRACT: Tertiary 2-chloro-2-methyl-5-methoxypentane (2) solvolyzes with a significantly reduced secondary b-
deuterium kinetic isotope effect (substrate with two trideuteromethyl groups), and with smaller entropy and enthalpy
≠
of activation than the reference saturated analog 4 [k /k = 1.35 Æ 0.01 VS k /k = 1.79 Æ 0.01; DDH =
H
D
H D
À1
≠
À1 À1
À11 kJ mol ; DDS = À30 J mol
K , in 80% (v/v) aqueous ethanol], indicating participation of the methoxy
group in the rate-determining step. 2-Chloro-2,5-dimethyl-8-methoxy-5(E)-octene (3) solvolyzes with a further
≠
reduction of the isotope effect, and drastically smaller activation parameters [k /k = 1.16 Æ 0.01; DDH =
H
D
À1
≠
À1 À1
À33 kJ mol ; DDS = À106 J mol
K , in 80% (v/v) aqueous ethanol], suggesting that the solvolysis of 3 proceeds
with extended p, n-participation, i.e. the assistance of both neighboring groups occurs in the rate-determining step.
Copyright  2002 John Wiley & Sons, Ltd.
KEYWORDS: Secondary b-deuterium isotope effects; tertiary chlorides; extended p, n-participation; solvolysis
INTRODUCTION
= 1.30 Æ 0.03, in 80% (v/v) aqueous ethanol (80E); k /
H
k = 1.29 Æ 0.02, in 97% (w/w) aqueous 2,2,2-trifluor-
D
Substrates having a neighboring group properly located
with respect to the reaction center solvolyze with
neighboring group participation. The abilities of the
oethanol (97T)] in comparison with its saturated analog
(k /k = 1.79 Æ 0.01, in 80E; k /k = 1.81 Æ 0.01, in
H
D
H D
1
97T), demonstrating the assistance of the double bond in
the rate-determining step. Essentially the same result was
obtained with tertiary chloride 2 (k /k = 1.35 Æ 0.01, in
double bond and the methoxy group to participate in
2–4
solvolytic reactions are comparable. They both act as
intramolecular nucleophiles and stabilize the carbocation
intermediate and the transition state. The similar behavior
of the double bond and the methoxy group is due to their
similar nucleophilicities. Mayr et al. investigated the5
reactivity of carbocations with different nucleophiles,
and found that the reaction rates of 4,4-dichlorobenzhy-
dryl cation with a trisubstituted double bond (2-methyl-2-
butene) and with various ethers are of the same order of
magnitude (H. Mayr, personal communication).
H
D
80E; k /k = 1.34 Æ 0.01, in 97T), indicating that the 5-
H
D
methoxy group takes part in the reaction. The existence
of n-participation of the methoxy group and formation of
a five-membered oxonium ion intermediate were stipu-
7
‡
lated earlier on the basis of product analysis and the r
4
value of the corresponding benzyl derivatives.
6
In a previous communication, we showed that the
solvolytic behaviors of tertiary chlorides 1 and 2 are very
alike. The most significant result reported is the reduction
of the secondary b-deuterium kinetic isotope effects
(
KIEs). Thus, tertiary chloride 1 has a considerably
lower secondary b-deuterium KIEs in solvolysis [k /kD
H
*
Correspondence to: O. Kronja, Faculty of Pharmacy and Biochem-
istry, University of Zagreb, A. Kovai c´ a 1, P.O. Box 156, 10000
Zagreb, Croatia.
E-mail: kronja@rudjer.irb.hr
†
Presented at the 8th European Symposium on Organic Reactivity
In this work, we examined a model substrate in which
simultaneous assistance of p- and n-electrons could
occur, i.e. we studied whether extended p, n-participation
(
ESOR-8), Cavtat (Dubrovnik), Croatia, September 2001.
Contract/grant sponsor: Ministry of Science and Technology of the
Republic of Croatia; Contract/grant number: 0006451.
Copyright  2002 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 556–560

EXTENDED p, n-PARTICIPATION IN SOLVOLYSIS OF SUBSTITUTED CHLORIDES
557
Table 1. Solvolysis rate constants and activation parameters of some tertiary chlorides having the methoxy group in the side-
chain
a
À4 À1 b
≠
À1 c
≠
À1
À1 c
Compound
Solvent
80E
t(°C)
k(10
s
)
DH (kJ mol
)
ÀDS (J K mol
76 Æ 7
)
2
45
1.55 (2)
3.64 (2)
8.74 (6)
0.204
2.95 (1)
8.57 (3)
23.9 (2)
1.91 (1)
2.18 (1)
2.37 (5)
4.10 (7)
8.51 (4)
0.41
77 Æ 2
5
6
2
5
5
5
9
7T
25
71 Æ 4
73 Æ 13
3
4
5
5
2-d6
80E
7T
80E
50
25
50
—
—
9
3
56 Æ 6
142 Æ 17
6
7
2
0
0
5
9
7T
35
11.3 (1)
30.3 (5)
55.7 (2)
2.05 (3)
10.10 (2)
64 Æ 8
92 Æ 25
4
5
5
5
3-d6
80E
7T
50
35
—
—
9
a
8
0E is 80% (v/v) aqueous ethanol; 97T is 97% (w/w) aqueous 2,2,2-trifluoroethanol.
b
The uncertainties of the last reported figure (standard deviation of the mean) are shown in parentheses. The rate constants lacking standard errors are
extrapolated.
c
Uncertainties are standard deviations.
of the neighboring groups occurs. This phenomenon has
not been reported earlier. Therefore, we sought more
information about the model in which there is simple n-
participation, as in the case of chloride 2, and to examine
the solvolytic behavior of the tertiary chloride 3, since it
combines the structural characteristics of both chlorides 1
and 2. We decided to determine whether enhancement of
the solvolytic reactivity, decrease in activation par-
chains consist of eight carbon atoms). Reaction rates and
activation parameters obtained in the solvolysis of both
reference chlorides were reported earlier.
9
RESULTS AND DISCUSSION
≠
≠
ameters (DH and DS ) and, most significantly, depres-
Substrates were prepared according to Scheme 1. The
8
sion of the secondary b-deuterium KIEs occur in
trans-trisubstituted double bond was introduced accord-
solvolysis of 2 and 3, in comparison with the same
parameters of the saturated tertiary substrates. Chloride 4
is a suitable reference for chloride 2 (both side-chains
consist of five carbon atoms), and chloride 5 is an
appropriate reference model for chloride 3 (the side-
10
ing to Johnson et al.’s procedure. The deuterated
Table 2. Relative solvolysis rates and b-deuterium secondary
kinetic isotope effects of some tertiary chlorides
a
b
D
Compound Solvent
ku/ks
k /k
H
Ref.
9
4
1
2
3
80E
7T
80E
7T
80E
7T
80E
7T
—
1.79 (1)
1.81 (1)
1.30 (3)
1.29 (2)
1.34 (1)
1.35 (1)
1.16 (1)
1.12 (1)
9
—
6
6
0.6
—
0.93
0.52
2.97
—
9
9
—
9
a
k
u
is the rate constant of the substrate with the neighboring group, k
s
is the
substrate with adequate length of the alkyl side-chain, k
The uncertainty of the last reported figures (standard deviation of the
mean) is shown in parentheses.
u
/k at 25°C.
s
b
Scheme 1
Copyright  2002 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 556–560

´
S. JURIC AND O. KRONJA
5
58
compound 3-d was obtained according to the same
located between the double bond and the oxygen atom in
6
procedure, but using methyl-d iodide.
the side-chain. Extended p-participation mechanism fits
3
≠
Chlorides 2, 3 and 3-d were solvolyzed in 80E and
excellently the values of DS , since it is known that the
6
9
7T. Solvolysis rates were followed with a pH-stat.
loss of one internal rotation in the transition state
decreases DS for ca 20 J mol K .
≠
À1 À1 13
The activation parameters were calculated from the
rate constants determined at several temperatures. The
rate constants and activation parameters are shown in
Table 1. Secondary b-deuterium KIEs obtained with 1
and 3, along with some reference chlorides, are given
in Table 2.
It has been proved that only a large rate enhancement
in the solvolysis of a compound having a neighboring
group in comparison with the corresponding compound
that lacks the neighboring group can be taken as valid
proof of neighboring group participation. A modest
rate effect, as obtained with 3, or even an inverse rate
effect, as obtained with 2 (Table 2), can conceal
considerable assistance. Therefore, in such a case, the
participation or its lack must be proved by other
methods.
We demonstrated earlier that the activation parameters
in the solvolysis of saturated tertiary chlorides, which
proceed through non-assisted reaction, are essentially the
same, regardless of the chain length. For example, the
It was pointed out earlier that the secondary b-
deuterium KIEs are the most sensitive probe for proving
14
the participation of the neighboring group.
Substrates deuterated at the b-position relative to the
reaction center show a rate depression relative to the
protio analogs. The cause of this KIE is the hyperconju-
gative electron release from the neighboring C—H(D)
bond to the incipient empty p-orbital in the transition
state. Because of the charge delocalization, less hyper-
conjugative interaction between the p-orbital of the
reaction center and the b-CH(D) bonds of the methyl
group occurs, resulting in a lower secondary b-deuterium
KIE. Recognizing that the kinetic isotope effects are
cumulative, the magnitudes of b-deuterium KIEs with
hexadeuterated substrates can show the extent of the
participation most clearly.
1
1
Numerous dimethylalkyl chlorides with the alkyl
11,15
side-chain ranging from ethyl to squalanyl,
whose
reactions proceed via unassisted processes, solvolyze
with the same secondary b-deuterium KIEs (kH/
kD = 1.8) for two deuterated methyl groups adjacent to
the reaction center. The existence of one neighboring
group that participates with its electrons in the rate9-
determining step reduces that value by more than 50%.
Thus, almost the same reduction of the b-deuterium
KIE for chlorides 1 and 2, as shown in Table 2,
indicates assistance of their p- and n-electrons,
respectively. However, the reduction of the secondary
b-deuterium KIE is considerably more pronounced in
the case of 3 (k /k = 1.17 in 80E and 1.12 in 97T) than
≠
activation parameters obtained with 4 are DH = 89.7 Æ
À1
≠
À1
À1
8
.3 kJ mol and ÀDS = 36.6 Æ 2.6 J K mol , and
≠ À1
those obtained with 5 are DH = 88.9 Æ 1.8 kJ mol and
≠
À1
À1 9
≠
ÀDS = 39.7 Æ 5.5 J K mol . Therefore, DH ꢀ 90
À1
≠
À1
À1
kJ mol and ÀDS ꢀ 35 J K mol can be taken as
standard values for the non-assisted reaction under given
conditions.
The solvolysis of the tertiary chloride 2 proceeds
through a five-membered oxonium ion. Bridging in the
transition state results in smaller DH and DS (Table 1)
than the above set of reference values. The lower values
of the activation parameters for 2 compared with 4
≠
≠
H
D
in the case in which simple n- or p-participation takes
place. Since b-KIEs are often interpreted as a measure
of the charge at the reaction center in the transition
state, it is apparent that the partial charge on the
reaction center in 3-TS is substantially lower than in the
substrates with one neighboring group (1 and 2). It is
therefore, obvious that the effects of neighboring p- and
n-electrons are additive, since the second neighboring
group (methoxy) further delocalizes the positive
charges in the transitions state. This consideration
inevitably leads to the conclusion that extended p,n-
participation mechanism is operative. This conclusion
is strongly supported with the above-considered
≠
À1
≠
À1 À1
(
DDH = À11 kJ mol ; DDS = À30 J mol K ; 80E)
are consistent with a mechanism involving two-electron
assistance. The entropy changes are mainly due to the
loss of some internal rotations, which is converted to
stiffer vibrations. Similar activation parameters were
obtained with chloride 1 having a double bond as a
≠
À1
≠
neighboring group (DH = 82 Æ 3 kJ mol and ÀDS =
À1
À1 12
6
7 Æ 10 J K mol ).
As shown in Table 1, the activation parameters
obtained for chloride 3 are dramatically different from
the values for the reference compounds. This result can
be rationalized only if extended participation is con-
≠
≠
sidered. DH values smaller than those for 1 and 2 (for ca
activation parameters, particularly DS . To the best of
À1
1
5 kJ mol ) arise from a further charge delocalization in
our knowledge, this is the first case in which extended
the transition state. The assumed extended p-participa-
tion mechanism requires a particular conformation in the
transition state which demands a considerably higher
p, n-participation has been reported.
≠
degree of order, causing a very negative DS value. A
≠
significant decrease in DS in comparison with 1 and 2
À1
À1
(
ca 70 J K mol , Table 1) is due to the loss of three
internal rotations around the three single C—C bonds in 3
Copyright  2002 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 556–560

EXTENDED p, n-PARTICIPATION IN SOLVOLYSIS OF SUBSTITUTED CHLORIDES
559
1
EXPERIMENTAL
1.79 g (40.5%). H NMR (CDCl
): ꢀ 1.74 (s, 3H), 1.81–
3
1
.83 (m, 2H), 3.36 (s, 3H), 3.54–3.57 (m, 2H), 4.21–4.25
13
Substrate preparation
(m, 1H), 4.85 (s, 1H), 5.01 (s, 1H). C NMR (CDCl ): ꢀ
3
18.04, 34.43, 58.73, 70.93, 74.49, 110.44, 146.89.
1
6
3
-Methoxypropanol (7). . To a stirred solution of
LiAlH (7.6 g, 0.20 mol) in 40 ml of dry diethyl ether, a
solution of methyl-3-methoxypropionate (6) (23.6 g,
Ethyl 4-methyl-7-methoxy-4(E)-heptenoate (10). A
mixture of 2-methyl-5-methoxy-1(E)-penten-3-ol (9)
(1 g, 7.69 mmol), triethyl orthoacetate (6.55 g, 54 mmol)
and propionic acid (0.18 g, 2.56 mol) was heated at
140°C for 1 h under conditions for distillative removal of
ethanol through a Vigreux column. The excess of
orthoacetate was then removed by distillation under
reduced pressure. The crude product was purified by
column chromatography on silica gel, eluting first with
light petroleum and then with light petroleum–dichloro-
4
0
.20 mol) in 50 ml of diethyl ether was added dropwise
at such a rate as to keep the reaction mixture refluxing.
Refluxing and stirring were continued for 3 h. The
reaction mixture was cooled, and the excess hydride
was decomposed with gradual addition of water. The
precipitate was washed with diethyl ether, and the
combined organic layer was dried over anhydrous
Na SO . The crude product was purified by column
2
4
1
chromatography on silica gel. Impurities were removed
with methylene chloride and the pure product with
methane (3:1). Ester 10 was obtained in 85% yield. H
NMR (CDCl ): ꢀ 1.11–1.13 (m, 3H), 1.77 (s, 3H), 1.94–
3
diethyl ether. The yield of pure alcohol 7 was 13.5 g
2.01 (m, 2H), 2.08–2.19 (m, 2H), 22.34–22.39 (m, 2H),
3.35 (s, 3H), 33.38–3.43 (m, 2H), 4.13–4.19 (m, 2H),
1
(
75%). H NMR (CDCl ): ꢀ 1.81–1.85 (m, 2H), 2.98 (s,
3
13
1
H), 3.35 (s, 3H), 3.54–3.58 (m, 2H), 3.73–3.77 (m, 2H).
5.31–5.35 (m, 1H). C NMR (CDCl ): ꢀ 13.91, 18.00,
3
1
3
C NMR (CDCl ): ꢀ 31.78, 58.60, 61.16, 71.33.
27.65, 28.18, 32.81, 58.54, 68.78, 74.10, 125.23, 143.05,
3
173.47.
3
-Methoxypropanal (8). Pyridinium chlorochromate
(
(
22.7 g, 0.11 mol) was suspended in methylene chloride
40 ml) and 3-methoxypropanol (7) (9.5 g, 0.11 mol) was
2,5-Dimethyl-8-methoxy-5(E)-octen-2-ol
(11).
Grignard reagent obtained from magnesium (0.97 g,
40 mmol) and iodomethane (5.7 g, 40 mmol) in 5 ml of
dry THF, as described above, was cooled to 0°C, and a
solution of ester 10 (4 g, 20 mmol) in THF was added
slowly to the cold mixture. The reaction mixture was
heated under reflux (1–2 h). When the reaction was
completed, and the Grignard complex was destroyed with
rapidly added at room temperature. After 2 h, the
oxidation was complete. The dark reaction mixture was
diluted with 10 ml of dry diethyl ether, the solvent was
decanted and the dark solid was washed twice with
diethyl ether. The product was isolated by filtration of the
organic extracts through Florisil and evaporation of the
solvent at reduced pressure. The crude product was
distilled (b.p. 108–110°C), yielding 3.4 g (36.8%) of the
pure product (8). H NMR (CDCl ): ꢀ 2.68–2.70 (m, 2H),
3
(
saturated aqueous NH Cl (2 Â 20 ml). The product was
4
extracted with diethyl ether (3 Â 25 ml). The combined
1
ether layers were dried over Na SO , the solvent was
3
2
4
13
.39 (s, 3H), 3.71–3.75 (m, 2H), 9.80 (s, 1H). C NMR
evaporated and the crude product was subjected to
column chromatography on silica gel, eluting first with
light petroleum–dichloromethane (3:1) and then with
light petroleum–dichloromethane (1:1). Evaporation of
CDCl ): ꢀ 43.66, 58.77, 29.45, 66.04, 201.03.
3
2
-Methyl-5-methoxy-1(E)-penten-3-ol (9). 2-Bromo-
propene (16.5 g, 0.14 mol) was dissolved in 15 ml of THF
and an aliquot of 1 ml of was added to magnesium (6.6 g,
the pooled alcohol-containing fractions yielded the pure
1
alcohol 11 as a viscous oil. H NMR (CDCl ): ꢀ 1.25 (s,
3
0
.27 mol) and a crystal of iodine at once. The mixture
6H), 1.38–1.42 (m, 2H), 1.73 (s, 1H), 1.83–1.88 (m, 2H),
was heated until the THF started to reflux. The remainder
of the 2-bromopropene solution was added dropwise at
such a rate as to maintain the mixture refluxing.
Refluxing and stirring of the reaction mixture were
continued for 1 h, then the reaction mixture was cooled to
2.26–2.33 (m, 2H), 3.31 (s, 3H), 3.34–3.36 (m, 2H),
13
5.28–5.32 (m, 1H). C NMR (CDCl ): ꢀ 17.70, 29.27,
3
29.90, 32.50, 40.16, 58.09, 68.45, 71.78, 121.34, 142.71.
1, 1, 1-d -2, 2, 2-d -Methyl-5-methyl-8-methoxy-
3
3
0
°C and 3-methoxypropanal (8) (3 g, 3.4 mmol) in 15 ml
5(E)-octen-2-ol (11-d ). The procedure is the same as
described above. From 0.17 g (7 mmol) of magnesium,
6
of THF was added slowly. Stirring was continued for 1 h
at room temperature. The Grignard complex was
1 g (7 mmol) of iodomethane-d (99% deuterium) and
3
hydrolyzed with a saturated solution of NH Cl, the water
0.55 g (3.5 mmol) of ester 10, 0.24 g (46%) of pure
4
1
layer was washed three times with diethyl ether. The
combined ether layers were washed with saturated
aqueous solution of NaCl and dried over Na SO . The
alcohol 11-d was obtained. H NMR (CDCl ): ꢀ 1.37–
6
3
1.42 (m, 2H), 1.72 (s, 1H), 1.83–1.88 (m, 2H), 2.25–2.33
(m, 2H), 3.31 (s, 3H), 3.34–3.36 (m, 2H), 5.28–5.32 (m,
2
4
13
solvent was evaporated and the crude product was
purified by silica gel column chromatography, eluting
with light petroleum followed by light petroleum–
dichloromethane (1:1). The yield of pure alcohol 9 was
1H). C NMR (CDCl ): ꢀ 17.50, 28.21, 31.42, 40.11,
3
58.23, 69.23, 71.80, 121.11, 142.31.
Chlorides 3 and 3-d . 2-Chloro-2,5-dimethyl-8-meth-
6
Copyright  2002 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2002; 15: 556–560

´
S. JURIC AND O. KRONJA
5
60
oxy-5(E)-octene (3) and 2-chloro-1, 1, 1-d -2,2,2-d -
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3
3
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(
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metrically with a pH-stat. Typically, 0.01 mmol of the
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(
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0
.004 M solution of sodium hydroxide in the same
1
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1
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8
0% completion. First-order rate constants were calcu-
ˇ
1
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We gratefully acknowledge the financial support of this
research by the Ministry of Science and Technology of
the Republic of Croatia (Grant No. 0006451).
1
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Copyright  2002 John Wiley & Sons, Ltd.
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