Carbocationic n-endo-trig cyclizations

Article abstract of DOI:10.1002/chem.200901246

Unsaturated benzyl cations (4-MeOC₆H₄)CH ₊-(CH₂)_n-CH=CH₂ (1) have been generated laser-flash photolytically in acetonitrile in the presence of enol ethers or 2-methylfuran. The reactions of the cations 1 (n = 2 and 4) with these π-nucleophiles follow second-order rate laws with rate constants comparable to those of the analogous saturated species (4MeOC₆H ₄)CH₊-(CH₂)₃CH₃. Product studies show the absence of cyclization products. In contrast, the carbocation (4-MeOC₆H₄)CH⁺-(CH₂) ₃-CH=CH₂ (Id) undergoes a highly reversible 6endo-trig cyclization which is approximately 10⁷ times faster than the corresponding intermolecular reaction of (4MeOC₆H₄)CH ⁺-(CH₂)₃CH₃ with hex1-ene. This cyclization yields a highly electrophilic, partially bridged carbocation, which accounts for the finding that Id is consumed eight times faster in trifluoroethanol solution than all other carbocations of this series. Quantum-chemical calculations (B3LYP/6311G(d,p) and MP2/6-31+G(2d,p)) have been performed to elucidate the structures of the involved carbocations. Consequences of these findings on the role of π-participation in solvolysis reactions are discussed.

Full text of DOI:10.1002/chem.200901246

FULL PAPER
DOI: 10.1002/chem.200901246
Carbocationic n-endo-trig Cyclizations
Lei Shi, Markus Horn, Shinjiro Kobayashi, and Herbert Mayr*[a]
Dedicated to Professor Yitzhak Apeloig on the occasion of his 65th birthday
ꢁ
ꢁ
Abstract: Unsaturated benzyl cations
(4-MeOC6H4)CH+
(CH2)3 CH=CH2
electrophilic, partially bridged carbo-
cation, which accounts for the finding
that 1d is consumed eight times faster
in trifluoroethanol solution than all
other carbocations of this series. Quan-
tum-chemical calculations (B3LYP/6-
(4-MeOC6H4)CH+
(1d) undergoes a highly reversible 6-
endo-trig cyclization which is approxi-
mately 107 times faster than the corre-
sponding intermolecular reaction of (4-
ꢁ
N
ꢁ
(1) have been generated laser-flash
photolytically in acetonitrile in the
presence of enol ethers or 2-methylfur-
an. The reactions of the cations 1 (n=2
and 4) with these p-nucleophiles follow
second-order rate laws with rate con-
stants comparable to those of the anal-
MeOC6H4)CH+
ACHTUNGTRENNUNG
ꢁ
311GACTHNUTRGNEN(UG d,p) and MP2/6-31+GACHTUNGTRENNUNG(2d,p))
have been performed to elucidate the
structures of the involved carbocations.
Consequences of these findings on the
role of p-participation in solvolysis re-
actions are discussed.
Keywords:
carbocations
·
ogous
saturated
species
(4-
electrophilicity · kinetics · laser-
flash photolysis · linear free energy
relationships
MeOC6H4)CH+
(CH2)3CH3. Product
ꢁ
studies show the absence of cyclization
products. In contrast, the carbocation
Introduction
To apply Equation (1) also to p-cyclizations, that is, to in-
tramolecular reactions of carbocations with p-systems, the
knowledge of effective molarities[6] is needed, that is, a cor-
rection term, which adjusts the predictions of Equation (1)
to intramolecular processes. For this purpose, we have com-
pared the rates of inter- and intramolecular reactions of the
1-(p-methoxyphenyl)ethyl cation 1a, its homologue 1b, and
the unsaturated derivatives 1c–e (Scheme 1) with different
nucleophiles.
Whereas Baldwinꢀs rules proved to be a useful guide for a
large variety of cyclization reactions,[1] their applicability to
carbocationic p-cyclizations[2] appears to be limited. Thus,
we have found that cationic 5-endo-trig cyclizations[3] as well
as 4-exo-dig cyclizations,[4] provide a straightforward access
to five- and four-membered carbocycles, though both cycli-
zation modes were termed as “disfavored” by Baldwinꢀs
rules.
Correlation equation (1), where N and s represent nucleo-
phile-specific parameters and E represents an electrophile-
specific parameter has been found to provide reliable esti-
mates for the rates of intermolecular reactions of carboca-
tions with p-systems.[5]
Scheme 1.
log k2ð20 ꢀCÞ ¼ sðN þ EÞ
ð1Þ
[a] Dr. L. Shi, M. Horn, Prof. Dr. S. Kobayashi, Prof. Dr. H. Mayr
Department Chemie und Biochemie
Results
Ludwig-Maximilians-Universitꢁt Mꢂnchen
Butenandtstrasse 5–13 (Haus F), 81377 Mꢂnchen (Germany)
Fax : (+49)89-2180-77717
Kinetic investigations: The carbocations 1a–e were generat-
ed by laser irradiation (266 nm, 7 ns, 40–60 mJ) of the corre-
sponding triphenylphosphonium tetrafluoroborates in
CH3CN (Scheme 2).[7a,b]
E-mail: Herbert.Mayr@cup.uni-muenchen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901246.
Chem. Eur. J. 2009, 15, 8533 – 8541
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8533

Scheme 2.
The resulting UV/Vis absorptions at lmax =340–360 nm
agreed with the previously reported[7c,d] UV/Vis spectra for
1a. When the benzyl cations 1a–e were generated in the
presence of a high excess of the p-systems 2a–d (Scheme 3),
Scheme 3.
exponential decays of the absorbances of the carbocations
were observed from which the first-order rate constants kobs
were obtained. These were then plotted against the variable
concentrations of 2a–d.
For the reactions of the carbocations 1a–c and 1e, the in-
tercepts of the kobs versus [2] plots were small (<106 sꢁ1) rel-
ative to kobs, and the second-order rate constants for the re-
actions of these carbocations with the p-systems were de-
Abstract in German: Ungesꢀttigte Benzylkationen (4-
Figure 1. Laser irradiation (266 nm, 7 ns) of 1b-PPh3 in CH3CN. a) UV/
Vis spectra at variable time in pure acetonitrile; b) plot of kobs versus [2-
methylfuran (2b)]; insert: absorbance at 350 nm as a function of time in
the presence of 0.02m 2b.
MeOC6H4)CH+
ACHTUNGTRENNUNG(CH2)n CH=CH2 (1) wurden in Acetonitril
ꢁ
ꢁ
Laserblitz-photolytisch in Anwesenheit von Enolethern und
2-Methylfuran generiert. Die Reaktionen der Kationen 1 (n=
2 und 4) mit diesen p-Nucleophilen folgten Geschwindig-
keitsgesetzen 2. Ordnung mit Geschwindigkeitskonstanten
vergleichbar denen, die fꢁr die analoge, gesꢀttigte Spezies (4-
ꢁ
rived from the slopes of these plots, as shown for a typical
example in Figure 1.
MeOC6H4)CH+
ACHTUNGTRENNUNG(CH2)3CH3 erhalten wurden. Produktstu-
A different behavior was found for carbocation 1d. As
shown in Figure 2, kobs for the reactions of 1d with the p-nu-
cleophiles 2 increases strongly with [2] at low concentrations
of 2 and transforms into linear plots with smaller slopes at
higher concentrations, from which the second-order rate
constants for the reactions of 1d with 2 (Table 1) were de-
rived.
In 2,2,2-trifluoroethanol (TFE), all carbocations 1a–e de-
cayed according to first-order rate laws, and 1d was con-
sumed approximately eight times faster than all other carbo-
cations listed in Table 1.
dien zeigen die Abwesenheit von Cyclisierungsprodukten.
Anders verhꢀlt sich das Carbokation (4-MeOC6H4)CH+
ꢁ
ꢁ
A
sierung eingeht, die ungefꢀhr 107 mal rascher verlꢀuft als die
entsprechende
intermolekulare
ACHTUNGTRENNUNG(CH2)3CH3 mit Hex-1-en. Diese Cyclisier-
Reaktion
von
(4-
MeOC6H4)CH+
ꢁ
ung fꢁhrt zu einem partiell verbrꢁckten Carbokation mit er-
hçhter Elektrophilie, was die Beobachtung erklꢀrt, dass 1d in
Trifluorethanol-Lçsung acht mal rascher verbraucht wird als
alle anderen Carbokationen dieser Messreihe. Um die Struk-
turen der beteiligten Carbokationen zu ermitteln, wurden
quantenchemische Rechnungen (B3LYP/6-311G
ACHTUNGTRENN(UNG d,p) und
Product studies: To investigate the products of the reactions
of the benzyl cations 1 with the p-nucleophiles 2a–d, the
carbocations 1a,b were generated in situ by treatment of the
MP2/6-31+G(2d,p)) durchgefꢁhrt. Konsequenzen unserer
Befunde zur Rolle der p-Beteiligung bei Solvolysereaktionen
werden diskutiert.
ACHTUNGTRENNUNG
benzyl alcohols (1a,b)-OH with BiACTHNUTRGNENUG(OTf)3 in nitromethane.
8534
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Chem. Eur. J. 2009, 15, 8533 – 8541

Carbocationic n-endo-trig Cyclizations
FULL PAPER
Scheme 4.
Scheme 5.
reoisomers[8] (Scheme 4). Under the same conditions,[8a] 1b-
OH reacted with 2a–d to give 3ba–3bd in 51–85% yield
(Scheme 5).
Figure 2. Dependence of kobs on the concentration of the nucleophile
(MeCN, 208C); a) reaction of 1d with 2c; b) reaction of 1d with 2d. The
linear parts of the curves were used to determine the second-order rate
constants.
Scheme 6.
When the BiACHTNUTRGNE(NUG OTf)3-catalyzed
Table 1. Second-order rate constants (mꢁ1 sꢁ1) for the reactions of carbocations 1a–e with the p-systems 2a–d
(in MeCN) and with trifluoroethanol (sꢁ1) at 208C.
reaction of 1d-OH with 2b in
nitromethane was carried out at
high substrate concentrations
([1d-OH]=0.25m, [2b]=0.5m),
the non-cyclized product 3db
was isolated in 69% yield, and
formation of a cyclization prod-
Carbocation
CF3CH2OH[a]
2a
2b
2c
2d
2e
1a (R=CH3)
1b (R=n-C4H9)
1c (R=(CH2)2CH=CH2)
1d (R=(CH2)3CH=CH2)
1e (R=(CH2)4CH=CH2)
8.1ꢄ106
4.3ꢄ106
–
8.2ꢄ107
6.6ꢄ107[b]
6.3ꢄ107
5.6ꢄ107[c]
6.8ꢄ107
6.3ꢄ107
3.4ꢄ107
–
–
4.3ꢄ105[d]
2.4ꢄ105
2.4ꢄ105
2.0ꢄ106
2.6ꢄ105
1.2ꢄ108
–
uct
(Scheme 6). At low substrate
concentrations ([1d-OH]=
was
not
observed
5.0ꢄ106[c]
5.7ꢄ106
2.6ꢄ107[c]
3.3ꢄ107
1.2ꢄ108[c]
1.3ꢄ108
[a] First-order rate constants (sꢁ1). [b] A second-order rate constant of k=6.9ꢄ107 mꢁ1 sꢁ1 was obtained when
P(4-Cl-C6H4)3 was used as photo-leaving group. [c] Second-order rate constants for the reactions of 1d with
2a–d from the slope kobs versus [2] at high nucleophile concentrations, see Equations (2)–(6). [d] Reference
0.005m, [2b]=0.011m), the re-
action became more complicat-
ed; while a separation of the
[7d] reports 3.9ꢄ105 sꢁ1
.
products was not achieved,
NMR and GC-MS analysis of
the product mixture indicated
the presence of dehydration products of 1d-OH as well as
of cyclized products in addition to 3 db.
As previously described by Rubenbauer and Bach,[8a] 1a-
OH reacted with the silyl enol ethers 2c and 2d in the pres-
ence of 2.5 mol% Bi
kanones 3ac and 3ad, respectively, as 1:1 mixtures of diaste-
(OTf)3 to give the 2-substituted cycloal-
Solvolysis in trifluoroethanol (2e) of benzyl chloride 1d-
Cl in the presence of 2-chloropyridine as a proton trap
Chem. Eur. J. 2009, 15, 8533 – 8541
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www.chemeurj.org
8535

H. Mayr et al.
yielded the cyclohexyl ether 3d’e exclusively (Scheme 7).
However, when the trifluoroethanolysis of 1d-Cl was per-
formed in the presence of the stronger base 2,6-lutidine,
3d’e and 3de were obtained in equal amounts (Scheme 7).
In contrast, solvolysis of 1c-Cl and 1e-Cl in CF3CH2OH led
to the exclusive formation of the non-cyclized benzyl ethers
3ce and 3ee, independent of the nature of the proton trap
(Scheme 8).
Scheme 9. Fast reversible cyclization of carbocation 1d.
then reacts with the nucleophile to give the cyclohexane de-
rivative 3d’.
Assuming a low equilibrium concentration of 1d’ the ki-
netics of the consumption of 1d (Scheme 9) can be de-
scribed by Equation (2). While the first term of Equation (2)
represents the formation of 3d, the second term reflects the
rate of formation of 3d’, that is, k1[1d] multiplied with the
partitioning ratio (forward reaction (k2’[Nu]) divided by the
sum of backward (kꢁ1) and forward reaction).
Scheme 7.
d½1dꢂ
dt
k02½Nuꢂ
ð2Þ
ꢁ
¼ k2½1d ꢂ½Nuꢂ þ k1½1dꢂ
kꢁ1 þ k0 ½Nuꢂ
2
Rearrangement of Equation (2) yields Equation (3) which
Scheme 8.
simplifies to Equation (4) if [Nu] is used in high excess and
thus remains almost constant.
Discussion
!
d½1dꢂ
dt
k02½Nuꢂ
ꢁ
¼
k2½Nuꢂ þ k1
½1dꢂ
ð3Þ
kꢁ1 þ k0 ½Nuꢂ
As expected, the carbocations 1a and 1b differ only slightly
in reactivity, and the somewhat smaller rate constants for 1b
can be explained by steric effects. From the exclusive forma-
tion of the non-cyclized ethers 3ce and 3ee in the trifluoro-
2
For [Nu] @ [1d]:
ACHTUNGTRENNUNGethanolyses of the benzyl chlorides 1c-Cl and 1e-Cl, even in
d½1dꢂ
ð4Þ
ð5Þ
ꢁ
¼ kobs½1dꢂ
dt
the presence of 2,6-lutidine (Scheme 8), one can derive that
under these conditions neither the 5-endo-trig cyclization of
1c nor the 7-endo-trig cyclization of 1e occurs. As a conse-
quence, the first-order rate constants of the reactions of the
cations 1c and 1e with trifluoroethanol are almost identical
to that of the saturated counterpart 1b (last column of
Table 1). Furthermore, the second-order rate constants for
the reactions of the saturated benzyl cation 1b and of the
unsaturated analogues 1c and 1e with the p-systems 2a–d
are closely similar indicating that the carbocationic center in
with
k02½Nuꢂ
kobs ¼ k2½Nuꢂ þ k1
kꢁ1 þ k0 ½Nuꢂ
2
At high concentrations of the nucleophiles, kꢁ1 !k2’[Nu],
and Equation (5) transforms to Equation (6).
kobs ¼ k2½Nuꢂ þ k1
ð6Þ
ꢁ
1c and 1e does not interact with the terminal C C double
bond. This observation is in line with the almost identical
UV/Vis spectra of 1b, 1c, and 1e.
According to Equation (6), the slopes of the linear parts
of the kobs versus [Nu] plots yield the second-order rate con-
stants k2, and the intercepts of these straight lines give the
cyclization rate constant k1 ꢃ 1.1ꢄ107 sꢁ1, which is inde-
pendent of the nature of the nucleophile (Figure 2 and Fig-
ures in the Supporting Information).
Carbocation 1d behaves differently, as revealed by the
concomitant formation of the benzyl ether 3de and the cy-
clohexyl ether 3d’e during the trifluoroethanolysis of 1d-Cl
(Scheme 7). According to Scheme 9, carbocation 1d either
reacts directly with the nucleophiles to give the non-cyclized
products 3d or undergoes a reversible cyclization with for-
mation of 1d’ (for structural discussion see below),[9] which
Table 1 shows that the second-order rate constants for the
direct reaction of 1d with p-nucleophiles (formation of 3d)
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Chem. Eur. J. 2009, 15, 8533 – 8541

Carbocationic n-endo-trig Cyclizations
FULL PAPER
are similar to those for the corresponding reactions of car-
respectively. The four energetically most favorable conform-
ers were then subjected to geometry optimizations on the
bocations 1a–c and 1e though the overall rate constants kobs
,
which include the formation of 3d’, are much larger for 1d.
At lower nucleophile concentration (with condition (4) still
fulfilled), Equation (5) does not transform into the linear
dependence (6), and the nonlinear relationship between kobs
and [Nu] as expressed by Equation (5) is observed in the
left parts of Figure 2.
B3LYP/G-311GACTHUNGETRNNU(G d,p) level (Table 2 and Table 3, entries 1–4).
Table 2. Geometry optimizations of 1D (four conformers) and 1D’ on
the B3LYP/6-311G
ACHTUNGTRENUN(NG d,p) level.
[a]
ꢁ
Conformer
DEtot
[kJmolꢁ1
C C distance [ꢅ]
G
]
1-2
2-3
1-3
From the observation that the trifluoroethanolysis of 1d-
Cl in the presence of the weakly basic 2-chloropyridine
yields the cyclohexyl ether 3d’e exclusively (Scheme 7), one
can derive that the direct trapping of 1d by CF3CH2OH is
outstripped by the fast cyclization of 1d. This conclusion is
in line with the fact that the decay of 1d in CF3CH2OH
(Table 1, right column) is much faster than that of the other
carbocations (1a–c, 1e). For the direct trapping of 1d by
CF3CH2OH a rate constant close to 2.4ꢄ105 sꢁ1 (as for 1b)
would be expected.
In previous work, we have shown that the rates of reac-
tions of carbocations with alkenes depend only slightly on
solvent polarity.[10] If we now assume that the cyclization of
1d occurs with a similar rate in trifluoroethanol as in aceto-
nitrile (k1 =1.1ꢄ107 sꢁ1), one can calculate the ratio kꢁ1/k’TFE
from Equation (5), where the term k2[Nu] is omitted be-
cause direct trapping of 1d does not occur in the absence of
2,6-lutidine (Scheme 7). Equation (7) is then obtained from
Equation (5) by replacing k2’[Nu] through k’TFE, that is, the
first-order rate constant for the reaction of 1d’ with trifluor-
oethanol.
1D-1
1D-2
1D-3
1D-4
1D’
8.52
7.21
10.2
3.30
0
5.62
4.33
5.27
5.13
1.80
1.33
1.33
1.33
1.33
1.40
4.50
3.90
4.55
4.43
2.40
[a] Relative to 1D’.
Table 3. Geometry optimizations of 1d (four conformers) and 1d’ on the
B3LYP/6-311G
ACHTUNGTRENUN(NG d,p) level.
[a]
ꢁ
Conformer
DEtot
[kJmolꢁ1
C C distance [ꢅ]
G
]
1-2
2-3
1-3
1d-1
1d-2
1d-3
1d-4
1d’
4.12
6.43
4.90
7.40
0
4.33
5.64
4.32
5.27
3.33
1.33
1.33
1.33
1.33
1.33
3.91
4.50
3.89
4.55
3.03
[a] Relative to 1d’.
Because of the reduced conformational flexibility of the
cyclohexane ring, chair structures of 1d’ and 1D’ with the
aryl substituent in equatorial position were used as input
with a bond-length of 1.54 ꢅ for C(1) C(2). Geometry opti-
mization at the B3LYP/G-311G
ening of the C(1) C(2) bond in both cases. The methoxy-
substituted cation 1d’ opened up fully until an energy mini-
mum at C(1) C(2)=3.33 ꢅ was reached, that is, a clearly
acyclic structure was formed (Table 3, last line). In contrast,
k0TFE
kꢁ1 þ k0TFE
ꢁ
2:0 ꢄ 106 ¼ 1:1 ꢄ 107
ð7Þ
(d,p) level led to the length-
ꢁ
From Equation (7) one calculates k’TFE/(kꢁ1 + k’TFE)=0.18
or kꢁ1/k’TFE =4.5, that is, the backward reaction kꢁ1 is 4.5
times faster than the reaction of 1d’ with trifluoroethanol.
When 1d is generated in trifluoroethanol in the presence of
2,6-lutidine, which partially deprotonates CF3CH2OH, 1d is
partially trapped by CF3CH2Oꢁ, and a mixture of 3d’e and
3de is obtained.
ꢁ
ꢁ
optimization of 1D’ led to a shallow minimum with C(1)
ꢁ
ꢁ
C(2)=1.80 ꢅ, C(2) C(3)=1.40 ꢅ and C(1) C(3)=2.40 ꢅ,
corresponding to a non-classical structure (Table 2, last
line).
As shown in Tables 2 and 3, in both cases the structure
obtained by optimization of the cyclohexyl system was
slightly more stable than the extended conformers with long
Quantum-chemical calculations have been performed in
order to elucidate structure and relative energies of the cat-
ions 1d and 1d’. For comparison, the parent compounds 1D
and 1D’ have also been investigated (Scheme 10). Confor-
mational analyses of the acyclic structures 1d and 1D on
the basis of the MM3 force field yielded 152 and 89 minima,
ꢁ
C(1) C(2) distances. Optimizations of the cyclohexyl struc-
ꢁ
tures 1d’ and 1D’ with fixed C(1) C(2) bond lengths show
that in both cases, classical cyclohexyl cations 1d’ and 1D’
do not correspond to minima on the B3LYP/6-311G
level (Figure 3). Ab initio geometry optimizations on the
MP2/6-31+G(2d,p) level, which proved to be a good com-
ACHTUNGTRENNUNG(d,p)
AHCTUNGTRENNUNG
promise between performance and accuracy for medium
sized organic cations,[11] have been performed on the preop-
timized structures 1D and 1d, respectively (Table 4 and
Table 5).
Optimizations on the MP2/6-31+GACHTUNTRGNEUNG(2d,p) level, starting
with the closed structures have also been performed. In the
case of the parent compound, a structure with a hydrogen
bridging the atoms 2 and 3 resulted (1D’’ in Table 4,
Scheme 10.
Chem. Eur. J. 2009, 15, 8533 – 8541
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8537

H. Mayr et al.
Optimization of the 3-(4-methoxyphenyl)cyclohexyl
cation (1d’) at the MP2/6-31+G
ACHTUNGTRENNUNG
ꢁ
ꢁ
C(1) C(2) distance of 1.54 ꢅ, yielded a structure with C(1)
C(2)=1.95 ꢅ. In contrast, starting at 3.33 ꢅ, the minimum
ꢁ
in the DFT calculations, gave a minimum with C(1) C(2)=
2.91 ꢅ (1d’’ in Table 5), which is 1.58 kJmolꢁ1 higher in
energy than the one with 1.95 ꢅ (Table 5).
In conclusion, the cyclized structures 1d’ and 1D’ do not
correspond to classical cyclohexyl cations. For both carboca-
tions, the ab initio method predicts a non-classical carbocat-
ion as a minimum on the energy hypersurface. While the un-
substituted parent system 1D’ is much more stable than its
open chain isomers (DE ꢃ40 kJmolꢁ1, Table 4), the experi-
mentally studied p-methoxyphenyl substituted carbocation
1d’ is only slightly stabilized by interaction of the carbocat-
Figure 3. Bond length scan for 1D’ and 1d’ on the B3LYP/6-311GACTHNUTRGNEU(GN d,p)
ꢁ
ionic center with the terminal C C double bond (DE
ꢁ
level. The distance C(1) C(2) was gradually increased by 0.02 ꢅ from
ꢃ4 kJmolꢁ1, Table 5).
ꢁ
1.40 to 1.88 ꢅ. Etot =0 is assigned to the conformer with C(1) C(2)=
1.80 ꢅ (1D’) and 1.88 ꢅ (1d’).
Consequences for p-participation in solvolysis reactions: Ex-
tensive kinetic investigations by the Zagreb group[12] have
shown that all 4-methoxy-substituted derivatives 4U-Cl and
4S-Cl listed in Table 6 solvolyze with approximately the
Table 4. Geometry optimizations of 1D (four conformers) and cyclic iso-
mers 1D’ and 1D’’ on the MP2/6-31+GACTHNUGRTENUNG(2d,p) level.
[a]
ꢁ
Conformer
DEtot
A
C C distance [ꢅ]
[kJmolꢁ1
]
1-2
2-3
1-3
1D-1
1D-2
1D-3
1D-4
1D’
52.6
43.2
52.6
45.6
0
5.53
3.96
5.15
4.92
1.83
1.45
1.34
1.34
1.34
1.34
1.39
1.40
4.42
3.60
4.43
4.31
2.27
2.55
Table 6. Relative solvolysis rates (kU/kS) of benzyl chlorides 4U-Cl and
4S-Cl in different solvents at 258C.[12b]
1D’’
31.6
[a] Relative to 1D’.
X
Solvent
R1, R2
H, Me
H, H
Me, H
Me, Me
0.49[a]
0.96[b]
1.04
1.07
1.50
1.13
2.57
3.05
5.73
0.89
2.42
1.43
5.93
6.18
10.3
1.08
3.22
2.23
16.1
18.9
58.2
Table 5. Geometry optimizations of 1d (four conformers) and cyclic iso-
mers 1d’ and 1d’’ on the MP2/6-31+GACTHNUGRTENUNG(2d,p) level.
4-OMe
4-Me
EtOH/H2O 95:5 (v/v)
EtOH/H2O 95:5 (v/v)
EtOH/H2O 80:20 (v/v)
EtOH/H2O 80:20 (v/v)
TFE/H2O 97:3 (w/w)
TFE/H2O 97:3 (w/w)
[a]
ꢁ
Conformer
DEtot
A
C C distance [ꢅ]
2-3
H
4-Br
3-Br
0.92[b]
1.15[c]
1.37[b]
[kJmolꢁ1
]
1-2
1-3
1d-1
1d-2
1d-3
1d-4
1d’
4.12
13.9
4.59
13.8
0
3.94
5.55
3.95
5.15
1.95
2.91
1.34
1.34
1.34
1.34
1.38
1.35
3.60
4.42
3.60
4.44
2.37
2.83
[a] At 58C. [b] At 508C. [c] At 308C.
same rates,[12b] indicating that breaking of the C Cl bond is
not nucleophilically assisted by the p-bond.[12e] As a conse-
quence, the ratio kU/kS is close to 1 for all compounds in the
first line of Table 6. When the 5,6-double bond is unsubsti-
tuted (R1 =R2 =H), nucleophilic p-participation was not
even observed when the arene ring was bearing an electron-
withdrawing substituent (e.g., 3-Br), and all kU/kS ratios in
the column H,H of Table 6 are close to 1. The ratio kU/kS in-
creases with decreasing electron releasing ability of the sub-
stituent X of the aromatic ring and increasing number of
methyl groups at the double bond until kU/kS =58 is reached
at the bottom right of Table 6.
ꢁ
1d’’
1.58
[a] Relative to 1d’.
Figure 4. MP2/6-31+GACHTUNGTRENNUNG(2d,p) optimized structure 1D’’ of the 3-phenylcy-
ꢁ
clohexyl cation, when starting with a bond length C(1) C(2) of 1.54 ꢅ.
Why does the unsubstituted terminal double bond not
ꢁ
ꢁ
Figure 4), when an input bond length C(1) C(2)=1.54 ꢅ
even assist the heterolysis of the C Cl bond in compounds
ꢁ
was used. Optimization starting with C(1) C(2)=1.88 ꢅ led
4U-Cl, which do not carry electron-donating substituents X,
though MP2 calculations showed that in the case of 1D
(=4U, X=R1 =R2 =H) cyclization is associated with a sta-
bilization of more than 40 kJmolꢁ1 (see Table 4)?
ꢁ
to a minimum with C(1) C(2)=1.83 ꢅ (1D’). The latter
structure is 31.6 kJmolꢁ1 lower in energy than the hydrogen
bridged structure.
8538
www.chemeurj.org
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 8533 – 8541

Carbocationic n-endo-trig Cyclizations
FULL PAPER
The observed cyclization rate constant of 1.1ꢄ107 sꢁ1 for
cation 1d (=4U, X=4-OMe, R1 =R2 =H) indicates that
there is still a small energy barrier for the intramolecular
attack of the carbenium center of 1d at the monosubstituted
tion, can be assigned to a non-classical structure of these in-
[12b]
ˇ ´
termediates in line with previous suggestions by Borcic.
Effective molarities:[6] Because of the lack of a sufficient
number of rate constants for the reactions of the carboca-
tions 1 with nucleophiles, it is not possible to determine
their electrophilicity parameters E reliably. With the as-
sumption that the relative reactivities of 1-(trimethylsiloxy)-
cyclohexene (2c) and hex-1-ene toward benzhydrylium ions
(3ꢄ107)[5e] also hold for carbocation 1b, one can estimate a
ꢁ
terminal C C double bond. Using the azide clock method,
Jencks and Richard[13] have shown that the unsubstituted 1-
phenylethyl cation 1 f reacts 2ꢄ103 times faster and the 3-
bromo-substituted 1-phenylethyl cation 1g reacts 2ꢄ104
times faster with the solvent (50:50 trifluoroethanol/water)
than the 4-methoxy-substituted analogue 1a (Scheme 11).
ACTHNUTRGNEUNG
second-order rate constant k=(3.4ꢄ107 mꢁ1 sꢁ1)/(3ꢄ107)=
1.1mꢁ1 sꢁ1 for the intermolecular reaction depicted in
Scheme 12.
Scheme 11. Rate constants (sꢁ1) for the reactions of 1-arylethyl cations
with the solvent in 50:50 TFE/water (258C, from reference[13]) and HFIP
(208C, from reference [7d]).
Scheme 12. Estimated second-order rate constant (mꢁ1 sꢁ1) for the reac-
tion of the carbocation 1b with hex-1-ene.
Exactly the same reactivity ratio has been observed for the
reactions of the laser-flash photolytically generated carboca-
tions 1a and 1 f with 1,1,1,3,3,3-hexafluoroisopropanol
(HFIP).[7d] With the assumption that similar substituent ef-
When this rate constant (1.1mꢁ1 sꢁ1) is compared with the
rate constant of the analogous intramolecular reaction in
Scheme 9, one arrives at an effective molarity EM=kcycl
/
k
acycl =(1.1ꢄ107 sꢁ1)/1.1mꢁ1 sꢁ1 =1ꢄ107 m for the 6-endo-trig
ꢁ
fects hold for the reaction with the C C double bond, one
cyclization depicted in Scheme 9. With the assumption that
similar effective molarities hold for related p-cyclizations,
one arrives at the rule of thumb that cationic 6-endo-trig
cyclizations are roughly 10 million times faster than calculat-
ed for the corresponding intermolecular process by Equa-
tion (1). Kinetic and product studies indicate that the effec-
tive molarities for the Baldwin-disfavored 5-endo-trig and
the Baldwin-favored 7-endo-trig cyclizations are significantly
smaller.
can estimate cyclization rate constants of 2ꢄ1010 sꢁ1 (1.1ꢄ
107 ꢄ2,000) for 4U (X=H, R1 =R2 =H) and of 2ꢄ1011 sꢁ1
(1.1ꢄ107 ꢄ20,000) for 4U (X=3-Br, R1 =R2 =H).
As emphasized by Jencks and Richard,[14] intermediates
can only be formed if their lifetimes exceed the duration of
a bond-vibration, typically 10ꢁ13 s. The preceding calcula-
tions show that all benzyl cations 4U with R1 =R2 =H listed
in Table 6 have cyclization rate constants <1013 sꢁ1 which
ꢁ
implies that p-participation for breaking the C Cl bond is
Cyclization experiments with other p-donors are needed
in order to examine whether the effective molarities are spe-
cific for certain cyclization modes and thus allow introduc-
ing a correction term in order to apply Equation (1) also for
cyclization reactions.
not needed, in line with kU/kS ꢃ 1 in the column H,H of
Table 6.
Typically, 1,1-dialkylethylenes and trialkylethylenes react
104–105 times faster with carbocations than monoalkylated
ethylenes.[15] Multiplication of the cyclization rate constant
k=1.1ꢄ107 sꢁ1 of 1d (=4U, X=4-OMe, R1 =R2 =H) with
this factor again yields cyclization rate constants <1013 sꢁ1.
Accordingly, the first line of Table 6 shows that none of the
solvolyses of the 4-methoxy-substituted benzyl chlorides
4U-Cl is assisted by p-participation. When carbocations 4U
with weaker electron donors X and more nucleophilic
double bonds in the side chain are employed, cyclization
rate constants> 1013 sꢁ1 can be estimated, implying that car-
bocations 4U corresponding to the lower right corner of
Table 6 should not be accessible as intermediates, and the
solvolyses of the benzyl chlorides 4U-Cl in this part of
Table 6 are assisted by p-participation. The fact that a
methyl group at R2 position of 4U-Cl generally accelerates
the solvolyses slightly more than a methyl group at R1 posi-
Experimental Section
General: 1H and 13C NMR spectra were recorded in CDCl3 on 300, 400
or 600 MHz NMR spectrometers (Varian). Chemical shifts are reported
in ppm relative to the deuterated solvent as the internal standard (dH =
7.26, dC =77.23). The following abbreviations were used to designate
chemical shift mutiplicities: br. s=broad singlet, s=singlet, d=doublet,
t=triplet, q=quartet, m=multiplet. ESI-MS was measured by a TSQ
7000 multistage mass spectrometer (Thermo-Finnigan). Chromatographic
purifications used Merck silica gel 60 (mesh 40–63 mm). Solvents were
distilled or dried prior to use over the indicated drying agents: dichloro-
methane (CaH2), diethyl ether (Na/benzophenone). 1-(4-Methoxyphenyl)-
ethanol (1a-OH) was purchased from Aldrich and was used as received.
Laser-flash photolysis setup: The laser pulse (7 ns pulse width, 266 nm,
40–60 mJ/pulse) originated from a Nd-YAG laser (Innolas Spitlight 600)
Chem. Eur. J. 2009, 15, 8533 – 8541
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8539

H. Mayr et al.
with second (532 nm) and fourth (266 nm) harmonic generators. The UV/
Vis detection unit comprised a Xe-light source, a spectrograph, a photo-
multiplier, and a pulse generator. For the data acquisition a 350 MHz-os-
cilloscope was used. The sample was kept in a temperature controlled
fluorescence cell, the temperature of which was maintained at 208C by a
circulating bath thermostat. A shutter was used to prevent the sample
from unnecessary exposure to the light from the Xe lamp.
TINKER program.[19] All quantum-chemical calculations have been per-
formed with Gaussian 03.[20] Optimized structures were confirmed as
being minima by frequency calculations on the respective level of theory.
No frequency calculations have been done in the case of the bond length
scans.
Preparation of benzyl alcohol 1c-OH (typical procedure):[16] 1-Bromo-
but-3-ene (18.2 g, 135 mmol) in diethyl ether (50 mL) was added to a sus-
pension of Mg turnings (3.28 g, 135 mmol) in diethyl ether (150 mL) over
1 h at 08C. The solution was stirred at room temperature for 2 h and
then cooled to 08C before 4-methoxybenzaldehyde (13.6 g, 100 mmol)
was added slowly. The reaction mixture was stirred overnight and then
poured onto ice/water (200 mL). Sulfuric acid (5m) was added until the
magnesium salts dissolved. After separation of the phases, the aqueous
phase was extracted with Et2O (2ꢄ50 mL). The combined organic phases
were dried (Na2SO4) and the solvent was removed in vacuo. The crude
product was purified by flash chromatography to yield 1-(4-methoxyphe-
nyl)pent-4-en-1-ol (1c-OH) (16.3 g, 84 mmol; 84%). 1H NMR (400 MHz,
CDCl3): d=1.71–1.80 (m, 1H; CH), 1.82–1.92 (m, 1H; CH), 1.96 (br. s,
1H; OH), 2.00–2.17 (m, 2H; CH2), 3.78 (s, 3H; OCH3), 4.61 (dd, J=
7.3 Hz, J=6.0 Hz, 1H; OCH), 4.94–5.05 (m, 2H;=CH2), 5.78–5.85 (m,
1H;=CH), 6.86 (d, J=8.6 Hz, 2H; HAr), 7.24 ppm (d, J=8.6 Hz, 2H,
Acknowledgements
We thank Professor Hendrik Zipse for advice concerning the quantum-
chemical calculations. Financial support by the Deutsche Forschungsge-
meinschaft (SFB 749) and the Fonds der Chemischen Industrie is grate-
fully acknowledged.
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H
Ar);13C NMR (100 MHz, CDCl3): d=30.3 (CH2), 38.1 (CH2), 55.5
(OCH3), 73.8 (OCH), 114.0 (CHAr), 115.0 (=C), 127.3 (CHAr), 137.0
(CAr), 138.4 (=C), 159.2 ppm (CAr).
Preparation of phosphonium salt 1b-PPh3 BF4 (typical procedure):[17]
The alcohol 1b-OH (388 mg, 2.00 mmol) was dissolved in CH2Cl2
(10 mL) and an equimolar amount of triphenylphosphonium tetrafluoro-
borate[18] was added. This solution was stirred at room temperature for
2 h. The precipitated salt was recrystallized from diethyl ether to yield
1b-PPh3 BF4 (1.03 g, 1.96 mmol; 98%). 1H NMR (600 MHz, CDCl3): d=
0.73 (t, J=7.2 Hz, 3H; CH3), 1.12–1.20 (m, 2H; CH2), 1.24–1.34 (m, 1H,
CH2), 1.42–1.50 (m, 1H; CH2), 1.90–1.98 (m, 1H; CH2), 2.12–2.18 (m,
1H; CH2), 3.76 (s, 3H; OCH3), 4.79–4.84 (m, 1H; PCH), 6.72 (d, J=
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8.6 Hz, 2H, HAr), 6.84 (dd, JACHTNUTRGNE(NUG H,P)=1.9 Hz, J=8.6 Hz, 2H; HAr), 7.51–
7.56 (m, 6H; HAr), 7.61–7.67 (m, 6H; HAr), 7.75–8.00 ppm (m, 3H; HAr);
13C NMR (150 MHz; CDCl3): d=13.8 (CH3), 22.3 (CH2), 29.3 (d, J-
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
J
N
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
Reaction of 1a-OH with 2c:[8a] 1-(4-Methoxyphenyl)ethanol (1a-OH,
76 mg, 0.50 mmol) and 1-(trimethylsiloxy)cyclohexene (2c) (1.0 mmol)
were dissolved in nitromethane (2 mL). BiACHTUNTGRNEUNG(OTf)3·x H2O (1 <x <4)
(8 mg) was added in one portion at room temperature, and the solution
was stirred for 1 h. The reaction was quenched by the addition of
EtOAc/water (50:50) and the aqueous layer was extracted with ethyl ace-
tate (2ꢄ20 mL). The combined organic layers were washed with water
(20 mL) and brine (20 mL), dried (Na2SO4), and the solvent was removed
under reduced pressure. The crude product was purified by flash chroma-
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dissolved in anhydrous diethyl ether (10–15 mL) in the presence of pyri-
dine (1 equiv), the solution was cooled to ꢁ158C and SOCl2 (3 equiv)
was added dropwise. After the reaction mixture had been stirred for 2 h,
the solvent was evaporated and the crude chloride was used directly.
Solvolyses of 1-Cl in 2,2,2-trifluoroethanol: To a mixture of the crude
benzyl chloride and 2,6-lutidine (or 2-chloropyridine, 3 equiv), TFE
(5 mL) was added during stirring and ice cooling. The mixture was stirred
for 2 h and diluted with pentane (20 mL), before HCl (5%, 30 mL) was
added. The aqueous layer was extracted with pentane (2ꢄ20 mL), the
combined organic layers washed with HCl (5%, 2ꢄ30 mL) and brine (3ꢄ
30 mL). After drying over Na2SO4 and evaporation of solvent, the prod-
uct was analyzed by NMR spectroscopy.
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Theoretical calculations: The conformational space has been searched
using the MM3 force field and the systematic search routine in the
8540
www.chemeurj.org
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 8533 – 8541

Carbocationic n-endo-trig Cyclizations
FULL PAPER
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ˇ ´
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´
ˇ ´
´
´
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Received: May 11, 2009
Published online: July 23, 2009
Chem. Eur. J. 2009, 15, 8533 – 8541
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8541