The synthetic potential of graphite-catalyzed alkylation

Article abstract of DOI:10.1016/j.tet.2007.05.005

Unmodified graphite is introduced as a mild catalyst for alkylation of aromatic compounds and primary alcohols, applicable when utilization of strong Lewis acids is not feasible. The electrophilic intermediate has a significant carbocationic character and can be formed on a partially rate-limiting step.

Full text of DOI:10.1016/j.tet.2007.05.005

Tetrahedron 63 (2007) 8351–8357
The synthetic potential of graphite-catalyzed alkylation
*
Grigoriy A. Sereda, Vikul B. Rajpara and Ryan L. Slaba
The University of South Dakota, Department of Chemistry, 414 E. Clark St., Vermillion, SD 57069, USA
Received 15 October 2006; revised 18 April 2007; accepted 1 May 2007
Available online 6 May 2007
Abstract—Unmodified graphite is introduced as a mild catalyst for alkylation of aromatic compounds and primary alcohols, applicable when
utilization of strong Lewis acids is not feasible. The electrophilic intermediate has a significant carbocationic character and can be formed on
a partially rate-limiting step.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
have identified the limits of applicability of graphite as a cat-
alyst for alkylation. Along with developing a simple and
convenient procedure for alkylation of functionalized aro-
matic compounds, we shed light on the possible reaction
mechanism.
Carbonaceous materials have received a great deal of atten-
tion as possible catalysts1–13 and construction blocks for the
design of new materials in the field of nanotechnology.14 A
number of reactions can be catalyzed by norit or charcoal,
such as racemization of 1,10-binaphthyl6 and nucleophilic
substitution.7 Compared to other types of carbonaceous cat-
alysts, graphite has a relatively low surface area, which
makes it inactive for many reactions in the absence of co-
catalysts.6 However, unmodified graphite is able to catalyze
several reactions, such as benzoylation of aromatic com-
pounds,2 cleavage of ethers,3 and oxidation.4,5
2. Results and discussion
We found that the amount of the catalyst for benzylation of
p-xylene 1 with benzyl chloride 2a could be significantly de-
creased while providing practical yields of the reaction prod-
uct 3a (Scheme 1). While using 0.25 g of graphite per
1 mmol of 2a produced 3a at a yield of 96% (Table 1, entry
1), 0.05 g of the catalyst still afforded an 89% yield (Table 1,
entry 3).
As opposed to other types of carbon and graphite-supported
catalysts, the mechanism of catalytic activity of unmodified
graphite remains largely unexplored. One reaction that has
been studied is thegraphite-catalyzed reduction of nitrobenz-
ene by hydrazine.10 However, there is no data in the litera-
ture on the mechanism of graphite-catalyzed alkylation,
acylation, and many other important organic reactions.
The recently described procedure1 for the graphite-catalyzed
alkylation of aromatic hydrocarbons employed the com-
pound to be alkylated as a solvent, which precludes applica-
bility of the reaction to high boiling, solid, rare, or toxic
substrates.
CH3
CH2Cl
CH3
Graphite
1-24 h
Reflux
Neat or PhCl
132-138 °C
R
CH3
R
CH3
1
2a-d
3a-d
R = H (a), CH3 (b), OCH3 (c), OC(O)CH3 (d)
Scheme 1. Benzylation of p-xylene.
In the present study, we have shown that graphite can be em-
ployed for reactions, where the use of traditional Lewis acids
is not feasible due to the instability of reactants (e.g., carbo-
cation rearrangement, Fries rearrangement). In our sug-
gested method, labile groups such as primary halide,
aromatic esters, and ethers remain intact. Exploring the reac-
tion for various reactants and under various conditions, we
Further decrease in the amount of graphite to 0.0125 g per
1 mmol of 2a led to a slight decrease in the yield (82%), ap-
parently due to the saturation of the catalytic surface (Table
1, entry 4). However, the yield of the benzylation product
was still in the practically acceptable range.
Reduction of the reaction time from 24 to 6 h did not lead to
a significant decrease in the yield of 3a, which still exceeded
80% (Table 1, entry 5). Therefore, we have optimized the
procedure of the graphite-catalyzed benzylation of p-xylene.
* Corresponding author. Tel.: +1 605 677 6190; fax: +1 605 677 6397;
e-mail: gsereda@usd.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.005

8352
G. A. Sereda et al. / Tetrahedron 63 (2007) 8351–8357
Table 1. Graphite-catalyzed alkylation of p-xylene
Entry
Alkylating agent
Ratio (alkylating
agent/xylene)
Graphite (gram per 1 mmol
of alkylating agent)
Additional conditions
t (h)
Yield (%)
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
BnBr
2b
2b
Neat
Neat
Neat
Neat
Neat
Neat
Neat
1:4
0.25
0.125
0.05
0.0125
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.125
0.125
0.05
0.05
0.1
—
—
—
—
—
—
24
24
24
24
6
3
1
24
3
3
96
91
89
82
87
83
67
92
29
1
—
PhCl solvent, 1.25 mL per 1 mmol of 2a
PhCl solvent, 1.25 mL per 1 mmol of 2a
PhCl solvent, 0.625 mL per 1 mmol of 2a
PhCOOH, 1 mmol per 1 mmol of 2a
CH3COOH, 1 mmol per 1 mmol of 2a
—
—
PhCl solvent, 2.5 mL per 1 mmol of 2b
—
PhCl solvent, 2.5 mL per 1 mmol of 2c
—
—
—
—
—
9
1:8
1:4
10
11
12
1315
1415
15
16
17
18
19
20
21
2215
23
24
25
26
27
28
29
30
Neat
Neat
Neat
Neat
1:1
3
3
23
0
1.5
1.5
24
24
24
24
24
24
24
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
88
100
83
100
38
47
100
0
Neat
1:1
2c
2c
2d
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
0.1
0.05
0.05
0.05
0.125
0.125
0
0.125
0.125
0.143
0.143
0.125
0.125
n-O2NBnCl
n-MeO2CBnCl
2-Bromobutane
2-Bromobutane
2-Bromobutane
2-Bromobutane
2-Bromobutane
2-Bromopentane
3-Bromopentane
2-Butyl tosylate
2-Chlorobutane
0
78
97
0
78
64
87
86
0
48% Aqueous HBr added
48% Aqueous HBr added
Graphite was pre-treated with dry HBr gas
Scaled up (ꢁ10) reaction of 22
16/17¼3:1
16/17¼3:1
—
—
0
Formation of 3a proceeded efficiently when benzyl chloride
and p-xylene (bp 138 ꢀC) reacted in 1:4 molar ratio in an in-
ert solvent chlorobenzene (bp 132 ꢀC, Table 1, entry 8).
In general, better yields of the product of alkylation were
achieved when the reaction was run under neat conditions
than in chlorobenzene as a solvent. Significantly higher con-
centration of the substrate under neat conditions increased
the reaction rate and suppressed undesired alkylation of
the reaction product. Nevertheless, performing the reaction
in chlorobenzene rather than in the bulk of a reactant, usually
led to the reaction product in a practical yield, which ex-
panded the applicability of the method to high boiling and
solid substrates as exemplified later in the text.
However, benzylation of p-xylene by 4-methoxybenzyl
chloride 2c (1:1 molar ratio) produced the product 3c with
a moderate yield of 38% (Table 1, entry 17). When p-xylene
was used as a solvent, the yield of the ester 3c increased to
47% due to the higher concentration of the compound to
be alkylated (Table 1, entry 18).
As opposed to the benzylating agents 2a–d with relatively
electron-rich aromatic nuclei, 4-carboxybenzyl chloride,
4-carbomethoxybenzyl chloride, and 4-nitrobenzyl chloride
were inactive under the reaction conditions (Table 1, entries
20 and 21). This pattern of reactivity suggests that the
step involving the formation of an alkylating carbocation-
like species (4, Scheme 2) is one of the partially rate-
determining steps of the whole reaction sequence.
Additional stabilization of the transition state (electron
donating substituents in the benzylating agent), leading to
this intermediate, accelerates the reaction, whereas insuffi-
cient stabilization (electron-withdrawing substituents)
blocks alkylation. In other words, low acidity of graphite
makes it significantly more difficult to generate an incipient
carbocationfrombenzylhalideswithanelectron-withdrawing
substituent.
Alkylation by benzyl chlorides, containing a moderately
electron-donating p-substituent (compounds 2b,d, Scheme
1) led to higher conversions and provided significantly better
yields than the unsubstituted benzyl chloride (Table 1,
entries 16 and 19). In p-substituted benzyl chlorides, the p-
position is occupied by the substituent, which makes the re-
action product less susceptible to the subsequent alkylations.
Thus, alkylation of p-xylene with 4-methylbenzyl chloride
2b in chlorobenzene afforded the product 3b in an excellent
yield (83%) even for a lower ratio (1:1) between the reagent
and the compound to be alkylated (Table 1, entry 15). The
reaction produced a quantitative yield of 3b when it was per-
formed in the bulk of p-xylene (Table 1, entry 16). Alkyl-
ation of p-xylene by 4-(chloromethyl)phenyl acetate 2d
quantitatively afforded the phenyl ester 3d, which can-
not be synthesized by the traditional Friedel–Crafts
alkylation due to the competing Fries rearrangement (Ta-
ble 1, entry 19).
CH3
Graphite
CH
3H
CH3
CH3
+
R
-H+
CH3
+
R
X
R
R-X
+
+
CH3
4
Scheme 2. Possible mechanism for graphite-catalyzed alkylation.

G. A. Sereda et al. / Tetrahedron 63 (2007) 8351–8357
8353
The intermediacy of a well-stabilized, selective, and moder-
ately active carbocation complex is consistent with our prior
observation that benzylation of toluene with benzyl chloride
does not produce the reaction product of meta-substitution.1
This observation is consistent with the seminal work of
Olah,15 who reported that the electron-donating effect of
the p-substituent increases both the positional and substrate
selectivities of TiCl4 catalyzed alkylation by the series of p-
substituted benzyl chlorides. Olah’s explanation of this ten-
dency rests on the assumption that the early transition states
of benzylation generated by stronger electrophiles change
through the continuum of states to the late transition states
as the electron-donating effect of the substituent increases.
Later, the detailed kinetic studies of both competitive and
non-competitive benzylations of benzene and toluene sug-
gested that the rate-determining step is the formation of
the electrophile,16 which is consistent with our results.
intercalation, which led to the increased distance between
basal planes, has been documented by X-ray diffraction
for alkylation of phenol, catalyzed by graphite in the pres-
ence of strong Lewis acids.9
Despite the lack of activity of primary alkyl halides,1 the
lack of skeletal rearrangements of the alkyl chain (benzyla-
tion of 3-bromo-1-phenylpropane 5, Scheme 3), and the
lack of de-alkylation, we observed a skeletal rearrangement
of the electrophilic intermediate during alkylation of p-
xylene with 2-bromopentane and 3-bromopentane (Table 1,
entries 27 and 28). Both reactions produced an identical
3:1 mixture of 1-(methylbutyl)benzene 16 and 1-(ethyl-
propyl)benzene 17. The observed 16:17 ratio is close to the
reported composition of their equilibrated mixture in the
presence of aluminum chloride.19 These data indicate that
the electrophilic intermediate is located on the potential
energy surface quite close to the straight carbocation
that rearranges, according to the following equation:
CH3CH+CH2CH2CH3¼CH3CH2CH+CH2CH3. However,
the lack of de-alkylation indicates that the graphite-catalyzed
reaction is irreversible, which is a distinct difference from
the Friedel–Crafts process, catalyzed by strong Lewis acids.
In an additional experiment, we refluxed a mixture of
2-sec-butyl-1,4-dimethylbenzene 15, graphite, and an excess
of phenol in p-xylene solvent. No reaction was observed,
which confirms that the graphite-catalyzed alkylation is
irreversible.
Because of the lack of reactivity of tert-butyl bromide to-
ward p-xylene,1 we studied alkylation of o-xylene by tert-
butyl halides. As expected, the reaction yields increased
from 53% for tert-butyl chloride to 98% for tert-butyl bro-
mide1 and iodide. This trend is similar to the known higher
reactivity of benzyl bromide versus benzyl chloride toward
p-xylene17a (Table 1, entries 13 and 14), but is significantly
different from the reactivity trend of 2-halobutanes, dis-
cussed next.
Alkylation by secondary alkyl bromides evidently proceeds
through an intermediate carbocation-like species as well.
Recently, we found that 2-bromobutane efficiently alkylates
p-xylene.17a However, bromopropanoic acid was inactive
because the development of the positive charge on carbon
in the corresponding transition state was disfavored by the
neighboring carboxy group. To obtain additional evidence
of a highly ionized reactive intermediate, we performed
alkylation of p-xylene by R-2-bromobutane.18 The reaction
yielded an optically inactive product due to racemization
of the carbocation-like electrophile.
Br
Br
CH2Cl
Graphite
24 h
PhCl, Reflux
132 °C
OC(O)CH3
5
2d
6
OC(O)CH3
Scheme 3. Benzylation of 3-bromo-1-phenylpropane.
Performing alkylation of p-xylene with 2-bromobutane
under highly acidic conditions (in the presence of aqueous
HBr) significantly increased the extent of conversion from
78 to 97% (Table 1, entries 22 and 23). However, in the ab-
sence of water (electrolytic dissociation is precluded) HBr
did not accelerate the reaction (Table 1, entry 25). The sig-
nificance of graphite as a catalyst was confirmed by the
lack of alkylation in the presence of aqueous HBr, but with-
out graphite. Scaling up the reaction by a factor of 10
resulted in a slight decrease in conversion from 78 to 64%
(Table 1, entries 22 and 26).
Keeping in mind that primary alkyl bromides, as opposed to
tertiary alkyl halides and benzyl halides, are inert in the
graphite-catalyzed alkylation, we explored the marginal
group of secondary butyl halides as alkylating agents. We
observed an unusual pattern of reactivity in the row of 2-
halobutanes: 2-bromobutane was the most active,17a and
no reaction was observed with 2-chlorobutane (Table 1, en-
try 30). However, 2-iodobutane showed no activity either,17a
which contradicts the expectation, based solely on the differ-
ent dissociation energies of the C–Hal bonds. Even 2-butyl
tosylate with an excellent leaving group was found inactive
(Table 1, entry 29), which makes secondary bromides
special and intriguing alkylating agents in the graphite-
catalyzed reactions.
The kinetic experiment revealed that concentration of the
product of alkylation increased logarithmically. If we as-
sume that most of the unreacted 2-bromobutane is present
in the form of free halide, these data suggest the first order
kinetics of 2-bromobutane (Fig. 1).
We believe that intercalation of the incipient anion formed
during the charge separation in the electrophilic agent be-
tween the basal planes of graphite contributes to the stabili-
zation of the electrophilic intermediate, which explains the
unique ability of 2-bromobutane to act as an alkylating
agent. The properties of the bromide-anion (e.g., size, solva-
tion, and polarizability) are probably optimal for inclusion
between the graphitic planes. This phenomenon of
The first-order dependence on halide does not suggest either
a first or second rate-limiting reaction step (Scheme 2). Two
possible scenarios may take place: (1) the first step is rate-
limiting; (2) the second step is rate-limiting, and the first
step is fast enough to bring the starting halide and
the electrophilic intermediate close to equilibrium. On

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G. A. Sereda et al. / Tetrahedron 63 (2007) 8351–8357
60 80 100
0
20
40
Benzylation of n-butanol 7 by unsubstituted benzyl chlo-
ride 1a, carried out at a significantly lower initial concen-
tration of alcohol (chlorobenzene was used as a solvent
and the starting materials were mixed in a 1:1 ratio),
did not produce any detectable amounts of the product.
This suggests the involvement of n-butanol in the rate-
determining step (probably, an electrophilic attack). It is
worth noting that no skeletal rearrangement of n-butanol
was observed during the reaction, which emphasizes
the synthetic value of the graphite-catalyzed alkylation,
especially for the substrates, labile under the Williamson
conditions.
0,00
-1,00
-2,00
-3,00
-4,00
-5,00
-6,00
Time t (min)
Figure 1. Kinetic data for alkylation of p-xylene with 2-bromobutane.
We found that the graphite catalyst can be recovered from
the reaction of alkylation of p-xylene by 2-bromobutane.
The reaction, catalyzed by the recovered graphite, produced
a lower yield (65% vs 78% for the fresh catalyst) of sec-
butyl-1,4-dimethylbenzene.20 The catalyst was recovered
again and used for the same experiment for the third time.
The activity of graphite decreased but it was sufficient to
result in 56% yield of the product.
the other hand, the kinetic data allow eliminating the fol-
lowing scenarios: (1) the second step is rate-limiting, the
first step is heavily shifted toward the intermediate, and
the catalyst is close to saturation (this situation would re-
sult in pseudo-zero order on the halide); (2) the first step
is rate-limiting, and the formation of the intermediate
involves more than one molecule of the halide (this situ-
ation would result in a higher reaction order on the
halide).
Elucidation of the exact relative contribution of basal planes
and their edges to the catalytic activity of graphite toward
alkylation is currently underway, and the results will be
reported elsewhere. At this moment we know that the cata-
lytic sites on the surface of graphite strongly absorb carb-
oxylic acids, which explains their inhibiting effect on the
graphite-catalyzed benzylation of p-xylene. Thus, the addi-
tion of 10 equiv of benzoic acid reduced the yield of the
hydrocarbon 3a from 83 to 23% (Table 1, entries 6 and
11). The addition of the same amount of acetic acid sup-
pressed the reaction completely (Table 1, entry 12). Accord-
ing to the literature,21 carboxylic acids strongly bind with
functional groups on the surface of graphite, generated
by chemisorbed oxygen, which points to their role in cata-
lytic activity.
We observed a significant decrease in the extent of conver-
sion in benzylation of p-xylene with benzyl chloride when
we decreased the concentrations of both the alkylating
agent and the substrate. Thus, decreasing the starting con-
centration of benzyl chloride by half, while using chloro-
benzene as a solvent for alkylation of p-xylene, reduced
the conversion from 92 to 29% (Table 1, entries 8 and 9).
The same reaction performed with twice the amount of
chlorobenzene solvent, produced just a trace amount of
the alkylation product. The influence of the substrate con-
centration on the reaction outcome indicates that the step
of the electrophilic attack (Scheme 2), which involves the
compound to be alkylated, is another rate-contributing
step in the reaction mechanism similar to the traditional
Friedel–Crafts process.
The synthetic applicability of graphite-catalyzed alkylation
is not limited to hydrocarbons. Benzylation of 1,4-dimeth-
oxybenzene 9 with 4-methylbenzyl chloride 2b (1:1 molar
ratio) produced 2,5-di-(4-methylbenzyl)-1,4-dimethoxyben-
zene 10 (Scheme 5) with a 26% yield based on the alkylating
agent. Mixing the reactants in the stoichiometric ratio of 1:2
resulted in nearly the same yield of 10 (28%) on the halide
1b. However, the yield of the product on the substrate 9
doubled.
As opposed to the previously discussed graphite-catalyzed
benzylation of aromatic compounds, the step of electrophilic
species formation seems to be kinetically less important for
benzylation of primary alcohols. Replacing the unsubsti-
tuted benzyl chloride 2a with 4-methylbenzyl chloride 2b
in the benzylation of n-butanol reaction does not increase
the efficiency of the reaction as it does for benzylation of
p-xylene. The reaction between 4-methylbenzyl chloride
2b and the bulk of n-butanol 7 (Scheme 4) produced ether
8 at 28% conversion, which is very close (29%) to the known
graphite-catalyzed benzylation of n-butanol with unsubsti-
tuted benzyl chloride.1 The consistent yields indicate that
there is no influence of the electron-donating CH3– group
at the para position of the benzyl chloride on the reaction
outcome.
The selectivity of graphite-catalyzed alkylation is best illus-
trated by the benzylation of 3-bromo-1-phenylpropane 5 by
4-(chloromethyl)phenyl acetate 2d, which produced the
bifunctional product 6 (Scheme 3). Neither of the two
reactants would be stable under traditional Friedel–Crafts
conditions.
O
CH2Cl
CH2Cl
Graphite
HO
OCH3
OCH3
Graphite
24 h
PhCl, Reflux
132 °C
H3C
24 h
+
+
Reflux
116 °C
28%
CH3
(Solvent)
CH3
CH3
OCH3
CH3
OCH3
2b
7
8
1b
9
10
Scheme 4. Synthesis of 1-(butoxymethyl)-4-methylbenzene.
Scheme 5. Benzylation of 1,4-dimethoxybenzene.

G. A. Sereda et al. / Tetrahedron 63 (2007) 8351–8357
8355
3. Conclusion
(j) Reaction (h) was conducted for 3 h with twice the
amount of the solvent (chlorobenzene). The yield of
hydrocarbon 3a was 11 mg (1%).
Graphite-catalyzed alkylation of aromatic compounds and
primary alcohols proved to be a versatile experimental pro-
tocol for organic synthesis, applicable when utilization of
strong Lewis acids is not feasible. The reaction mechanism
presents an interesting case of controlled charge separation
in the step of the formation of the electrophile, which can
be fine tuned by varying the structure of the alkylating agent
and its leaving group. The extent of charge separation neces-
sary for an electrophilic reaction develops under relatively
mild conditions, which makes the reaction a selective
approach for the alkylation of aromatic compounds and
primary alcohols.
4.3. 1,4-Dimethyl-2-(4-methylbenzyl)benzene23 (3b)
(a) A mixture of 4-methylbenzyl chloride (2b, 0.26 mL,
2 mmol), p-xylene (1, 0.25 mL, 2 mmol), chlorobenz-
ene (5.0 mL, solvent), and graphite (0.10 g) was re-
fluxed for 24 h with continuous stirring, cooled to
room temperature, and filtered on a fritted funnel with
suction. The solids were washed with hexane (10 mL).
The combined filtrates were evaporated in vacuum to
yield 1,4-dimethyl-2-(4-methylbenzyl)benzene (3b,
0.35 g, 83%), which was identical to the known com-
pound by NMR.23
(b) Reaction (a) was conducted with p-xylene (5 mL) as
a solvent and provided 0.42 g (100%) of 3b.
4. Experimental
4.1. General
4.4. 1,4-Dimethyl-2-(4-methoxybenzyl)benzene (3c)
All necessary materials were purchased from Aldrich Co.,
Fischer Scientific, GFS Chemicals, J. T. Baker Chemical
Company, Chempure, Scientific Adsorbents Incorporated
and were used as such without purification. Graphite powder
was purchased from Aldrich (catalogue no. 28,286-3
(a) A mixture of 4-methoxybenzyl chloride (2c, 0.272 mL,
2 mmol), p-xylene (1, 0.25 mL, 2 mmol), chlorobenzene
(5.0 mL, solvent), and graphite (0.20 g) was refluxed for
24 h with stirring, cooled to room temperature, and fil-
tered on a fritted funnel with suction. The solids were
washed with hexane (10 mL). The combined filtrates
were evaporated in vacuum and chromatographed on
a silica gel column, eluted by 5% ethyl acetate in hexane
to yield 174 mg (38%) of 1,4-dimethyl-2-(4-methoxy-
1
particles <20 mm). H NMR spectra were recorded on a
Mercury-200 spectrometer with tetramethylsilane as an
internal reference. The reaction progress was monitored
by TLC.
1
benzyl)benzene (3c) as a colorless oil, n2D0 1.5680. H
4.2. 2-Benzyl-1,4-dimethylbenzene22 (3a)
NMR (CDCl3) d 2.20 (s, 3H), 2.30 (s, 3H), 3.80 (s,
3H), 3.90 (s, 2H), 6.8–7.1 (m, 7H). Anal. Calcd for
C16H18O: C, 84.91; H, 8.02. Found: C, 84.88; H, 8.18.
(b) Reaction (a) was conducted with p-xylene (10 mL) as
a solvent and provided 215 mg (47%) of 3c.
(a) A mixture of benzyl chloride (2a, 0.460 mL, 4 mmol), p-
xylene (1, 5.0 mL, solvent), and graphite (1.00 g) was re-
fluxed for 24 h with continuous stirring, cooled to room
temperature, and filtered on a fritted funnel with vacuum
suction. The solids were washed with hexane (10 mL).
The combined filtrates were evaporated in vacuum to
yield 2-benzyl-1,4-dimethylbenzene (3a, 0.753 g,
96%), identical to the known compound by NMR.22
(b) Reaction (a) was conducted with 0.500 g of graphite and
provided 0.713 g (91%) of hydrocarbon 3a.
(c) Reaction (a) was conducted with 0.200 g of graphite and
provided 0.698 g (89%) of hydrocarbon 3a.
(d) Reaction (a) was conducted with 0.050 g of graphite and
provided 0.643 g (82%) of hydrocarbon 3a.
(e) Reaction (a) was conducted by refluxing the reaction
mixture for 6 h and provided 0.682 g (87%) of hydrocar-
bon 3a.
(f) Reaction (a) was conducted by refluxing the reaction
mixture for 3 h and provided 0.651 g (83%) of hydrocar-
bon 3a.
(g) Reaction (a) was conducted by refluxing the reaction
mixture for 1 h and provided 0.525 g (67%) of hydrocar-
bon 3a.
(h) Reaction (a) was conducted using chlorobenzene (5 mL)
as a solvent and provided 0.721 g (92%) of hydro-
carbon 3a; p-xylene and benzyl chloride were used in
a 4:1 ratio.
(i) Reaction (h) was conducted for 3 h with an 8:1 ratio of
p-xylene and benzyl chloride. The yield of hydrocarbon
3a was 0.227 g (29%).
4.5. 4-(2,5-Dimethylbenzyl)phenyl acetate (3d)
A mixture of 4-(chloromethyl)phenyl acetate (2d, 0.369 g,
2 mmol), p-xylene (1, 5 mL), and graphite (0.10 g) was re-
fluxed for 24 h with stirring, cooled to room temperature,
and filtered on a fritted funnel with suction. The solids
were washed with hexane (10 mL). The combined filtrates
were evaporated in vacuum to yield 4-(2,5-dimethylbenzyl)-
phenyl acetate (3d, 0.508 g, 100%). 1H NMR (CDCl3) d 2.18
(s, 3H), 2.22 (s, 3H), 2.23 (s, 3H), 3.90 (s, 2H), 6.9–7.4 (m,
7H). Mp 33–34 ꢀC. Anal. Calcd for C17H18O2: C, 80.28; H,
7.13. Found: C, 80.46; H, 7.16.
4.6. 1-(Butoxymethyl)-4-methylbenzene24 (8)
A mixture of 4-methylbenzyl chloride (2b, 0.4 mL, 3 mmol),
n-butanol (7, 5 mL), and graphite (0.1 g) was refluxed for
24 h with stirring, cooled to room temperature, and filtered
on a fritted funnel with suction. The solids were washed
with hexane (10 mL). The combined filtrates were evapo-
rated in vacuum to yield 1-(butoxymethyl)-4-methylbenzene
(8, 0.150 g, 28%), identical to the known compound.24 1H
NMR (CDCl3) d 0.90 (t, 3H), 1.40 (m, 2H), 1.60 (m, 2H),
2.30 (s, 3H), 3.45 (t, 2H), 4.45 (s, 2H), 7.10 (d, 2H), 7.20
(d, 2H). 13C NMR (CDCl3) d 14.28, 19.74, 21.47, 32.22,
70.33, 73.05, 128.04, 129.33, 135.99, 137.37.

8356
G. A. Sereda et al. / Tetrahedron 63 (2007) 8351–8357
4.7. Alkylation of 1,4-dimethoxybenzene with 4-methyl-
benzyl chloride (2b)
to room temperature, and filtered through a pad of silica
gel on a fritted funnel with vacuum suction. The solids
were washed with hexane (3ꢁ5 mL). The combined fil-
trates were evaporated in vacuum to yield 4-tert-butyl-
1,2-dimethylbenzene (11, 0.555 g, 98%), identical to
the known compound by NMR.1
(a) A mixture of 1,4-dimethoxybenezene (9, 553 mg,
4 mmol), 4-methylbenzyl chloride (2b, 0.53 mL,
4 mmol), chlorobenzene (5 mL), and graphite (0.13 g)
was refluxed for 24 h with stirring, cooled to room tem-
perature, and filtered on a fritted funnel with suction.
The solids were washed with hexane (10 mL) and ethyl
acetate (5 mL). The combined filtrates were evaporated
in vacuum and triturated with 5 mL of hexane. The
solids were filtered off and crystallized from hexane to
produce 180 mg (26%) of 2,5-di-(4-methylbenzyl)-1,4-
dimethoxybenzene 10. 1H NMR (CDCl3) d 2.30 (s,
6H), 3.65 (s, 6H), 3.90 (s, 4H), 6.60 (s, 2H), 7.4 (m,
8H). Mp 152–153 ꢀC. Anal. Calcd for C24H26O2: C,
83.20; H, 7.56. Found: C, 83.49; H, 7.61.
(b) A mixture of 1,4-dimethoxybenezene (9, 553 mg,
4 mmol), 4-methylbenzyl chloride (2b, 1.06 mL,
8 mmol), chlorobenzene (5 mL), and graphite (0.13 g)
was refluxed for 24 h with stirring, cooled to room tem-
perature, and filtered on a fritted funnel with suction.
The solids were washed with hexane (10 mL) and ethyl
acetate (5 mL). The combined filtrates were evaporated
invacuum, triturated with 5 mL of hexane, and the solids
were filtered off to produce 382 mg (28%) of 2,5-di-(4-
methylbenzyl)-1,4-dimethoxybenzene 10, identical to
the compound, prepared in experiment (a).
4.10. 2-sec-Butyl-1,4-dimethylbenzene (15)
(a) A mixture of 2-bromobutane (0.44 mL, 4 mmol),
p-xylene (1, 5.0 mL, solvent), 48% aqueous HBr
(0.04 mL), and graphite (0.5 g) was refluxed for 1.5 h
with continuous stirring, cooled to room temperature,
and filtered through a pad of silica gel on a fritted funnel
with vacuum suction. The solids were washed with hex-
ane (3ꢁ5 mL). The combined filtrates were evaporated
in vacuum to yield 2-sec-butyl-1,4-dimethylbenzene
(15, 0.630 g, 97%), identical to the known compound
by NMR.17b
(b) A mixture of 2-bromobutane (0.44 mL, 4 mmol),
p-xylene (1, 5.0 mL, solvent), and 48% aqueous HBr
(0.04 mL) was refluxed for 1.5 h with continuous stir-
ring, cooled to room temperature, and evaporated in vac-
uum to yield traces (6 mg) of unidentified material.
(c) A mixture of 2-bromobutane (0.44 mL, 4 mmol),
p-xylene (1, 5.0 mL, solvent), and graphite (0.5 g, pre-
treated overnight with gaseous HBr, produced in a
desiccator, containing 1 mL of 48% aqueous HBr and
100 g of P2O5) was refluxed for 1.5 h with continuous
stirring, cooled to room temperature, and filtered
through a pad of silica gel on a fritted funnel with vac-
uum suction. The solids were washed with hexane
(3ꢁ5 mL). The combined filtrates were evaporated
in vacuum to yield 2-sec-butyl-1,4-dimethylbenzene
(15, 0.506 g, 78%).
(d) A mixture of 2-bromobutane (4.4 mL, 40 mmol),
p-xylene (1, 50 mL, solvent), and graphite (5.0 g) was
refluxed for 1.5 h with continuous stirring, cooled to
room temperature, and filtered through a pad of silica
gel on a fritted funnel with vacuum suction. The solids
were washed with hexane (3ꢁ50 mL). The combined
filtrates were evaporated in vacuum to yield 2-sec-
butyl-1,4-dimethylbenzene (15, 4.15 g, 64%).
(e) A mixture of 2-bromobutane (0.22 mL, 2 mmol),
p-xylene (1, 2.5 mL, solvent), and graphite (0.25 g)
was refluxed for an array of times (15, 30, 45, 60, 75,
and 90 min) with continuous stirring, cooled to room
temperature, and filtered through a pad of silica gel on
a fritted funnel with vacuum suction. The solids were
washed with hexane (3ꢁ5 mL). The combined filtrates
were evaporated in vacuum to yield 2-sec-butyl-1,4-
dimethylbenzene (15). The experimental results are
presented in Table 2 and Figure 1.
4.8. Alkylation of 1-bromo-3-phenylpropane with
4-(chloromethyl)phenyl acetate (2d)
A mixture of 1-bromo-3-phenylpropane (5, 0.30 mL,
2 mmol), 4-(chloromethyl)phenyl acetate (2d, 0.369 g,
2 mmol), chlorobenzene (5 mL), and graphite (0.20 g) was
refluxed for 24 h with stirring, cooled to room temperature,
and filtered on a fritted funnel with suction. The solids were
washed with hexane (10 mL) and ethyl acetate (5 mL). The
combined filtrates were evaporated in vacuum and separated
on a silica gel HPLC column, eluted by 1.3% of ethanol in
hexane to yield 0.42 g (60%) of 4-[4-(3-bromopropyl)ben-
zyl]phenyl acetate 6 as a colorless thick oil. 1H NMR
(CDCl3) d 2.15 (m, 2H), 2.25 (s, 3H), 2.75 (t, 2H,
J3¼6 Hz), 3.40 (t, 2H, J3¼6 Hz), 3.95 (s, 2H), 6.9–7.2 (m,
8H). 13C NMR (CDCl3) d 21.39, 33.43, 33.76, 34.39,
41.12, 121.70, 128.94, 129.29, 130.02, 138.62, 138.83,
139.03, 149.13, 169.93. Anal. Calcd for C18H19BrO2: C,
62.26; H, 5.51. Found: C, 62.47; H, 5.28.
4.9. 4-tert-Butyl-1,2-dimethylbenzene1 (11)
(a) A mixture of tert-butyl chloride (12, 0.38 mL,
3.5 mmol), o-xylene (13, 5.0 mL, solvent), and graphite
(1.000 g) was refluxed for 24 h with continuous stirring,
cooled to room temperature, and filtered through a pad
of silica gel on a fritted funnel with vacuum suction.
The solids were washed with hexane (3ꢁ5 mL). The
combined filtrates were evaporated in vacuum to yield
4-tert-butyl-1,2-dimethylbenzene (11, 0.300 g, 53%),
identical to the known compound by NMR.1
4.11. 2,5-Dimethyl-1-(1-methylbutyl)benzene (16) and
2,5-dimethyl-1-(1-ethylpropyl)benzene (17)
(a) A mixture of 2-bromopentane (0.44 mL, 3.5 mmol), p-
xylene (1, 5.0 mL, solvent), and graphite (0.5 g) was re-
fluxed for 1.5 h with continuous stirring, cooled to room
temperature, and filtered through a pad of silica gel on
a fritted funnel with vacuum suction. The solids were
washed with hexane (3ꢁ5 mL). The combined filtrates
(b) A mixture of tert-butyl iodide (14, 0.35 mL, 3.5 mmol),
o-xylene (13, 5.0 mL, solvent), and graphite (1.000 g)
was refluxed for 24 h with continuous stirring, cooled

G. A. Sereda et al. / Tetrahedron 63 (2007) 8351–8357
8357
Table 2. Kinetic data for alkylation of p-xylene with 2-bromobutane
Time t Conversion Unreacted C2-bromobutane Ln
(min) (%) 2-bromobutane (%) (Mol/L) (C2-bromobutane
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)
0
0.0
37.0
60.8
70.1
80.6
86.7
90.1
100.0
63.0
39.2
29.9
19.4
13.3
9.9
0.080
0.050
0.031
0.024
0.016
0.011
0.008
ꢂ2.53
ꢂ2.99
ꢂ3.46
ꢂ3.73
ꢂ4.17
ꢂ4.54
ꢂ4.84
15
30
45
60
75
90
were evaporated in vacuum to yield 0.494 g (87%) of
a mixture of 1-(methylbutyl)benzene19 (16) and 1-(eth-
ylpropyl)benzene19 (17) in the molar ratio of 3:1 (by
NMR). This ratio was determined by the integration of
the triplet at 0.8 ppm (side chain methyl groups of 17)
and the doublet at 1.2 ppm (one of the two side chain
1
methyl groups of 16). H NMR (CDCl3) d 0.80 (t),
0.90 (t), 1.20 (d), 1.2–1.3 (m), 1.5–1.7 (m), 2.25 (s),
2.30 (s), 2.65 (m), 2.95 (m), 6.8–7.1 (m).
(b) A mixture of 3-bromopentane (0.44 mL, 3.5 mmol),
p-xylene (1, 5.0 mL, solvent), and graphite (0.5 g) was
refluxed for 1.5 h with continuous stirring, cooled to
room temperature, and filtered through a pad of silica
gel on a fritted funnel with vacuum suction. The solids
were washed with hexane (3ꢁ5 mL). The combined
filtrates were evaporated in vacuum to yield 0.490 g
(86%) of a mixture of 1-(methylbutyl)benzene19 (16)
and 1-(ethylpropyl)benzene19 (17) in the molar ratio of
3:1 (by NMR).
4.12. Attempt of de-alkylation of 2-sec-butyl-1,4-di-
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A mixture of 2-sec-butyl-1,4-dimethylbenzene (15, 0.19 g,
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solvent), and graphite (0.1 g) was refluxed for 1.5 h with
continuous stirring, cooled to room temperature, and filtered
through a fritted funnel with vacuum suction. The solids
were washed with chloroform (3ꢁ5 mL). The combined fil-
trates were evaporated in vacuum to yield 0.47 g of a mixture
of the starting materials (by NMR).
20. Shi, Z.; He, C. J. Am. Chem. Soc. 2004, 126, 13596–
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Acknowledgements
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We thank the State of South Dakota (2010 Research Initia-
tive and 2010 Individual SEED Grant) for financial support
of this work. We also acknowledge NSF URC Grant
0532242 for the purchase of an elemental analyzer used in
this research.
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1987, 28, 6205–6206.
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