Triflic acid-catalyzed adamantylation of aromatics in [BMIM][OTf] ionic liquid; synthetic scope and mechanistic insight

Article abstract of DOI:10.1039/b416997b

A mild and efficient process has been developed for the one-pot adamantylation of aromatic substrates employing 1-AdaOH, 1-AdaCl, 1-AdaBr, and 1-Br-3,5,7-trimethyladamantane as adamantylating agents, with triflic acid (TfOH) as promoter and n-butylmethylimidazolium triflate [BMIM][OTf] room temperature ionic liquid (IL) as solvent. The influence of reaction temperature, reaction time and the amount of TfOH was gauged in model reactions employing 1-AdaOH, 1-AdaCl and 1-AdaBr with toluene as the substrate. Under optimal conditions, the reactions exhibit high para selectivity with little or no adamantane side-product being formed. The synthetic scope of this transformation was tested for representative alkylbenzenes and haloalkylbenzenes. Comparative reactions carried out in 1,2-dichloroethane (DCE) produce increased amounts of the meta isomer and substantial amounts of adamantane. Substrate selectivities (K_T/K_B) were measured in competitive experiments in [BMIM][OTf] and in DCE as solvents. Isomerization tests were performed to shed light on the origin of the meta isomer. A DFT study was also conducted to compare relative stabilities of the isomeric products, to gauge the relative stabilities of the intermediate isomeric benzenium ions of adamantylation and their charge distribution modes, and to explore the intramolecular process for isomerization in the benzenium ion. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b416997b

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A R T I C L E
Triflic acid-catalyzed adamantylation of aromatics in [BMIM][OTf]
ionic liquid; synthetic scope and mechanistic insight†‡
Kenneth K. Laali,* Viorel D. Sarca,§ Takao Okazaki,¶ Aaron Brockꢀ and Paul Derꢀ
Department of Chemistry, Kent State University, Kent, OH, 44242, USA.
E-mail: klaali@kent.edu; Fax: 330-6723816; Tel: 330-6722988
Received 8th November 2004, Accepted 24th January 2005
First published as an Advance Article on the web 14th February 2005
A mild and efficient process has been developed for the one-pot adamantylation of aromatic substrates employing
1-AdaOH, 1-AdaCl, 1-AdaBr, and 1-Br-3,5,7-trimethyladamantane as adamantylating agents, with triflic acid
(TfOH) as promoter and n-butylmethylimidazolium triflate [BMIM][OTf] room temperature ionic liquid (IL) as
solvent. The influence of reaction temperature, reaction time and the amount of TfOH was gauged in model
reactions employing 1-AdaOH, 1-AdaCl and 1-AdaBr with toluene as the substrate. Under optimal conditions, the
reactions exhibit high para selectivity with little or no adamantane side-product being formed. The synthetic scope of
this transformation was tested for representative alkylbenzenes and haloalkylbenzenes. Comparative reactions
carried out in 1,2-dichloroethane (DCE) produce increased amounts of the meta isomer and substantial amounts of
adamantane. Substrate selectivities (KT/KB) were measured in competitive experiments in [BMIM][OTf] and in DCE
as solvents. Isomerization tests were performed to shed light on the origin of the meta isomer. A DFT study was also
conducted to compare relative stabilities of the isomeric products, to gauge the relative stabilities of the intermediate
isomeric benzenium ions of adamantylation and their charge distribution modes, and to explore the intramolecular
process for isomerization in the benzenium ion.
the para isomer) were also formed.8 These findings indicated
Introduction
that, under these conditions, the formed 1-adamantyl cation (1-
There is growing interest in adamantane and its derivatives as
Ada+) reacts with the arene, and in competition undergoes an
building blocks in polymer chemistry for the construction of
intermolecular hydride-shift to form adamantane. The latter is
star polymers, copolymers and dendrimers,1–3 and in the field of
the likely precursor to 2-Ada+ which leads to the formation of
molecular recognition for the synthesis of adamantyl-appended
2-phenyl- and 2-tolyladamantanes as by-products.8 Significant
macrocycles4 and adamantylated calixarenes.5 Another promis-
amounts of adamantane were also formed when authentic
ing area involving adamantane is the generation of carboca-
1-tolyladamantane was reacted with B(OTf)3–CH2Cl2.8 This
tions appended to an adamantane scaffold via the bridgehead
indicated an intermolecular process. Also, 2-tolyadamantane
positions, notably the 1,3,5,7-tetracations and 1,3-dications,
rapidly isomerized to 1-tolyladamanatane in B(OTf)3–CH2Cl2,
and the potential of these systems in self-assembly.6
Despite the fact that direct electrophilic adamantylation
reflecting the intermolecular nature of 2-Ada+ isomerization to
1-Ada+.8
of aromatics represents a simple and logical route for the
A solid acid catalyst version for aromatic adamantylation
synthesis of aryladamantanes,7 the scope of Friedel–Crafts
was later reported by Olah and associates,9 whereby toluene
type adamantylation of aromatics has not been extensively
could be adamantylated with 1-AdaBr in quantitative yields at
investigated and mechanistic data are scarce.
temperatures above 100 ◦C over Nafion-H and other solid acids.
Olah and associates used boron (tris)triflate, B(OTf)3, as a
Under these conditions, little or no adamantane was formed,
super Lewis acid for adamantylation of benzene and toluene
and the regioselectivity also improved (with the para isomer
with isomeric 1- and 2-haloadamantanes.8 With toluene as
predominating, but some meta was also formed).9 Furthermore,
the substrate, adamantylation using 1-adamantyl chloride (1-
AdaCl) and 1-adamantyl bromide (1-AdaBr) was effected at
rt in CH2Cl2 solvent, producing a mixture of meta- and para-
tolyladamantanes with the meta isomer predominating (the for-
there was no isomerization of the para product to meta, which
ruled out an intermolecular process (de-adamantylation–re-
adamantylation), but did not rule out isomerization within the
benzenium ion (adamantyl shift and/or methyl shift).9
mation of an ortho isomer is unfavorable in this transformation
In a relatively recent study, Prakash et al.10 conducted a
on steric grounds). The reaction was accompanied by significant
survey of various lanthanide triflates and Ga(OTf)3 as catalysts
formation of adamantane as a side product. Small amounts
for adamantylation of toluene using 1-AdaBr. Conversions
of isomeric 2-tolyadamantanes (with preferential formation of
and isomer distributions were highly variable depending on
the choice of the metallic triflate. With Ga(OTf)3 the reaction
† Presented in part at the Symposium on Ionic Liquids in Organic
Synthesis, ACS National Meeting, Philadelphia, USA, Aug 2004
(Abstract #322).
‡ Electronic supplementary information (ESI) available: optimized
structures for the arenium and benzenium ions; DFT calcluations. See
http://www.rsc.org/suppdata/ob/b4/b416997b/
§ Present address Department of Chemistry, Tulane University, New
Orleans.
could be effected at rt in reasonable yields, but significant
amounts of the meta isomer were formed. Complete conversion
could be effected at 100 ◦C, but predominant formation of the
meta isomer was observed, as well as notable amounts of di-
tolyladamantane.10
There is tremendous current interest in the utility and appli-
cation of room temperature ionic liquids (RTILs), especially the
imidazolium-based ILs, as “green” solvents and catalysts for a
wide variety of organic and organometallic transformations.11–13
In the area of electrophilic aromatic substitution, several
studies on alkylation and acylation of aromatics in RTILs have
been reported14 and the efficacy of various metallic triflates as
¶ Department of Energy and Hydrocarbon Chemistry, Kyoto Univer-
sity, Kyoto, Japan.
ꢀAB is an undergraduate student participant from Westminster College
(Summer 2004). PD is a KSU undergraduate student participant
(Summer 2004).
1 0 3 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 3 4 – 1 0 4 2
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

View Online
catalysts for these reactions has been probed.15 The halogenation
of alkenes and alkynes in RTILs have also been examined.16
Several recent studies demonstrated that changes in the
nature of the imidazolium core or the counterion could bring
about notable changes in the reaction mechanism in certain
nucleophilic displacement reactions, and that the nucleophilicity
order of typical nucleophiles differs in IL solvents as compared
to that in regular molecular solvents.17,18 A kinetic study on the
bromination of alkynes indicated that viscosity and hydrogen
bonding effects could also modify the reaction pathway and
reactivity in these media as compared to conventional molecular
solvents.19 It has also been reported that in the reaction of
toluene and HNO3, the course of the reaction changes as a
function of the IL counterion.20
The interest of this laboratory in the ionic liquid area is
mainly focused on electrophilic chemistry and on the synthetic
utility of various classes of onium salts as reagents for organic
synthesis in these media. To these ends, we have so far reported
on aromatic nitration,21 transfer-acetylation and deacetylation
of aromatics,22 fluorodediazoniation,23 and transfer-fluorination
to aromatics using onium dication salts, in particular the
SelectfluorTM reagent.24
The present study focuses on adamantylation of aromat-
ics in n-butylmethylimidazolium triflate [BMIM][OTf], as sol-
vent, employing 1-AdaOH, 1-AdaCl, 1-AdaBr, and 1-Br-3,5,7-
trimethyladamantane as adamantylating agents, with TfOH
as catalyst. Excellent yields, high para selectivity, negligible
formation of adamantane, mild reaction conditions, and the
use of readily available TfOH, are noteworthy features in the
IL version of this transformation. The preparative scope of
the reaction was tested by using representative substituted
benzenes. The origin of the meta isomer was evaluated via
control isomerization experiments. For comparison, and in
representative cases, the use of immobilized Sc(OTf)3 as an
adamantylation catalyst was evaluated. In light of the recent
mechanistic and kinetic studies showing notable differences
in the IL solvents,19–21 for competitive experiments, substrate
selectivities (KT/KB) for admantylation in [BMIM][OTf] have
been compared with those in dichloroethane (DCE). To shed
light on relative arenium ion stabilities and relative product
stabilities (isomer distributions), and with the aim of better
addressing intermolecular rearrangement within the arenium
ions, a DFT study was also carried out.
a series of adamantylation experiments were performed using
toluene as substrate, employing 1-AdaOH, 1-AdaCl and 1-
AdaBr as adamantylating agents, and with [BMIM][OTf] as
solvent (Fig. 1).
Fig. 1 Adamantylation of toluene.
The toluene to AdaX molar ratio was kept at 6 : 1, and the
reactions were performed in small Schlenk tubes. The results are
summarized in Table 1.
It can be seen that although reasonable conversions could
be obtained in rt reactions, increased conversions are achieved
with increasing reaction time and/or by increasing the amount
of TfOH. Depending on the choice of adamantylating agent
employed, near quantitative conversions could be reached at
60–80 ◦C after overnight stirring. The reaction exhibits high
para selectivity with little or no adamantane by-product being
formed. These favorable features, in combination with easy
separation of the organic phase by addition of ether and the use
of ILs in place of CH2Cl2 or MeNO2, make the present system
quite attractive. Our survey study also established that the IL
solvent could be recycled and reused numerous times without
any noticeable drop in conversion.
Control experiments indicated that adamantylation with 1-
AdaCl and 1-AdaBr reagents do not proceed under these
conditions in the absence of TfOH, i.e. AdaX by itself, even
in an ionic liquid solvent, was incapable of adamantylation.
The observed TfOH-catalyzed process with 1-AdaCl and 1-
AdaBr must, therefore, occur by initial halogen protonation
forming halonium ions 1-AdaXH+ with subsequent loss of HX
to generate the bridgehead adamantyl cation as the common
electrophile (Fig. 2).
Comparison between adamantylation in [BMIM][OTf] and
1,2-dichloroethane (DCE)
The previous adamantylation studies employed B(OTf)3,
Nafion-H and other solid acids and Ga(OTf)3.8–10 To obtain
a meaningful comparison between adamantylation in the ionic
liquid solvent vs. that in a molecular solvent, it was necessary
Results and discussion
To determine the effect of temperature, reaction time and
AdaX : TfOH ratio on product distribution and conversion,
Table 1 TfOH-catalyzed adamantylation of toluene with 1-AdaX (6 : 1) in [BMIM][OTf]a
Composition of reaction mixture
Adamantane m-Tolyladamantane p-Tolyladamantane
1-Ada-X
TfOH/eq. Reaction time/h or d Temperature/◦C Yield (%) (%)
(%)
(%)
1-AdaOH 0.5
5 d
6 d
20 h
20 h
1 h
20 h
4 d
6 d
20 h
20 h
20 h
20 h
20 h
20 h
Rt
60
60
65
65
Rt
Rt
Rt
60
60
60
60
80
80
44
100
100
100
100
22
53
79
96
100
22
1
1
4
2
—
—
—
—
2
—
—
—
5
3
1
2
2
—
—
4
2
5
—
—
2
5
5
40
98
94
96
100
22
49
77
89
100
22
0.5
1.2
0.5
0.5
1.2
1.2
1.2
1.2
2.0
0.6
1.2
1.2
2.0
1-AdaCl
1-AdaBr
16
100
100
14
90
90
5
a For each group of reactions, fresh IL was employed in the 1st run and used/recycled IL was utilized in subsequent experiments.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 3 4 – 1 0 4 2
1 0 3 5

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p-fluoroanisole. With mesitylene (not included in Table 3) the
conversion was quite modest (<20%) and significant amounts of
adamantane were formed. Clearly the reactivity of the aromatic
substrate and steric factors are both important in this process.
Adamantane formation becomes competitive as reaction with
the aromatic substrate becomes energetically more demanding.
The synthetic scope of this transformation was also tested by
using 1-AdaCl, 1-AdaBr, and 1-Br-3,5,7-trimethyladamantane
as adamantylating agents. The results are summarized in Table 4.
Isomer distribution and identity are also indicated. Once again,
the [BMIM][OTf] used for these reactions was recycled and
reused multiple times.
These reactions have similar overall characteristics to those
performed with 1-AdaOH. The conversions are quantitative or
close to quantitative and there is little or no adamantane present.
High para selectivity was observed except in the EtPh reaction
performed at 85 ◦C.
Fig. 2 Proposed reaction mechanism for IL adamantylation.
to conduct the reactions with a common catalyst. Table 2
summarizes the data for TfOH-catalyzed adamantylation with
1-AdOH, 1-AdaCl, and 1-AdaBr in DCE as solvent. Clearly,
there are major differences with respect to adamantane for-
mation, as a side reaction and with regard to regioselectivity.
The DCE reactions are exemplified by significant formation of
adamantane and increased formation of m-tolyladamantane,
which in most cases exceeds the p-tolyladamantane product. It
should be noted that the DCE reactions require quenching, acid
neutralization and aqueous work-up.
Isomerization test
In a control experiment, an isomeric mixture consisting of
ca. 95% p-tolyladamantane and 5% m-tolyladamantane was
allowed to react with TfOH in [BMIM][OTf] as solvent under
the same set of reaction conditions used in the adamantylation
reactions. GC analysis of the reaction mixture, following the
usual isolation procedure, indicated no noticeable change in the
isomeric composition following this treatment. A similar control
experiment was performed on an isolated isomeric mixture
obtained via the EtPh reaction. Once again, GC analysis of the
reaction mixture following the above treatment did not indicate
any noticeable increase in the meta isomer at the expense of para.
These control experiments seem to rule out an intermolecular
process as being responsible for the formation of meta isomer
and lend support to the idea that isomerization occurs within
the arenium ion as was also suggested by Olah et al. for
adamantylation over Nafion-H and other solid acid catalysts.9
On the synthetic scope
The synthetic scope of adamantylation in the IL solvent with
TfOH as catalyst was tested towards a series of substituted
benzenes. Table 3 summarizes the outcomes when 1-AdaOH
was used as adamantylating agent. The [BMIM][OTf] solvent
employed in these reactions was systematically recycled and
re-used. High para selectivity was observed in reactions with
monosubstituted benzenes (PhOMe and EtPh). Also given in
Table 3 are isomer distribution and isomer identities. With
anisole, increasing the reaction time resulted in the formation
of more meta isomer (entry 2). The yields decreased with
introduction of electron withdrawing substituents (entries for
p-fluorotoluene and p-chlorotoluene) and adamantane started
to appear as side products. This was not the case with
Competitive adamantylation in [BMIM][OTf] and in DCE
Competitive adamantylation experiments were carried out with
1-AdOH, 1-AdaCl and 1-AdaBr as adamantylating agents for
the 1 : 1 molar mixtures of toluene and benzene in [BMIM][OTf]
as solvent. The reactions were subsequently repeated under the
same set of conditions in DCE. The results are summarized in
Table 2 TfOH-catalyzed adamantylation of toluene with 1-AdaX (6 : 1) in 1,2-dichloroethane (DCE)
Composition of reaction mixture
Reaction
Temperature/
Conversion
(%)
Adamantane m-Tolyl-adamantane
p-Tolyl-adamantane
(%)
1-Ada-X TfOH/eq. time/h or d ◦C
(%)
(%)
1-AdOH 0.5
0.5
5 d
4 h
6 d
1.5 h
1.5 h
Rt
65
Rt
65
65
100
100
100
100
100
33
26
39
33
42
41
38
36
44
36
26
36
25
23
22
1-AdaCl
1.2
0.5
0.5
1-AdaBr
Table 3 TfOH-catalyzed adamantylation of aromatics with 1-AdaOH in [BMIM][OTf] (arene : 1-AdaOH : TfOH = 6 : 1 : 1)
Reaction time/h
Arene substrate or d
Temperature/ Conversion
Adamantane Aryl-adamantane Isomer distribution
◦C
(%)
(%)
(%)
and identity (%)
Anisolea
Anisole
Ethylbenzene
p-Cl-toluenea
p-F-anisole
p-F-toluene
m-Xylene
5 h
1 h
2 h
20 h
3 h
2 h
5 d
85
85
85
65
70
70
65
100
99
100
86
100
54
100
—
2
—
39
—
—
5
100
97
100
47
100
54
95
66 (p); 34 (m)
99 (p); 1 (m)
95 (p); 5 (m)
71; 22; 7
100 (1,2,4)
100 (1,2,4)
100 (1,3,5)
a These runs employed fresh IL whereas others were run in used IL.
1 0 3 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 3 4 – 1 0 4 2

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Table 5. The KT/KB values in the ionic liquid solvent are in
the range of 16–17, irrespective of the adamantylating agent.
Substrate selectivity in DCE, on the other hand, is close to
unity. As mentioned earlier, there are also notable differences in
product distribution (significantly more adamantane formation
in DCE) and in regisoselectivity (substantially higher amounts
of m-tolyladamantane in DCE).
The substrate selectivity data reflect a comparatively later
transition state for adamantylation in the IL solvent (more
benzenium ion-like).25 This is compatible with a more complete
formation (i.e., increased stability) of the 1-Ada+ electrophile
in the ionic liquid medium. Formation of adamantane as a
major side reaction in DCE solvent using TfOH as catalyst
is similar to the results obtained previously by Olah et al.8
in CH2Cl2 solvent using B(OTf)3 as catalyst, and could stem
from disproportionation of aryl-adamantanes, which may also
be responsible for the observed high meta isomer formation in
DCE (via de-adamantylation–re-adamantylation) and for the
observed KT/KB values near unity.
In an effort to shed some light on the nature of the electrophile
in IL adamantylation, in a competitive experiment a 1 : 1 mixture
of 1-AdaBr and 1-Br-3,5,7-trimethyladamantane was allowed to
react with anisole (6 eq.) in the presence of TfOH (1 eq.) at 65 ◦C
for 2 h. The ratio of 1-anisyl-3,5,7-trimethyladamantane to 1-
anisyladamantane was 2 : 1 by GC (no adamantane by-product
was detected). The finding shows that methyl groups at the
3,5,7-positions increase the reactivity of the electrophile, and
this is more compatible with the formation of a 1,3,5-Me3Ada+
X− rather than a polarized complex.
On the utility of Sc(OTf)3 for adamantylation in IL solvent
The efficacy of Sc(OTf)3 as an immobilized Lewis acid for
Friedel–Crafts chemistry has already been realized.15 In the
context of the present study, and for comparison, 1-AdaCl
was allowed to react with toluene in the presence of 0.3 eq. of
Sc(OTf)3 immobilized in [BMIM][OTf] at 70 ◦C. After overnight
stirring, 1-tolyladamantane was formed in low yield (ca. 5%).
Similar observations were made previously by Prakash et al.10
for the toluene–1-AdaBr system using Sc(OTf)3 (employing
excess arene as solvent). The reaction between 1-AdaCl and
p-methylanisole employing 0.4 eq. of Sc(OTf)3 in [BMIM][OTf]
after 20 h at 65 ◦C gave a modest 8% conversion to a single isomer
(see Experimental section for further details). The conversion
was greatly increased (97%) when the reaction was performed at
90 ◦C for 20 h (Table 6).
The data indicate that Sc(OTf)3–[BMIM][OTf] system is less
efficient as compared to TfOH–[BMIM][OTf] for adamantyla-
tion, requiring more reactive arenes, higher temperatures and
longer reaction times to reach high conversions. However,
both systems offer the advantages of little or no adamantane
formation and high regioselectivity.
DFT Study of adamantylation reaction
Relative energies of the benzenium ions for attack at the ortho,
meta and para positions of toluene 1 (o-1H+, m-1H+, andp-1H+),
ethylbenzene 2 (o-2H+, m-2H+, and p-2H+) and anisole 3 (o-3H+,
m-3H+, and p-3H+) were computed by DFT at the B3LYP/
6-31G(d) level (see Scheme 1). Relative energies for the resulting
neutral isomeric aryladamantane products 1–3 were also com-
puted. In addition, carbocations 4H+ and 5H+ (and 5aH+)
representing transition states for adamantyl shift and ethyl shift
in the arenium ion were also calculated (Scheme 1).
The energy data are summarized in Table 7. The NPA-derived
overall charges over CH (and oxygen) units in the benzenium
ions were also determined and are sketched (along with overall
charge delocalization modes) in Fig. 3 and 4.
Optimized geometries and bond-lengths for the benzenium
ions and the neutral isomeric products are gathered in the
supplementary information.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 3 4 – 1 0 4 2
1 0 3 7

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Table 5 Competitive adamantylation of benzene–toluene (1 : 1) promoted by TfOH (6 : 6 : 1) in [BMIM][OTf] or DCE at 65 ◦C, for 20 h
Tolyladamantane (%)
Adamantyl
compounds
Conversion
(%)
Adamantane
(%)
Ph-adamantane
(%)
Ratio Ph-adamantane :
tolyladamantane
Solvent
m-%
p-%
1-AdaOH
1-AdaCl
1-AdaBr
1-AdaOH
1-AdaCl
1-AdaBr
[BMIM][OTf]a
100
100
100
100
100
100
0.13
—
5.8
6.0
94.2
4.9
94.0
6.2
94.4
5.2
37.6
65.0
31.4
61.0
28.4
63.0
1 : 16.2
95.1
93.8
94.8
35.0
39.0
37.0
1 : 15.6
0.1
5.6
1 : 16.8
C2 H4 Cl2
18.5
26.0
26.5
43.9
42.4
45.1
1.17 : 1
1.36 : 1
1.62 : 1
a Fresh IL was employed.
Table 6 Sc(OTf)3-catalyzed adamantylation of aromatic compounds with 1-AdaX in [BMIM][OTf] (Arene : 1-AdaX : Sc(OTf)3 = 6 : 1 : 0.4)
Adamantyl
compounds derivatives
Benzene
Reaction Temperature/
time/h
Conversion
(%)
Adamantane Aryl-adamantane Isomer distribution
◦C
(%)
(%)
and identity (%)
1-AdaCl
p-Me-Anisole
p-Me-Anisolea
20
20
65
90
8
97
—
—
100
100
100 (1,2,4)
100 (1,2,4)
a Performed in used IL.
Table 7 Energies (E), zero point energies (ZPE), Gibbs’ free energies (G), and relative energies (DE and DG) for the studied molecules by DFT
method at the B3LYP/6-31G(d) level
Compound
Molecular point group
E/hartrees
ZPE/hartrees
G/hartrees
DE/kcal mol−1
DG/kcal mol−1
o-1
C1
C1
C1
C1
C1
C1
Cs
C1
C1
C1
C1
C1
C1
Cs
C1
C1
C1
C1
C1
C1
C1
C1
C1
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−736.305548
−736.289951
−736.311718
−700.384628
−700.349173
−700.347739
7.4
0.1
9.2
0.3
m-1
p-1
(0)
(0)
o-1H+
m-1H+
p-1H+
0.8a
4.1a
(0)a
0.0a
8.4
−2.1a
3.9a
(0)a
0.0a
10.3
0.4
o-2
m-2
0.1
p-2
(0)
(0)
o-2H+
m-2H+
p-2H+
1.3b
4.4b
(0)b
0.0b
2.2
−1.8b
4.3b
(0)b
0.0b
3.1
o-3
m-3
−0.3
−0.2
p-3
(0)
(0)
o-3H+
m-3H+
p-3H+
4H+
3.4c
14.7c
(0)c
(0)a
19.5a
20.5a
3.9c
13.7c
(0)c
(0)a
5H+
22.2a
23.1a
5aH+
a Relative energy to that of p-1H+. b Relative energy to that of p-2H+. c Relative energy to that of p-3H+.
Scheme 1
1 0 3 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 3 4 – 1 0 4 2

View Online
Fig. 3 NPA-derived overall charge over CH and O units for the protonated cations by B3LYP/6-31G(d). Dark circles are roughly proportional to
the magnitude of NPA charges; threshold was set to 0.1.
meta isomeric carbocations are consistent with benzenium ions.
The charge delocalization maps show that the positive charge
resides ortho/para to the site of attack. With 3, contribution
by mesomeric oxonium ions are revealed by positive charge
localization on the methoxy methyl. The stability order p-3H+ >
o-3H+ > m-3H+ seems to reflect a balance of steric and electronic
effects of the –OMe substituent.
The carbonium ions 4H+, 5H+ and 5aH+ were found to be
transition states at the B3LYP/6-31G(d) level. Their optimized
geometries are included in the supplementary information.
Consideration of their relative energies at this level (Table 7),
leads to the conclusion that ∼Ada shift is more facile than ∼Et
shift as an intramolecular process within the arenium ion.
To examine the effect of the basis set on relative benzenium
ion energies for ortho attack, isomeric carbocations o-1H+,
m-1H+, and p-1H+ as well as o-2H+, m-2H+, and p-2H+
were subsequently computed at the B3LYP/6-31G(d)//HF/6-
31G(d) level. The data (summarized in Table 8) show that at this
level of theory, relative arenium ion stabilities for both substrates
follow the sequence para > meta > ortho, showing that the
HF/6-31G(d) level affords better geometries.
Fig. 4 NPA-derived overall charge over CH units for the benzenium
ions by B3LYP/6-31G(d)//HF/6-31G(d). Dark circles are roughly pro-
portional to the magnitude of NPA charges; threshold was set to 0.1.
Comparative discussion and summary
For isomeric 1 and 2, relative product stability order is para >
meta > ortho, but the meta isomer lies only <1 kcal mol−1
above ortho. With 3, differences in energies between isomers are
small, with the meta isomer being very slightly favored over para
(meta > para > ortho). Focusing on the benzenium ions, where
for 3 the stability order p-3H+ > o-3H+ > m-3H+ is derived,
for 1 and 2 the ortho isomer was computed to be lower in
energy than para! A closer look at the NPA-derived charges
and charge delocalization maps (Fig. 3) revealed that o-1H+ and
o-2H+ cations have the characteristics of oriented p-complexes
The system [BMIM][OTf]–TfOH is an efficient medium for
the adamantylation of arenes employing 1-AdaOH, 1-AdaCl,
1-AdaBr and 1-Br-3,5,7-Me3-Ada as adamantylating agents.
Since adamantylation with 1-adamantyl halides does not
proceed without TfOH under the reaction conditions em-
ployed, an activation step involving halonium ion formation 1-
AdaXH+ is presumed with subsequent formation of Ada+ and
HX. Adamantylation can be effected under mild conditions,
in high yields, high chemoselecivity (little or no adamantane)
and high para regioselectivity. Reactions carried out in DCE
as solvent exhibit increased formation of adamantane and low
regioselectivity (mixtures of para and meta isomers with meta
of arene–1-Ada+ which are also reflected in their optimized
+
˚
geometries showing very long Ar–Ada distances (2.83–2.84 A).
Charge delocalization and optimized geometries for the para and
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 3 4 – 1 0 4 2
1 0 3 9

View Online
Table 8 Energies (E), zero point energies (ZPE), Gibbs’ free energies (G), and relative energies (DE and DG) for the studied carbocations at the
HF/6-31G(d) level (rows at the B3LYP/6-31G(d)//HF/6-31G(d) level in parentheses)
Compound
o-1H+
Molecular point group
E/hartree
ZPE/hartree
0.390083
0.389168
0.389125
0.420788
0.419913
0.420338
G/hartree
DE/kcal mol−1
DG/kcal mol−1
C1
(C1
C1
(C1
Cs
(Cs
C1
(C1
C1
(C1
C1
−656.9238588
−661.4059522
−656.9259046
−661.4073465
−656.9359873
−661.4146831
−695.9581842
−700.720307
−695.9611839
−700.7220399
−695.9718343
−700.7292251
−656.572793
−656.576907
−656.587618
−695.578356
−695.583396
−695.593674
7.6a
9.3a
5.6a)
6.3a
m-1H+
p-1H+
6.7a
4.5a)
(0.0)a
(0.0)a)
8.6b
(0.0)a
9.6b
o-2H+
5.6b)
6.7b
m-2H+
p-2H+
6.5b
4.5b)
(0.0)b
(0.0)b)
(0.0)b
(C1
a Relative energy to that of p-1H+. b Relative energy to that of p-2H+.
often exceeding para). The synthetic scope of this reaction was
tested for representative alkylbenzenes and haloalkylbenzenes,
and the results are compared. Decreasing the reactivity of
the arene nucleophile or increasing the steric crowding on the
nucleophile reduces the conversions and leads to increased
formation of adamantane.
Substrate selectivities (KT/KB) measured in [BMIM][OTf]
are higher than those obtained in DCE. The data imply a
comparatively later, more benzenium-ion like TS in the IL
solvent involving a more selective electrophile. A competitive
experiment with a 1 : 1 mixture of 1-AdaBr and Br-3,5,7-
Me3Ada gave a product ratio of 1 : 2, indicative of inductive
stabilization of the adamantyl electrophile by the methyl groups
located at other bridgehead positions.
pre-treatment. The aromatic compounds were highest purity
commercial samples, their purity checked by GC prior to use.
Triflic acid (Aldrich) was distilled under nitrogen and stored in
a Nalgene bottle in a freezer.
Et2O used for extraction was dried over sodium and distilled.
1,2-Dichloroethane (DCE) used for the comparative study
was distilled prior to use.
Sc(OTf)3 was purchased from Aldrich and was handled under
nitrogen.
Typical optimized procedure
The [BMIM][OTf] ionic liquid (1.15 g, 4.43 mmol) was charged
into a Schlenk tube and 1-AdaCl (0.171, 1 mmol) was added
under nitrogen. The closed Schlenk tube was placed in an
ultrasonic bath at rt for several minutes (typically 10–15 min) to
increase solubility. After addition of toluene (0.552, 6.0 mmol)
under nitrogen and magnetic stirring at rt for 10 min. the Schlenk
tube was cooled to 0 ◦C and TfOH (0.1 mL, 1 mmol) was
added under nitrogen via a micropipette. The Schlenk tube was
re-sealed and placed in a thermostatic bath at 60 ◦C under
magnetic stirring for 20 h. Typical work-up procedure involved
addition of dry Et2O (4 mL × 5) and neutralization of combined
extracts (as a precaution for subsequent GC and GC-MS analy-
sis) by washing with water (4 mL × 2), with 5% NaHCO3 (4 mL ×
2) and water (4 mL × 2) respectively, followed by separation of
the organic phase, drying (MgSO4) and simple filtration. The
procedure was similar for 1-AdaOH reactions and for 1-AdaBr.
In the latter case, the reactions were carried out at 80 ◦C. In
competitive experiments great care was taken to prepare and
transfer the benzene–toluene equimolar mixtures as carefully
as possible for both the IL and the DCE reactions. Reactions
in DCE solvent (either single substrate or competitive) were
performed at 65 ◦C in small round-bottom flasks under a blanket
of nitrogen. These reactions required TfOH neutralization and
standard aqueous work-up (5% NaHCO3, extraction with ether,
drying over MgSO4 and filtration). For Sc(OTf)3-catalyzed
reactions, the Lewis acid catalyst was immobilized in the IL
by sonication. Following the general procedure outlined above,
the reactions were conducted at 90 ◦C to increase conversion.
Reaction mixtures were first analyzed by capillary-GC (on a
fused silica column) followed by GC-MS (ion-trap instrument).
Conversions were determined by GC and are based on the
amount of 1-AdaX reacted. The minor meta isomers typically
had shorter retention times than para. Subsequent vacuum dry-
ing of the reaction mixtures left behind the aryl-adamantanes,
which were rechecked by GC and GC-MS analysis. Since several
attempts to remove minor isomers from the isomeric mixtures
by crystallization techniques proved unsuccessful, they were
directly assayed by NMR (300 MHz). In several cases, the aryl-
adamantane products had previously been reported9 and/or
Selected control experiments ruled out an intermolecular
process for the isomerization (formation of meta product) in
[BMIM][OTf], pointing to an intermolecular process within the
benzenium ion.
Based on DFT calculations ∼Ada shift is considerably more
facile than ∼Et shift in the benzenium ion of para attack for
adamantylation of ethylbenzene. DFT also provided insight
as to charge delocalization modes in the benzenium ions
and their relative stabilities, and regarding relative energies of
the neutral isomeric products. Computation at the B3LYP/6-
31G(d)//HF/6-31G(d) level did a better job in predicting
the benzenium ion stability order as para > meta > ortho.
Optimized geometries and the NPA-derived charges for the
benzenium ions of ortho attack in admantylation of PhMe and
PhEt at the B3LYP/6-31G(d) level have the appearance of 1-
Ada+–Arene oriented p-complexes which may be responsible
for the computed lower energy of the ortho “benzenium ions”.
Based on limited studies performed with Sc(OTf)3 as catalyst
in the present study, it may be concluded that [BMIM][OTf]–
TfOH system is superior to [BMIM][OTf]–Sc(OTf)3, as higher
temperatures and more reactive arenes are needed to achieve
high conversions in the latter system, but both systems exhibit
high para regioselectivity with little or no adamantane by-
product formation.
Experimental
General
All items of glassware were oven-dried at 120 ◦C and flushed with
nitrogen prior to use. Adamantylation reactions were performed
in small Schlenk tubes under nitrogen with magnetic stirring.
Reagents were transferred and manipulated under a stream
of dry nitrogen. The adamantane derivatives (1-AdaOH, 1-
AdaCl, 1-AdaBr and 1-Br-3,5,7-trimethyladamanatane) were
high purity commercial samples (Aldrich) which were used
without further purification. The [BMIM][OTf] ionic liquid was
purchased from ACROS and from Merck and used without any
1 0 4 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 3 4 – 1 0 4 2

View Online
were commercially available (Aldrich, TCI-America etc). The
para isomers were readily recognizable in the 1H NMR as
they gave rise to a pair of doublets in the aromatic region
(typically with J = 8–9 Hz). With m-xylene, the product was
C-5 adamantylated; this was readily apparent in the NMR [2
aromatic proton resonances (in 2 : 1 ratio) and 4 aromatic
carbons]. Substitution patterns for the p-disubstituted substrates
followed the expected directive effects.
in the subsequent run and the cycle was repeated several times
without compromising the efficiency of the adamantylation
reactions (as can be seen in the reported conversions summarized
in Tables 1–4).
DFT calculations
Structures for o-1, m-1, p-1, o-2, m-2, p-2, o-3, p-3, m-3, and
their protonated carbocations were optimized using molecular
point groups shown in the supplementary information by the
density functional theory (DFT) method at B3LYP/6-31G(d)
or by the Hartree–Fock method at HF/6-31G(d) level using
the Gaussian 03 package.26 Transition structures, 4H+ and 5H+,
and 5aH+, for adamantyl shift and ethyl shift were located by
changing the bond angles for Ca–Cb–Cc in 4H+, 5H+, and 5aH+
(see Scheme 2). Computed geometries were verified by frequency
calculations. Furthermore, global minima were checked by
manually changing the initial geometries and by comparing the
resulting optimized structures and their energies. The supple-
mentary information summarizes the total energies (E), relative
energies (DE), zero point energies (ZPE), Gibbs’ free energies
(G), relative Gibbs’ free energies (DG), by B3LYP/6-31G(d),
HF/6-31G(d) and by B3LYP/6-31G(d)//HF/6-31G(d) levels.
Gibbs’ free energies were evaluated by frequency calculations at
298 K under 1 atm pressure which is the default for Gaussian 03
program.
1-p-Tolyladamantane. MS (m/z%, 70 eV, EI mode) 226
(100, M+); 183 (22), 169 (80), 115 (20), 91 (30); 1H NMR
(CDCl3): 7.26 (d), 7.12 (d), 2.32 (Me), 2.08 (Ada), 1.76 (Ada),
1.89 (Ada).
1-(p-Ethylphenyl)adamantane. MS (m/z%, 70 eV, EI mode)
1
240 (80, M+), 197 (40), 183 (80), 155 (100), 91 (38); H NMR
(CDCl3) 7.25 (d), 7. 15 (d), 2.63 (Et), 2.08 (Ada), 1.90 (Ada),
1.77 (Ada), 1.23 (Et); 13C NMR (CDCl3) 148.8 (Ar, C), 141.4
(Ar, C), 127.7 (Ar, CH), 124.9 (Ar, CH), 43.4 (Ada), 37.0 (Ada),
36.0 (Ada), 29.2 (Ada), 28.5 (Et), 15.7 (Et).
1-p-Anisyladamantane. MS (m/z%, 70 eV, EI mode) 242
1
(100, M+), 185 (83), 148 (32), 77 (15); H NMR (CDCl3) 7.27
(d), 6.85 (d), 3.79 (OMe), 2.08 (Ada), 1.76 (Ada), 1.89 (Ada);
13C NMR (CDCl3) 157.5 (Ar, C), 143.9 (Ar, C), 125.9 (Ar, CH),
113.5 (Ar, CH), 55.4 (OMe), 43.5 (Ada), 36.9 (Ada), 35.7 (Ada),
29.2 (Ada).
1-(m-Fluoro-o-anisyl)adamantane. MS (m/z%, 70 eV, EI
mode) 260 (100, M+), 217 (20), 203 (45), 166 (20), 91 (10), 77
1
(8); H NMR (CDCl3) 6.93 (dd), 6.86–6.74 (m), 3.80 (OMe),
2.05 (Ada), 1.76 (Ada); 13C NMR (CDCl3) 157.4 (d, JCF = 237
Hz), 155.0, 140.6 (d, JCF = 6 Hz), 114.0 (d, JCF = 24 Hz), 112.5
(d, JCF = 9 Hz), 112.3 (d, JCF = 22 Hz), 55.7 (OMe), 40.5 (Ada),
37.2 (Ada), 29.1 (Ada); 19F NMR (CDCl3, CFCl3) −124.4 ppm.
1-m-Xylyladamantane. MS (m/z%, 70 eV, EI mode) 240
1
(100, M+), 197 (20), 183 (62), 91 (20); H NMR (CDCl3) 6.98
(d, poorly resolved; 2H), 6.83 (broad singlet appearance; 1H),
2.32 (Me), 2.08 (br-s; Ada), 1.91 (d, Ada), 1.76 (t, Ada); 13C
NMR (CDCl3) 151.6, 137.5, 127.4, 122.9, 43.4 (Ada), 37.0
(Ada), 36.1 (Ada), 29.2 (Ada), 21.8 (Me).
Scheme 2
1-p-Tolyl-1,5,7-trimethyladamantane. MS (m/z%, 70 eV, EI
mode) 268 (100; M+), 253 (53), 197 (100), 121 (47), 105 (35), 91
(25); 1H NMR (CDCl3) 7.24 (d), 7.11 (d), 2.30 (Me), 1.44 (Ada),
1.12 (Ada), 0.88 (Me).
Acknowledgements
We thank the NSF-REU program (NSF 03-577) and the NCI
of NIH (2 R15 CA 078235-02A1) for summer support for the
undergraduates who participated in this work.
1-p-Anisyl-3,5,7-trimethyladamantane. MS (m/z%, 70 eV,
EI mode) 284 (100, M+), 269 (33), 213 (61), 121 (58), 91 (28); 1H
NMR (CDCl3) 7.27 (d), 6.85 (d), 3.79 (OMe), 1.43 (Ada), 1.12
(Ada), 0.88 (Me).
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 3 4 – 1 0 4 2
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1 0 4 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 3 4 – 1 0 4 2