Green, Mild, and Efficient Friedel–Crafts Benzylation of Scarcely Reactive Arenes and Heteroarenes under On-Water Conditions

Article abstract of DOI:10.1002/cssc.201900137

Metal-free Friedel–Crafts benzylation (FCB) of scarcely reactive arenes and heteroarenes was performed under on-water conditions by an environmentally sustainable procedure. The catalytic strategy exploits the hydrophobicity of the resorcinarene macrocycle 1 a. The proposed mechanism is based on the activation of benzyl chloride by H-bonding interactions with catalyst 1 a. In fact, under on-water conditions the hydrophobic amplification of the strength of the H-bonding interactions between the OH groups of the resorcinarene catalyst and the chlorine atom of benzyl chloride leads to polarization of the C?Cl bond, which consequently promotes electrophilic attack of the π nucleophile. Thus, many arenes and heteroarenes were efficiently benzylated under mild on-water conditions by using resorcinarene 1 a as catalyst. The FCB of benzene is industrially relevant for the synthesis of diphenylmethane, and hence the on-water procedure was extended to the gram-scale synthesis of diphenylmethane, starting from benzene and benzyl chloride in the presence of resorcinarene catalyst 1 a.

Full text of DOI:10.1002/cssc.201900137

Accepted Article
Title: Green, Mild, and Efficient Friedel-Crafts Benzylation of Scarcely
Reactive Arenes and Heteroarenes Under On-Water Conditions
Authors: Carmine Gaeta, Pellegrino La Manna, Annunziata Soriente,
Margherita De Rosa, Antonio Buonerba, Carmen Talotta, and
Placido Neri
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10.1002/cssc.201900137
ChemSusChem
FULL PAPER
Green, Mild, and Efficient Friedel-Crafts Benzylation of Scarcely
Reactive Arenes and Heteroarenes Under On-Water Conditions
Pellegrino La Manna, Annunziata Soriente,* Margherita De Rosa, Antonio Buonerba,* Carmen Talotta,
Carmine Gaeta,* and Placido Neri
Abstract: A metal-free Friedel-Crafts benzylation (FCB) of scarcely
reactive arenes and heteroarenes has been performed under on-
water conditions through an environmentally-sustainable procedure.
Our catalytic strategy exploits the hydrophobicity of the
resorcinarene macrocycle (1a). The proposed mechanism is based
on the activation of benzyl chloride by H-bonding interactions with
catalyst 1a. In fact, under on-water conditions the hydrophobic
amplification of the strength of the H-bond interactions between the
OH groups of the resorcinarene catalyst and the chlorine atom of the
benzyl chloride, led to the polarization of the C–Cl bond that
consequently promotes the electrophilic attack of the π-nucleophile.
Thus, many arenes and heteroarenes have been efficiently
benzylated under mild on-water conditions using resorcinarene 1a
as the catalyst. The FCB of benzene is industrially relevant for the
synthesis of diphenylmethane, thus we here extended the on-water
procedure to the gram-scale synthesis of diphenylmethane, starting
from benzene and benzyl chloride in the presence of resorcinarene
catalyst 1a.
polyalkylated byproducts. As reported recently by Sato and
Nakamura, another problem is associated with the scarcity of
the chemical metal element in the Earth’s crust.[5] Thus, much
attention has been focused on the study of green strategies, for
the FC alkylation of arenes. At this regards, the zeolites have
shown good performances in the alkylation of arenes,[6] however
the drastic reaction conditions,[7] such as high temperatures and
reagents in the gas phase,[7] have limited their industrial
application. In addition, the FC alkylation with zeolites are
carried out using alkenes and alcohols as alkylating agents,[8]
while the use of benzyl chloride in FCB still remains very
challenging.[9]
H
H
O
H
H
O
H
H
H
H
O
H
O
O
O
H
H
O
H
H
H
H
O
H
O
H
H
H
A
O
O
B
H
H
H
H
O
O
H
O
C
H
H
H
H
Introduction
H
H
O
O
H
H
H
H
H
The Friedel-Crafts (FC)[1] alkylation of arenes and heteroarenes
are among the most investigated reactions for the industrial
synthesis of active pharmaceutical compounds[2] and fine
chemicals.[3] Among them, the Friedel-Crafts benzylation (FCB)
of scarcely reactive aromatic substrates, such as benzene,
toluene, or ethylbenzene using benzyl chloride, provides an
useful method to obtain fine-chemical products.[3] Usually, the
FCBs are conducted on industrial scale through metal-transition
catalysis,[4] using non-sustainable processes in which expensive
metal-catalysts are used. Widely diffuse is also the liquid phase
FCB of aromatic substrates using homogenous Brønsted/Lewis
acid catalyst (e.g.: BF3 and H2SO4).[1-3]
Generally, the FCBs require stoichiometric amounts of metal-
catalyst, which is difficult to recover, and consequently generate
a significant amount of waste in which toxic metal-substances
are present. In addition, the metal-catalyzed FCBs of arenes are
characterized by low selectivity and formation of undesired
H
O
H
O
O
O
H
H
H
Hydrophobic Hydration[12,13a] of
non-polar reagents (A and B) and catalyst (C).
Figure 1. Hydrophobic hydration model.[12,13a]
Among the green strategies, the catalysis "under on-water
conditions"[10-12] is attracting a lot of interest because can be
considered as a totally metal-free catalysis. Water as solvent of
organic reactions has many advantages, besides being
environmentally friendly, in comparison to commonly employed
organic solvents: it’s less expensive, not toxic or flammable.[10-12]
When insoluble reactants and catalyst are stirred under on-water
conditions, the hydrophobic effect[13] forces the species to form
supramolecular aggregates,[13] while the water molecules
assemble around them without breaking H-bonds (Figure 1).[13]
At this point, the water molecules on the shell establish van der
Waals interactions[13] with the hydrophobic molecules; this
phenomenon has been described as hydrophobic hydration
(Figure 1). [12,13]
[a]
Dr. P. La Manna, Prof. Dr. A. Soriente,* Dr. M. De Rosa, Dr. A.
Buonerba,* Dr. C. Talotta, Prof. Dr. C. Gaeta,* Prof. Dr. P. Neri
Dipartimento di Chimica e Biologia "A. Zambelli"
Università di Salerno
Via Giovanni Paolo II, Fisciano (SALERNO), 84084, Italy
E-mail: titti@unisa.it, cgaeta@unisa.it, abuonerba@unisa.it
The proximity effect between the hydrophobic reactants and the
amplification of non-covalent interactions between catalyst and
Supporting information for this article is given via a link at the end of
the document.
substrates (hydrophobic amplification) lead to
a reaction
acceleration.[12] Recently, we have reported[14] a hydrophobic
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10.1002/cssc.201900137
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amplification of weak hydrogen bond interactions in the catalysis
of VMAR (Vinylogous Mukaiyama Aldol Reaction) under on-
water conditions. Before, Schreiner and Rueping[15] showed that
water as medium is compatible with the hydrogen-bonding
activation of substrates.
show another structural feature, very attractive from the catalytic
point of view. In details, as shown in Figure 2, four OH groups
of 1a act as donors in intramolecular H-bonds while the
remaining four OH groups are still available to form
intermolecular H-bonds.[20] In fact, as is well known, the four free
H-bond valences of 1a play a crucial role for its self-assembling
to a large hexameric capsule in organic solvents.[22] Very
recently,[23] the ability of a resorcinarene derivative to act as a
hydrogen bonding organocatalyst in an organic reaction in
aqueous medium has been highlighted. Paquin[24] and us[25d]
have shown that the FCB can be catalyzed through
a
mechanism involving the activation of the PhCH2−X bond by
hydrogen bonding. On the basis of these considerations and as
part of our ongoing studies on eco-friendly catalytic procedures,
[25]
we have here investigated the FCB of scarcely reactive
Figure 2. Chemical drawings of catalysts 1a-d employed in this work.
arenes,
under
on-water
conditions,
using
C-
undecylresorcin[4]arene 1a as catalyst.
In 2011 Song and coworkers[16] reported the hydrogen-bonding
mediated organocatalysis in water of Michael addition of 1,3-
dicarbonyls to β-nitroolefins. In 2015, the same authors[17a]
reported an example of hydrophobic amplification of H-bonds in
Results and Discussion
As a model reaction we investigated the FCB of toluene with
benzyl chloride (Scheme 1). When 2 and 3 were vigorously
stirred under on-water conditions at 50 °C for 32 h, in the
presence of catalyst 1a, the benzylated products 4a-b were
obtained in 93 % yield (entry 5, Table 1) with a preference for
the para-substituted regioisomer 4b (4b/4a ratio of 70/30). When
typical organic solvents were used, such as CH2Cl2, THF,
CH3OH, or CH3CN (entries 1-4 in Table 1), no trace of
benzylated products 4a or 4b was detected in the mixture.
Analogously, no conversion of 2 and 3 in 4 was observed when
the reaction was conducted in the absence of catalyst 1a under
on-water conditions (entry 6, in Table 1). In order to collect
proofs of the influence of the hydrophobic hydration effect on the
reaction rate, we performed the FCB in Scheme 1 under
different conditions. In particular, when the antihydrophobic10d
LiClO4 salt was added to the reaction mixture, then, as expected,
a decreased of the reaction rate was observed (entry 9, Table 1).
Differently, when NaCl was used, then the 90 % of yield was
reached after 16 h, instead of 32 h (entries 8 and 5 in Table 1).
As it is known,[12,17a] in fact, the water-solubility of organic
molecules is lowered upon addition of NaCl, thus driving them to
the hydrophobic aggregation. Differently,[10c,17a] D2O leads to a
significant reduction of the hydrophobic effect [10c, 17a] because of
its higher viscosity (ca. 20% higher than that of H2O) which
makes more difficult the mixing. Accordingly, when 2 and 3 were
mixed in the presence of 1a as catalyst and D2O as the solvent,
then a decrease of the reaction rate was observed (Table 1,
entries 10 and 11), confirming the role of the hydrophobic
hydration effect. The influence of the amount of water on the
reaction rate was also evaluated, and the best result was
obtained using 1 mL of H2O under the given experimental
conditions (SI).
organocatalytic Michael addition of malonates to nitroalkenes.
[18]
García-Tellado et al.
reported an interesting example of
hydrogen-bonding organocatalysis in water of a multicomponent
aza-Henry reaction.
Scheme 1. Friedel-Crafts benzylation between toluene 2 and benzyl chloride 3
catalyzed by 1a under on-water conditions.
Large cyclophanes, such as calixarene[19] and resorcinarenes [20]
(Figure 2), are promising for applications in catalysis under on-
water conditions, thanks to their inherent hydrophobicity. In
addition, such bowl-shaped macrocycles offer the possibility to
discriminate the substrates because they have a hydrophobic
[14]
internal cavity able to host them in a selective way.
At this
regard, the recognition ability of calixarene macrocycles has
been exploited, very recently, by our group[14] in the catalysis of
VMAR. In fact, the calix[4]arene catalyst was able to accelerate
the VMAR under on-water conditions operating a molecular
recognition of the substrate by endo-cavity inclusion. [14]
Resorcinarenes are
a class of macrocycles obtained by
condensation of resorcinol with aliphatic aldehydes under acidic
[20]
conditions.
The native resorcin[4]arene macrocycle shows
some structural features that make it an ideal candidate as
catalyst for reactions under on-water conditions. C-
undecylresorcin[4]arene[20] 1a (Figure 2) adopts a bowl-shaped
conformation[20] with a hydrophobic cavity able to host size-
complementary guests.[21] The OH groups of resorcinarene 1a
For the reaction of toluene with benzyl chloride, under the
reaction conditions of entry 5 of Table 1, an E-factor value of 0.2
was estimated (the amount of water was excluded from the
calculus because of the potential recyclability of this green
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10.1002/cssc.201900137
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solvent). This value is even more favorable with respect to those
obtained for the same reaction carried out in the presence of
classical FC agents based on aluminium or iron chlorides, which
are in the range of 0.25-0.30 (also in this case, the solvent was
on-water conditions in the presence of 1a as catalyst, was also
verified with 1,3-dimethylbenzene and mesitylene. Thus, while
1,3-dimethylbenzene (Log P = 1.90) was benzylated in 92 %
yield after 24 h, mesitylene (Log P = 2.07) was reacted within 8
h (94 %) (Scheme 2).
excluded from the calculus).[1d,e]
.
The role played by the hydrophobicity of the resorcinarene in the
catalysis of the FCB reaction in Scheme 1 was also investigated.
When the reaction between 2 and 3 was performed under on-
water conditions in the presence of 1c bearing shorter feet (C-
methyl groups), which shows a Log P= 2.07 significantly lower
than that of C-undecyl resorcin[4]arene 1a (Log P= 12.7), then
no appreciable conversion to products 4 was observed.
At this point, we studied the scope of the FCB reaction under on-
water conditions in the presence of resorcinarene catalyst 1a by
exploring a variety of aromatic-nucleophiles (Scheme 2) at
different hydrophobicity. When ethylbenzene was reacted under
on-water conditions at 50 °C in the presence of benzyl chloride
and catalyst 1a, then the para-benzylated product 5 was
obtained in 92
% yield after 16 h, with an excellent
regioselectivity ratio with respect to the ortho-regioisomer
(para/ortho = 85/15).
Scheme 2. Friedel-Crafts benzylation between different arene substrates and
benzyl chloride 3 catalyzed by 1a under on-water conditions.
Table 1. Solvent screening for the FCB of 2 with 3 catalyzed by 1a under on
water conditions.
Entry[a]
Medium
Time
(t)
Yield[b]
(%)
4a/4b[c]
TON[d]
TOF[e]
(h-1)
1
2
CHCl3
THF
32
32
32
32
32
32
16
16
72
32
64
0
0
-
-
-
-
-
-
3
CH3OH
CH3CN
H2O
0
-
-
-
4
0
-
-
-
5
3
30/70f
-
9.3
-
0,29
-
6
H2O[g]
H2O
0
7
66
90
64
50
91
25/75
24/76
23/75f
34/66
25/75
6.6
9.0
6.4
5.0
9.1
0.41
0.56
0.09
0.16
0.14
8
brine
LiClO4
D2O
9
10
11
D2O
[
a]
Reaction conditions: 3 (0.163 mmol); 2 (0.244 mmol, 1.5 equiv. w.r.t. 3); 1a
(catalyst loading of 10 mol % w.r.t. 3); solvent (1 mL); 50 °C. [b] Determined by
1H NMR analysis.
literature data (see experimental section).
products/mol catalyst).
Contains traces of dibenzylated product.
catalyst.
[c]
Determined by 1H NMR analysis, according to the
Reaction conditions: 3 (0.163 mmol); ArH (0.244 mmol, 1.5 equiv. w.r.t. 3); 1a
[a]
[d]
(catalyst loading of 10 mol
ethylbenzene (Log P = 2.14), contains 15 % of ortho-regioisomer.
%
w.r.t. 3); H2O (1 mL); 50 °C.
From
From
Overall turnover number (mol
Overall turnover frequency (TON/reaction time).
[b]
[è]
[f]
cumene (Log P = 2.47), contains 12 % of ortho -regioisomer. [c] From p-tert-
[g]
Blank reaction performed without
[d]
butylbenzene (Log P = 2.94), contains 16 % of ortho-regioisomer.
xylene (Log P = 1.90) , contains 7 % of dibenzylated products.
mesitylene (Log P = 2.07), contains 25 % of dibenzylated product.
From m-
[e]
From
From
[f]
anisole. [g] From 1,3-dimethoxybenzene. [h] From trimethoxybenzene, contains
Interestingly, when tert-butylbenzene (Log P26= 2.94), more
hydrophobic than toluene (Log P = 1.17) and ethylbenzene (Log
P= 2.14), was used as the substrate, then the FCB was
dramatically accelerated. In fact, it was complete within 6 h
(91 % yield). Cumene (Log P = 2.47), which shows an
intermediate hydrophobicity between ethylbenzene and tert-
butylbenzene, was benzylated to 6 in the presence of 1a within 8
h with 91 % yield (Scheme 2). The correlation between Log P
and the acceleration of the FCB of aromatic substrates, under
[i]
13 % of dibenzylated product.
From thiophene, contains 26 % of 3-
[j]
[k]
regioisomer. From 2-bromothiophene.
50 % of 3-regioisomer
From N-methylpyrrole, contains
In order to define the catalytic role of the OH groups of 1a, we
decided to perform experiments using catalyst 1b, which is the
corresponding totally O-methylated resorcinarene. As reported
in Table 2, when 2 and 3 were stirred under on water conditions
in the presence of 1b, no trace of products was detected, thus
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confirming that the activation of benzyl chloride by H-bonding
interactions with the OH groups of 1a, plays a crucial role in
promoting the FCB. Notably, in the presence of 1d, as the
monomeric counterpart of macrocycle 1a, no conversion of 2
and 3 in 4 was observed under on-water conditions. Clearly, this
result evidences the role played by the resorcinarene
macrocyclic structure in the FCB catalysis. In conclusion, these
results suggested that the combined action of the hydrophobic
hydration effect and the hydrogen bonding activation of the
substrate 3, plays a fundamental role in promoting the FCB
reaction under on-water conditions. Interestingly, resorcinarene
catalyst 1a shows good catalytic performances respect also with
more active π-nucleophiles in different positions along the Mayr's
In order to evaluate the synthetic utility of our on-water protocol,
we attempted the FCB of benzene with benzyl chloride to form
diphenylmethane (16). Diphenylmethane is an useful molecule
for many industrial processes.[3] It is typically used in the
fragrance industry,[3] in the production of pesticides and
insecticides, as a plasticizer, as a solvent for dyes, and as
stabilizing agent for saturated linear polyesters and jet fuels.[3]
The industrial production of diphenylmethane is obtained by the
Friedel–Crafts reaction of benzyl chloride with benzene in the
presence of a Lewis acid catalyst, such as AlCl3.[28] Interestingly,
when benzene (1.5 equivalents) and
benzyl chloride (1
equivalent) were vigorously stirred at 50 °C in the presence of
1a (10 mol %), under on-water conditions, then
diphenylmethane 16 and p-dibenzylbenzene 17 (Scheme 3)
were obtained in 78 and 22 % yield, respectively. In order to
demonstrate the synthetic utility of our on-water FCB protocol,
the gram scale synthesis of diphenylmethane was attempted.
The FCB reaction between benzene and benzyl chloride was
performed at 100 mmol scale using 10 mol % of 1a, in 400 mL of
H2O. The suspension was mechanically stirred at 50 °C for 32 h.
At this point, after cooling, n-hexane (cooled at −10 °C) was
added and the catalyst 1a was quantitatively recovered by
simple filtration from the reaction mixture (recovery yield >99%).
The aqueous phase was washed with n-hexane (2 x 100 mL)
and the organic layers were collected and evaporated under
reduced pressure; the obtained crude oil (90 % yield) was
scale.[27]
(Scheme 2) were benzylated efficiently, within 16 h, in 90 % and
91 yield, respectively, and surprisingly no traces of
In particular, anisole and 1,3-dimethoxybenzene
%
dibenzylated products were observed despite their high
[27]
nucleophilicity.
1,3,5-Dimethoxybenzene gave, within 16 h, a
93 % yield of benzylation products, which included a 13 % of the
dibenzylated one.
Table 2. Investigation of the role played by the resorcinarene skeleton in the
FCB catalysis of 2 with 3.
Entry[a]
Catalyst
Time (t)
Yield[b] (%)
4a/4b[c]
1
analyzed by H NMR which showed the presence of 16 and 17
1
2
3
4
1a
1b
1c
1d
32
32
32
32
93
0
23/71
in a 75/25 ratio.
-
40/60
-
Characterization of the solid state structure of the catalyst
1a and its clathrates with the reactants 2 and 3 under on-
water conditions.
5
0
Alkyl halides are typically considered weak hydrogen bond
acceptor,[29] therefore additional factors, to the “simple” hydrogen
bonding, could be involved in this exceptional activation of the
C–Cl bond by 1a. For this reason, the reaction environment, the
crystalline and the thermal behavior of 1a in the presence of
water and reactants were investigated by X-ray diffraction (XRD),
thermogravimetric analysis (TGA), differential scanning
calorimetry (DSC), and attenuated total reflection infrared
spectroscopy (ATR-IR).
XRD studies. Previously, important information has been
reported regarding the formation of co-crystalline structures
between 1a and common solvents and/or small organic
molecules.[30] Due to its amphiphilic nature, 1a forms layered
crystalline structures consisting of alternating hydrophilic and
hydrophobic layers. To the best of our knowledge, in all the
crystalline known structures,[30] the resorcinarene macrocycles,
adopting a cone conformation, are located in the hydrophilic
layer, while the undecyl tails form the hydrophobic layer (see
Figure S1). These structures strictly resemble to the bilayer
sheet formed by lipids in biological systems like cell membranes.
The thickness of the bilayer in 1a crystalline structures is of 24-
25 Å and falls along the longest side of the crystalline unit cell.[30]
Under the reaction conditions adopted in the current work, 1a
forms a crystalline structure in water. In fact, in the presence of
water, 1a swells yielding a slurry that analyzed by XRD was
[a] Reaction conditions: 1.5 equiv (243.9 μmol) of 2, 1 equiv (162.6 μmol) of 3,
10 % mol of catalyst, 1 mL of medium reaction and 50 °C. [b] Determined by 1H
NMR analysis. [c] Determined by 1H NMR analysis, according to the literature
data (see experimental section).
The FCB under on-water conditions in the presence of
resorcinarene 1a as catalyst represents a useful protocol also in
the case of heteroarene substrates. In fact, thiophene and N-
methylpyrrole (Scheme 2) were benzylated in 84-85 % yield,
within 16 h, affording the 2- and 3-regioisomers in both
instances.
Scheme 3. Friedel-Crafts benzylation between benzene and benzyl chloride 3
catalyzed by 1a under on-water conditions.
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Figure 3. X-ray diffractograms (a-e) with the corresponding d-spacing patterns (a'-e') of 1a under the reaction conditions of Table 1: in the absence of
reagents (a and a'); in the presence of sole 2 (b and b'); in the presence of sole 3 (c and c'); in the presence of 2 and 3 (d and d'); in the presence of
reaction products 4a and 4a (e and e'; entry 5 of Table 1).
found crystalline (Figure 3a). The most intense reflection was
found at the lower diffraction angle of 3.66°. The corresponding
interplanar distance (d) of 24 Å (see Figures 3b and 4a) for the
crystalline planes originating this reflection is compatible with the
bilayer thickness up to now observed for 1a crystal structures,[30]
as an evidence of the formation of this arrangement under the
reaction conditions in Table 1. On these bases, we propose the
packing model in Figure 4a, in which resorcinarene molecules
are facing each other to form a hydrophilic layer sealed by H-
bonding interactions involving water molecules (vide infra).[30j]
The alkyl tails of 1a are interdigitated between them and form a
hydrophobic layer. The layers of dimeric resorcinarene
structures in Figure 4a are sealed by H-bonding interactions
of pure 1a (Figure 3c). This information rules out the simple
effects of orientation of the crystals induced by the presence of
the reactants and rather points out the formation of co-crystalline
structures of 1a with the reagents. By mixing 1a with both 2 and
3 under on-water conditions, the above mentioned reflections
were found simultaneously present in the corresponding XRD
diffractogram (Figure 3d), as an evidence of the formation of co-
crystalline structures of 1a with both the reagents. The
interplanar distance of 24 Å remained unmodified in all the
instances (Figure 3), indicating that the thickness of the bilayer
was not altered by the presence of the reagents. This suggests
the probable formation of endo-complexes in which the
reactants 2 and 3 are hosted inside the cavities of 1a in accord
to the model proposed in Figures 4a and 4b. A completely
different diffraction pattern was found after 32 h of reaction of 3
with toluene, when the formation of the coupling product is
complete. Also in this case the X-ray diffraction pattern indicated
the inclusion of the reaction products into the crystalline
structure of resorcinarene 1a.
involving water molecules, in a similar way to the bilayer motif of
[30a]
1a reported by Pietraszkiewicz
using DMF as solvent. After
addition of 10 equiv of toluene 2 to 1a on-water, the diffraction
pattern presents novel moderate reflections at 6.51° and 7.48°.
Considering that toluene can be hosted inside the cavity of 1a
[31]
(Figures 4a and 4b), this finding is an evidence of the
formation of a co-crystalline structure of 1a with 2.
In the same way, in the presence of benzyl chloride the X-ray
pattern of 1a under on-water conditions presents intense
reflections at 4.35° and 4.87°, absent in the on-water spectrum
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(a)
(b)
(c)
Figure 4. (a) Proposed model of the 3D packing of resorcinarene 1a molecules in the solid state, under on-water conditions adopted in the present
work. The bilayer motif has been proposed on the basis of the XRD studies in Figure 3 and in accord with literature data.[30] The presence of H-
bonded H2O (in green) in the channel plays a crucial role for the formation of the crystalline structure as evidenced by XRD (Figure 3a), TGA and
DSC analysis. (b) DFT-optimized structure of the supramolecular complex 3@1a·1a obtained at B3LYP/6‐31G(d,p) level of theory and used for the
computation of the IR spectrum. (c) DFT-optimized structure of the supramolecular complex 2+3@1a·1a obtained at B3LYP/6-31G(d,p) level of
theory. Undecyl chains are removed for clarity.
Thermogravimetric analysis (TGA) and differential scanning
calorimetry (DSC) analysis.
contrary, in the presence of water the release of 3 is bimodal
with a further distinct release of 3 shifted at higher temperatures
in the range 180-220 °C. The quantity of 3 released during this
stage is approximatively equimolar with respect to resorcinarene
1a. This amount of 3 can be ascribed to that included in the
crystalline structure of 1a formed in the presence of water, which
requires for its volatilization a temperature even superior than
that for boiling (179 °C). This conclusion was further
substantiated by DSC analysis (Figure 5). The thermal profile of
1a, anhydrified by exposure to phosphorous pentoxide in vacuo,
mixed with 10 equiv of 3 shows an endotherm peak due to the
Further evidences on the effective inclusion of 2 and 3 in the
crystalline structure of hydrate 1a has been obtained by
investigating the thermal behavior of this system by TGA and
DSC measurements. Figure S2 shows the thermogravimetric
profile of 1a in the solid state and after stirring on-water. The
detectable thermal transitions are due to the evolution of
adsorbed water (found in 1a even after drying in vacuo; see
Figure S2) in the temperature range 25-100 °C, while the
decomposition of the catalyst starts at 280 °C. After treatment of
1a with 10 equiv of 2, a monomodal release of the reactant was
observed (Figure S3a), which becomes bimodal in the presence
of water (Figure S3b). In the same way, the evolution of 3 from
1a (3:1a molar ratio of 10) in the absence of water is monomodal
and occurs in the temperature range of 50-150 °C. On the
evaporation of
3
in the thermal range 80-150 °C,
superimposable to that found by thermogravimetric analysis of
the same sample (compare Figure 5a with S4a). For the
corresponding sample prepared by on-water mixing, three
endothermic peaks were found at temperature ranges matching
those observed by TGA and ascribed to the evaporation of water,
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10.1002/cssc.201900137
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benzyl chloride non-included and included in the resorcinarene
crystalline structure (compare Figure 5b with S4). Interestingly,
in the same thermogram a strong exotherm transition is evident
in the range 80-120 °C, with peak at 101°C (Figure 5a), which
has been attributed to the perfection of the crystalline structure
already present at room temperature (XRD pattern in Figure 3d).
To the same sample, the application of a preliminary thermal
ramp, at rate of 10 °C/min from 25 °C to 100 °C and cooling
again to 25 °C, was found sufficient for the complete in situ
removal of the water and consequent disruption of the co-
crystalline structure of 1a with 3 formed on-water. Actually, the
thermal stage at 180-220 °C, attributed to the release of
included benzyl chloride, was found absent in the subsequent
thermal ramp from 25 °C to 250 °C, showing exclusively the
monomodal release of 3 in the range 80-150 °C. This is an
additional evidence on the key role of the water in the formation
of the co-crystalline structure of 1a with 3. In fact, these results
corroborate the bilayer packing model proposed in Figure 4a
and above all, confirm the crucial role played by the water
molecules in the stabilization of the layers of dimeric structures
of 1a.
DFT calculations. On the basis of these results, we have
envisioned a supramolecular complex model in which the
reactants 2 and 3 are hosted inside a dimeric capsule 1a·1a
sealed by a network of H-bonding interactions involving water
molecules (Figures 4a,b). The model in Figure 4b has been
optimized by DFT calculations at B3LYP/6-31G(d,p) level of
theory. The result reported in Figure 4b suggests that the
supramolecular complex 3+2@1a·1a could be stabilized by a
catalytically relevant H-bond between the chlorine atom of 3 and
the OH group of 1a (Figure 4b), with a O···Cl distance of 3.36 Å
and a O–H···Cl angle of 145.0°. The presence of the O–H···Cl
H-bond (Figures 4b-c) would make possible the polarization of
the C–Cl bond and consequently the activation of the substrate 3
for the nucleophilic attack of toluene (Figure 4a). The water
molecules play a crucial role in the stabilization of the bilayer
motif in Figure 4a, consequently we have proposed their
involvement in a network of H-bonding interactions, which
sealed the two resorcinarene caps in 3+2@1a·1a (Figure 4b).
Finally, DFT calculation suggest that a water molecule of the
network is also H-bonded to the chlorine atom of 3, thus
participating to the activation of its C–Cl bond.
Figure 6. FT-IR spectra, with diagnostic bands labelled, of: a) 1a (KBr pellet);
b) 3 (ATR-IR); c) 1a compounded with an equimolar amount of 3 (ATR-IR); d)
1a compounded with an equimolar amount of on water 3 (ATR-IR); e) 1b
compounded with an equimolar amount of 3 on water (ATR-IR). Spectra b-e
normalized with respect to the band at 694 cm-1 due to the out of plane
deformation of the C-H of the phenyl ring of benzyl chloride (δ(C−H)ϕ).
FT-IR investigation. Evidences of the presence of H-bonding
interactions between the OH group of 1a and the chlorine atom
of 3 in the presence of water were obtained by ATR-IR
spectroscopy. Figure 6 shows the IR spectra of 1a (spectrum a),
of neat 3 (spectrum b), and of an equimolar mixture of 1a and 3
in the absence (spectrum c) and in the presence of water
(spectrum d) (for the spectra in the whole range 4000-400 cm-1,
see Figure S5). The spectra are normalized w. r. t. the strong
band due to the out-of-plane deformation of aromatic methines
Figure 5. DSC traces of 1a (anhydrified by exposure to P2O5 in vacuo)
compounded with 10 equiv of 3 (heating and cooling rate of 10 °C/min): a) in
absence of water (resorcinarene anhydrified by exposure to P2O5 in vacuo for
5 days); b) on water; c) on water, in situ deprived of water by means of a
preliminary thermal cycle 25-100-25 °C (violet curve) and reanalyzed in the
thermal range 25-250-25 °C (green curve).
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δ(C−H)ϕ at 694 cm-1 (complete spectra are reported in Figure S7).
In details, the ATR IR spectrum of 3 in Figure 6b shows the
presence of two intense bands at 694 and 673 cm-1 attributable
benzyl chloride on-water, the diagnostic IR band for the C-Cl
bond resulted unaffected (see Figure 6e).
to the out-of-plane deformation of aromatic C–H groups, and to
[32]
the stretching of the C–Cl bond
(σC−Cl). In addition, the band
Conclusions
at 1264 cm-1 in the IR spectrum of benzyl chloride in Figure 6b is
attributed to the wagging motion of its methylene group. The IR
absorption bands of 3 resulted unaffected by the simple mixing
with the catalyst 1a (compare Figure 6b and 6c). On the contrary,
with the addition of water (Figure 6d) to the mixture of 3 + 1a, a
strong attenuation of the IR absorption bands at 673 and 1280
cm-1 was found, with the concomitant formation of broad bands
peaked at 600 cm-1 and at 1340 cm-1, while the band at 694 cm-1
remained unchanged. In order to rationalize these results, we
have performed a computation of the IR spectra of the benzyl
chloride, under the different conditions reported in Figure 6, by
DFT calculations at the B3LYP/6-31G(d,p) level of theory.
Regarding the IR spectrum of 3, the stretching of the C–Cl bond
at 673 cm-1 (Figure 6b) was calculated at 666 cm-1, while the
out-of-plane deformation of aromatic C–H groups at 694 cm-1
was computed at 712 cm-1. In addition, DFT calculations confirm
that the band at 1280 cm-1 in the IR spectrum of benzyl chloride
in Figure 6b can be attributed to the wagging motion of the
methylene group of 3, which was computed at 1299 cm-1.
Regarding the sample prepared by mixing 1a + 3 in the
presence of water, XRD, TGA, and DSC studies indicate clearly
the formation of the bilayer packing motif proposed in Figure 4a
with the inclusion of 3 in the crystalline structure of hydrate 1a.
Consequently, in order to simulate as closely as possible, the
model proposed in Figure 4a, we have computed the IR
spectrum of a benzyl chloride molecule hosted inside a dimeric
capsule of 1a sealed by a network of H-bonding interactions
(Figure 4c). In this dimeric model, the chlorine of 3 establishes
The results here described clearly indicate that the Friedel-Craft
benzylation (FCB) of scarcely reactive arenes with benzyl
chloride can be performed on-water, as the reaction medium,
through an environmental-friendly catalytic strategy, which is
completely metal-free. The products of the FCB of benzene and
toluene with benzyl chloride constitute useful molecules for
many industrial processes. At this regard, we have shown that
our FCB procedure under on-water conditions can be easily
scaled up to a gram-scale. Under on-water conditions the
hydrophobic amplification of H-bonding interactions between the
OH groups of the resorcinarene catalyst and the chlorine atom
of the benzyl chloride led to the polarization of the C–Cl bond,
which promote the FCB reaction with scarcely reactive arenes
and heteroarenes. XRD studies indicate that under on-water
conditions, the resorcinarene catalyst adopts a bilayer structure
in which macrocyclic molecules are facing each other sealed by
a network of H-bonding interactions involving H2O molecules.
DSC and TGA analysis clearly show the effective formation of
endo-complexes in which the reactants are hosted inside the
bilayer structure of the resorcinarene catalyst. The crucial role
played by the H2O molecules in stabilizing this bilayer packing is
corroborated by DSC and TGA analysis, where their removal led
to the disruption of the co-crystalline structure. This result
suggests that, under on-water conditions, the reactants form
endo-complexes through their inclusion into the resorcinarene
cavities driven by the hydrophobic aggregation. In accord with
the hydrophobic hydration model, the bridged water molecules
establish minimal van der Waals contacts12,13a with the reactants.
Finally, ATR-IR studies corroborated by DFT calculations clearly
evidenced the presence of H-bonding interactions between the
resorcinarene OH groups and the chlorine atom of the benzyl
chloride. As previously reported by Paquin24 and us,25d,e this H-
bonding is catalytically relevant for promoting the FCB reaction.
From the present work, it is clearly emerging that the exploitation
of the hydrogen-bond-donor ability of resorcinarene macrocycle
under on-water conditions opens up new possibilities for eco-
friendly supramolecular organocatalysis and we expect that its
applications can be broadened in the coming years.
multiple H-bonding interactions (as acceptor) with
a
resorcinarene hydroxyl group and with water molecules (as
donors). In the calculated IR spectrum of 3 H-bonded inside the
dimeric capsule 3@1a·1a (Figure 4c), the absorption band
attributed to the stretching of the C–Cl bond was computed at
617 cm-1, a value very close to that found experimentally in
Figure 6d (600 cm-1) and lower with respect to that calculated for
the free benzyl chloride at 666 cm–1 (experimental at 673 cm-1 in
Figure 6b).[33] The shift of the stretching frequency of the C–Cl
bond at lower wave-numbers is in accordance with the presence
of an hydrogen-bonding interaction (C–Cl···H–O). Interestingly,
DFT calculations computed the wagging frequency of the
methylene ClCH2Ph group of 3, H-bonded inside the dimeric
capsule 3@1a·1a, at 1311 cm-1 (experimental at 1340 cm-1 in
Figure 6d), a value significantly shifted at higher wave-numbers
with respect to that found for 3 + 1a and in the absence of water
(experimental at 1264 cm-1 and calculated at 1299 cm-1). In
summary, the comparison between experimental and DFT-
computed ATR-IR spectra of 3 and 1a, under dry and wet
conditions, corroborates our hypothesis concerning the
Experimental Section
All chemicals were reagent grade and were used without further
purification. Anhydrous solvents were purchased from Aldrich. Reaction
temperatures were measured externally; column chromatography was
performed on Merck silica gel (60, 15-40 μm). Reactions were monitored
by thin-layer chromatography (TLC) on silica gel plates (0.25 mm) 60 F254
.
All experiments were carried out in oven-dried 4 mL glass vials. NMR
spectra were recorded on Bruker Avance 600 spectrometer [600.13 MHz
(1H)], Bruker Avance-400 spectrometer [400 ( 1H)] or Bruker Avance-300
spectrometer [300 ( 1H)]; chemical shifts are reported relative to the
residual solvent peak (CHCl3: δ 7.26, CDCl3). Derivatives 1a-d were
formation of
a catalytically relevant H-bonding interaction
between 3 and catalyst 1a.[34] An additional confirmation was
obtained with octamethylated resorcinarene 1b (Scheme 1),
lacking of the OH functionalities. In fact, by mixing 1b with
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10.1002/cssc.201900137
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synthesized according to literature procedures.[35] X-ray diffraction (XRD)
patterns were obtained in reflection mode with an automatic Bruker D8
diffractometer using the Nickel-filtered Cu Kα radiation. The specimens
were prepared by draining the excess of water with filter paper and
stratification of the sample onto XRD sample holder. Fourier transform
infrared (FTIR) measurements were carried out on a Bruker Vertex 70
spectrometer equipped with a deuterated triglycine sulfate detector and a
Ge/KBr beam splitter. The spectra were collected in the range of 4000–
400 cm−1 using 128 scans with resolution of 2 cm−1. Solid samples were
analyzed as KBr pellets. Reaction slurries were analyzed in attenuated
total reflectance mode (ATR) using a multiple reflection ATR accessory
from Bruker with horizontal geometry equipped with a KRS-5 crystal.
Specimens for ATR-IR measurements were prepared by draining the
excess of water with filter paper and stratification of the sample onto the
sample holder. Thermogravimetric analysis (TGA) was performed in
nitrogen flux on a Netzsch TG 209 F1 analyzer at heating rate of
10 °C/min. Differential scanning calorimetry (DSC) analysis was
performed in nitrogen flux with a Q2000 calorimeter from TA instruments
at heating and cooling rate of 10 °C/min. The specimens for thermal
analyses were prepared by draining water excess with filter paper prior to
the measurements.
1-benzyl-2,4-dimethylbenzene (8). From the general procedure, using m-
xylene (25.9 mg, 29.8 μL) and benzyl chloride (20.6 mg, 18.7 μL). A white
solid was obtained (29.8 mg, 92%), constituted by
a mixture of
monobenzylated and dibenzylated product (93/7). The NMR spectral
data of two compounds were in accord with those reported in
literature.[37b]
2-benzyl-1,3,5-trimethylbenzene (9). From the general procedure, using
mesitylene (29.3 mg, 34 μL) and benzyl chloride (20.6 mg, 18.7 μL). A
colorless oil (29 mg, 94%) was obtained as a mixture of monobenzylated
1
and dibenzylated product (75/25). The H NMR signals of two compunds
were in accord with those reported previously.[36f]
1-benzyl-4-methoxybenzene (10). From the general procedure, using
anisole (26.4 mg, 26.5 μL) and benzyl chloride (20.6 mg, 18.7 μL). A
colorless oil was obtained (29 mg, 90%). The NMR spectral data were in
accord with those reported in literature.[36g]
1-benzyl-2,4-dimethoxybenzene (11). From the general procedure, using
1,3-dimethoxybenzene (33.7 mg, 31.9 μL) and benzyl chloride (20.6 mg,
18.7 μL). A waxy solid (33.8 mg, 91%) was obtained. The NMR spectral
data of 10 were in accord with those reported in literature.[36h]
General Procedure for the FCB catalysis under on water conditions.
A suspension of appropriate arene or heteroarene (0.24 mmol) and
catalyst (0.016 mmol) was vigorously stirred in presence of the benzyl
chloride (0.16 mmol) in H2O (1 mL in a 4 mL glass vial). The suspension
was kept under vigorous magnetic stirring at 50 °C for the time reported
in Tables 1-2 or Scheme 2. Then the suspension was cooled at room
temperature and filtered. The filtrate was extracted with n-hexane (3 x 2
mL), while the solid catalyst (precipitate) was washed with cool n-hexane
(at − 10 °C) (3 x 2 mL), filtered and dried (recovery yield of the catalyst
>99%). The combined organic layers were transferred in a separation
funnel and washed with H2O (3 x 2 mL). The organic layer was dried
over Na2SO4, filtered and concentrated under reduced pressure. The
residue was passed through a short silica plug. The solvent, n-hexane
was removed under reduced pressure and the product was analyzed by
1H NMR spectroscopy.
2-benzyl-1,3,5-trimethoxybenzene (12). From the general procedure,
using 1,3,5-trimethoxybenzene (41 mg) and benzyl chloride (20.6 mg,
18.7 μL). A white solid was obtained (36.4 mg, 93%) as mixture of of
monobenzylated and dibenzylated product (87/13). The NMR spectral
data of two compounds were in accord with the values previously
reported.[36i,j]
2-benzylthiophene and 3-benzylthiophene (13). From the general
procedure, using thiophene (19.5 mg, 20.5 μL) and benzyl chloride (20.6
mg, 18.7 μL). A colorless oil was obtained (24.1 mg, 85%), as a mixture
of 2- and 3-regioisomer (74/26). The NMR spectral data of two isomers
were in accord with those previously reported.[37a]
2-benzyl-5-bromothiophene (14). From the general procedure, using 2-
bromothiophene (39.8 mg, 23.6 μL) and benzyl chloride (20.6 mg, 18.7
μL). A colorless oil was obtained (37.3 mg, 91%). The NMR spectral data
of 13 were in accord with those reported in literature.[37b]
1-benzyl-4-methylbenzene 4b and 1-benzyl-2-methylbenzene 4a. From
the general procedure, using toluene (22.5 mg, 25.9 μL) and benzyl
chloride (20.6 mg, 18.7 μL). A colorless oil (27.5 mg, 93 %) was obtained
constituted by a mixture of 4b and 4a in 75/25 ratio. The 1H NMR signals
of 4b and 4a were in accord with those reported previously.[36a]
2-benzyl-1-methyl-1H-pyrrole and 3-benzyl-1-methyl-1H-pyrrole (15).
From the general procedure, using 1-methyl-1H-pyrrole (19.8 mg, 21.6
μL) and benzyl chloride (20.6 mg, 18.7 μL). A light yellow oil (23.4 mg,
84%) was obtained constituted by a a mixture of 2- and 3-regioisomer
(50/50). The NMR spectral data of two isomers were in accord with those
reported in literature.[25d]
1-benzyl-4-ethylbenzene and 1- benzyl-2-ethylbenzene (5). From the
general procedure, using ethylbenzene (25.9 mg, 29.9 μL), and benzyl
chloride (20.6 mg, 18.7 μL). A colorless oil (29.3 mg, 92%) was obtained,
1
constituted by a mixture of para and ortho-regioisomers (85/15). The H
NMR signals of 1-benzyl-4-ethylbenzene and 1- benzyl-2-ethylbenzene
were in accord with those reported previously.[36b]
Diphenylmethane (16). From the general procedure, using benzene (19.9
mg, 22.7 μL) and benzyl chloride (20.6 mg, 18.7 μL). A colorless oil was
obtained (27.5 mg, 90%) constituted by a mixture of monobenzylated 16
and 1,4-dibenzylated 17 product (78/22). The NMR spectral data of two
compounds were in accord with those reported in literature.[37c]
1-benzyl-4-isopropylbenzene and 1-benzyl-2-isopropylbenzene (6). From
the general procedure, using cumene (29.3 mg, 34 μL) and benzyl
chloride (20.6 mg, 18.7 μL). A waxy solid (31.1 mg, 91%) was obtained
constituted by a mixture para and ortho-regioisomers (88/12). The 1H
NMR signals of 1-benzyl-4-isopropylbenzene and 1-benzyl-2-
isopropylbenzene were in accord with those reported previously.[36c]
Acknowledgements
[35d]
1-benzyl-4-(tert-butyl)benzene
and 1-benzyl-2-(tert-butyl)benzene
The authors acknowledge the Regione Campania (POR
[35e]
(7). From the general procedure, using tert-butylbenzene (32.7 mg,
37.7 μL) and benzyl chloride (20.6 mg, 18.7 μL). A colorless oil (33.2 mg,
91%) was obtained constituted by a mixture para and ortho-regioisomers
(84/16). The 1H NMR signals of two isomers were in accord with those
reported previously.[36d,e]
CAMPANIA
FESR
2007/2013
O.O.2.1,
CUP
B46D14002660009) for the FT-ICR mass spectrometer facilities,
Farma-BioNet (CUP B25C13000230007), the Centro di
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Dobrzycki, K. Wozniak, F. Benevelli, J. Klinowski, W. Kolodziejski,
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[10c, 17a]
to a significant reduction of the hydrophobic effect
because of
the higher viscosity of D2O. As suggest by a reviewer, the scarce
efficiency of the catalyst 1a in the presence of D2O as solvent, can also
be attributed to the deuterium isotope effect on H-bonding.
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A sustainable on-water procedure for
the Friedel-Crafts benzylation (FCB)
P. La Manna, A. Soriente,* M. De Rosa,
A. Buonerba,* C. Talotta, C. Gaeta* and
P. Neri
of
scarcely
reactive
aromatic
substrates is here reported. Under on-
water condition the resorcinarene
macrocycle is able to catalyze the
FCB of arenes and heteroarenes
through hydrophobic amplification of
H-bond interactions and hydrophobic
hydration effect.
Page No. – Page No.
Green, Mild, and Efficient Friedel-
Crafts Benzylation of
Reactive Arenes and Heteroarenes
Under on Water Conditions
Scarcely
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