Stereospecific synthesis of resorcin[4]arenes and pyrogallol[4]arenes in dynamic thin films

Article abstract of DOI:10.1039/c3cc45176c

Acid catalysed condensation of resorcinol and pyrogallol with aromatic aldehydes using a microfluidic vortex fluidic device (VFD) under continuous flow conditions results in the selective formation of resorcin[4]arenes and pyrogallol[4]arenes as predominantly their C_4v isomers. Notably C_2v isomers and C_2h isomers can be also prepared with the latter being converted to the C_4v isomer when the VFD operates in confined mode. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc45176c

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Stereospecific synthesis of resorcin[4]arenes and
pyrogallol[4]arenes in dynamic thin films†
Cite this: Chem. Commun., 2013,
4
9, 10932
a
a
a
b
Lyzu Yasmin, Travis Coyle, Keith A. Stubbs and Colin L. Raston*
Received 10th July 2013,
Accepted 9th October 2013
DOI: 10.1039/c3cc45176c
www.rsc.org/chemcomm
Acid catalysed condensation of resorcinol and pyrogallol with aromatic the crown (C ) conformers. In these specific cases, the kinetically
4v
aldehydes using a microfluidic vortex fluidic device (VFD) under favoured chair isomer is converted into the thermodynamically
continuous flow conditions results in the selective formation of more stable crown isomer after longer reaction times.
resorcin[4]arenes and pyrogallol[4]arenes as predominantly their
4v isomers. Notably C2v isomers and C2h isomers can be also pyrogallol[4]arenes involving different aldehydes using a micro-
prepared with the latter being converted to the C4v isomer when fluidic vortex fluidic device (VFD), in controlling chemical reactivity
Herein we report the synthesis of resorcin[4]arenes and
C
the VFD operates in confined mode.
and selectivity, as part of a program on developing more efficient and
alternative synthetic protocols for targeted organic reactions. This
17
Resorcin[4]arene and pyrogallol[4]arene macrocycles are a versatile system has already demonstated capability in organic reactions,
sub-class of calixarenes with 8 or 12 upper rim hydroxyl groups, fabricating nanoparticles,
18,19
20
exfoliating graphene, and wrapping
respectively. These versatile molecules can be used for further graphene, graphene oxide and polymers ladden with super-
2
1–23
chemical elaboration, for H-bonding and for metal ion complexation paramagnetic magnetite nanoparticles, around algal cells.
in building complex materials. These materials include the
The design of the VFD is simple with variation in the rotational
1
–3
4
formation of hexameric or dimeric capsules, tubular arrays,
speed, angle of inclination and feed flow rates effective at fine tuning
5
17
and organic nanotubes. The traditional synthesis of these the outcome of the reaction being conducted. The device is
macrocycles involves acid-catalyzed condensation of resorcinol designed to have jet feeds which direct liquid to the end of a tube
or pyrogallol with aromatic or aliphatic aldehydes in an alcoholic and with the intense micromixing in the resulting dynamic thin
medium under reflux. The reaction times for these reactions vary film, the residence time can be controlled by varying both the feed
6
–8
from hours to several days,
affecting reaction conditions.
nature of the aldehydes also rate and the length of the tube. The thin liquid film created inside
9
–14
24
the rotating tube produces a very high heat and mass transfer rate.
Resorcin[4]arene and pyrogallol[4]arenes macrocycles are It also has a longer residence time than the related spinning disc
6,7
24
non-planar and can exist in different forms, which include processing apparatus (SDP) which allows the organic reaction
the crown (C4v) boat (C2v), chair (C2h), diamond (C ) and saddle to occur efficiently in a single pass within a few minutes. The
2d) arrangements. The relative positions of the substituents effectiveness of the VFD in controlling chemical reactivity in the
s
(
D
1
7
at the methylene bridges can be all cis (rccc), cis–trans–cis (rctc), continuous flow mode is explored in the present work for
15
cis–cis–trans (rcct) and cis–trans–trans (rctt). The C4v symmetry the synthesis of the resorcin[4]arene and pyrogallol[4]arene
has the rccc configuration and simple torsion of this gives C2v macrocycles, with optimisation dependent on the choice of
symmetry. The chair (C2h) isomer has rctt configuration. Critically, the extended operating parameters relative to traditional batch
the reaction conditions and the nature of the side chains at the processing, which include flow rates, rotational speeds and
bridging carbon atoms affect the stereoselectivity of the cycliza- inclination angles.
16
tion. Hoegberg described the condensation of various benz-
The general procedure for using the VFD in continuous flow
aldehydes with resorcinol and found that only two different mode for the preparation of calix[4]arenes 4a–i involved treating
stereoisomeric octols were formed, namely, the chair (C2h) and resorcinol 1 or pyrogallol 2 and aldehydes 3a–e in a 20 : 1 mixture of
ethanol and concentrated hydrochloric acid (Scheme 1). This is in
a
School of Chemistry and Biochemistry, The University of Western Australia,
contrast to earlier studies using traditional batch processing which
typically involve a 4 : 1 ratio of solvents. The acidic ethanol solution
Crawley, WA 6009, Australia
7
b
School of Chemical and Physical Sciences, Flinders University, Bedford Park, SA,
was delivered through one feed jet to a 10 mm diameter standard
5
042, Australia. E-mail: colin.raston@flinders.edu.au
ꢀ1
NMR tube at a flow rate of 1 mL min . The rotational speed, angle
of inclination of the tube and temperature were set at 7000 rpm,
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc45176c
1
0932 Chem. Commun., 2013, 49, 10932--10934
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C4v and C2h being 3 : 4. Possible reasons for the formation of
this mixture lie in the substitution pattern of vanillin which
may cause steric hindrance during the cyclization and so the
amount of the C4v isomer may therefore increase. Interestingly,
the VFD significantly reduces the reaction time for the prepara-
tion of 4h, which is consistent with the microfluidic platform
providing a ‘soft’ form of energy to increase molecular collisions
1
7
for reactions under diffusion control. As a comparison the C2h
isomer is usually prepared in 5 days using traditional method
1
0
processing with no formation of the C4v isomer.
We further investigated whether the percentage conversion of
the stereoisomers found using vanillin and resorcinol 1 could be
controlled by changing the different reaction parameters for the
VFD. Systematic variation of rotational speed, temperature, flow
rate, angle of tilt and acid used, resulted in formation of both the
Scheme 1 General reaction procedure for the preparation of calix[4]arenas.
ꢀ1
(
a) Ethanol, conc. HCl, 80 1C, 7000 rpm, 451 inclination angle, 1 mL min
.
C4v and C2h stereoisomers in all cases, albeit with different percent
4
51 and 80 1C respectively, with the choices of speed and angle conversions and different ratios of the isomers (Table 2). The
1
7
based on earlier work using this instrument. In most cases rotational speed is a key processing parameter of the VFD, in
2
4
the reaction produced a precipitate, which was collected using controlling the thickness of the dynamic thin film.
simple filtration. The solid products were washed with water to
At high speed (7000 rpm) the conversion to 4h was high
remove any acid and purified, by crystallisation from ethanol, yielding with a mixture of the C4v and C2h isomers whereas at
to give the desired compounds 4a–i in good yields (Table 1). All lower speed (3000 rpm) the ratio was more in favour of the C2h
1
13
compounds obtained had H and C NMR spectra that were isomer. The angle of tilt of the VFD was also seen to play an
6
,7,10,13
consistent with literature values
previously reported for important role in the reactions. At an angle of 451, where both
C
4v isomers (see ESI†). Of note is that in all cases the reactions gravitational and centrifugal forces create shear within the
were conducted using a single pass on the VFD which translates resulting thin film formed, a higher conversion to C4v was
to 10 min processing for 10 mL of solution, at the designated observed compared to an angle of 01 where only centrifugal
ꢀ1
17
flow rate of 1 mL min
The macrocycles 4a–f were characterised as their rccc crown
C ) isomer, which is the favoured isomer formed using traditional rate from 1 mL min to 3 mL min , over 1 mL increments. We
.
forces are present.
The effect of flow rate was also investigated by varying the input
ꢀ
1
ꢀ1
(
4v
batch processing for aliphatic aldehydes with resorcinol 1 and found that the best rate for the conversion to 4h of C4v isomers
ꢀ
1
pyrogallol 2. There were no signs of the formation of the other was 1 mL min (43%), with higher flow rates resulting in lower
isomers, in particular the kinetically favoured rctt chair (C2h). Of conversions. This could be attributed to the reduced residence
note was the preparation of the resorcin[4]arene 4g which was time of the liquid in the VFD and therefore less chance for
isolated exclusively as the rccc crown isomer. Previous traditional conversion. The optimal temperature was found to be 80 1C and
7
literature preparations of 4g were found to only form the rctt switching the acid used from hydrochloric acid to p-toluene
chair isomer (C ) after short reaction times and only after longer sulfonic acid or acetic acid in ethanol resulted in reduced
2h
reaction times did the formation of the rccc crown isomer result. conversion and no conversion, respectively.
Of interest was that the reaction of pyrogallol 2 with vanillin
The VFD is unique in that it has two formats under which
afforded exclusively the pyrogallol[4]arene macrocycle 4i as its C2v chemical reactions can take place, continuous flow and confined
1
7
(boat) isomer in high yield.
mode. To evaluate the effects of performing chemical reactions
The calix[4]arene macrocycle 4h (synthesised from vanillin in the confined mode we took the mixture of isomers of 4h
and resorcinol 1) was prepared in both the rccc C4v and rctt C2h
isomers under VFD continuous flow conditions with the ratio of
Table 2 Investigation into the conformation of 4 h using different parameters
of reaction in VFD under continuous flow conditions
Table 1 Synthesis of calixarene macrocycles using continuous flow VFD operating
Variation of
parameters
C4v
(%)
C2h
(%)
Yield
(%)
ꢀ1
at 7000 rpm, 451 tilt angle and 80 1C at a flow rate of 1 mL min
Parameters
0
Rotational speed (rpm)
7000
43
30
43
27
43
25
43
14
43
37
0
57
70
57
73
57
75
57
86
57
63
0
99
96
99
81
99
74
99
37
99
90
0
Product
–R
–R
Yield (%)
Isomer
3000
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
g
h
i
3a
3b
3c
3a
3b
3c
3d
3e
3e
H
H
H
OH
OH
OH
H
H
OH
32
43
40
42
42
75
56
99
84
C
C
C
C
C
C
C
C
C
4v
4v
4v
4v
4v
4v
Angle of inclination (degrees)
45
0
1
3
80
60
ꢀ1
Flow rate (mL min
Temperature (1C)
Acid
)
4v
HCl
p-TSA
Acetic acid
4v and C2h
2v
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times did not improve this conversion. This also provides
further evidence that intense shear is present under confined
mode operation of the VFD, and arises from the cross vector of
2
0
centrifugal force and gravity. Of interest is that compound 4i
in the C2v isomer cannot be converted to the C4v isomer using
the same approach.
In conclusion, we have established a novel and facile method for
the synthesis of different resorcin[4]arenes and pyrogallol[4]arenes
as the C4v isomer, with one exception, using the microfluidic VFD
under continuous flow conditions. The type of isomers that can be
formed, as well as conversion between them, can be controlled by
varying the parameters of the VFD, with an added advantage of
significantly reducing the reaction times and the amount of catalyst
required. This method has potential for controlling for formation of
other calixarenes, and a plethora of chemical reactions.
Support of this work by the Australian Research Council,
The University of Western Australia and Centre for Microscopy,
Characterisation and Analysis at the University of Western
Australia is greatly acknowledged.
Scheme 2 VFD conditions: confined mode, ethanol, conc. HCl, 60 1C, 7000 rpm,
4
51 inclination angle, 1 mL solution of 4h (1 mmol, C4v and C2h) treated for
one hour.
Notes and references
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Fig. 1 Part of the 400 MHz H NMR spectrum of (a) compound 4h (3 : 4 mixture
of C4v and C2h isomers), (b) intermediate product 4h (30 min) and (c) compound
4
h (predominating C4v isomer). * corresponds to the C4v isomer and ꢁ corre-
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1
1
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6
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1
1
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3, 2282.
1
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1
(
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C
2
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2
013, 5, 2627.
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2
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1
0934 Chem. Commun., 2013, 49, 10932--10934
This journal is c The Royal Society of Chemistry 2013