A Lewis acid-mediated conformational switch

Article abstract of DOI:10.1039/c4ob01556h

Molecules that change conformation in response to a stimulus have numerous uses, such as artificial chemoreceptors, novel drug delivery strategies and liquid crystal technology. Here we describe the design, synthesis and conformational behaviour of an iso

Full text of DOI:10.1039/c4ob01556h

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A Lewis acid-mediated conformational switch†
Peter C. Knipe, Hannah Lingard, Ian M. Jones, Sam Thompson* and
Andrew D. Hamilton*
Cite this: Org. Biomol. Chem., 2014,
12, 7937
Molecules that change conformation in response to a stimulus have numerous uses, such as artificial
chemoreceptors, novel drug delivery strategies and liquid crystal technology. Here we describe the
design, synthesis and conformational behaviour of an isonicotinamide-substituted diphenylacetylene
upon recognition of Lewis acids, including metalloporphyrins. Binding of these at a remote site – the
pyridyl nitrogen – increases hydrogen-bond donor ability of the proximal amide NH, causing an increased
preference for the alkyne rotamer in which this hydrogen bond is maintained.
Received 23rd July 2014,
Accepted 18th August 2014
DOI: 10.1039/c4ob01556h
www.rsc.org/obc
Brønsted acidity of the corresponding amide would increase
its hydrogen bond donor strength, and thus favour the confor-
Introduction
Dynamic control of molecular conformation by the application mation in which it is hydrogen bonded to the ester (Fig. 1).
of an external stimulus is a field that has attracted much inter-
est in recent years,1–6 with diverse stimuli such as Brønsted
acids,7–16 metal cations,17–24 halide anions,25–30 light31–36 and
redox couples37–39 being employed. The potential applications
of such molecules are equally diverse, including sensors,40–42
liquid crystal displays,8 and targeted drug delivery.43 Induced
conformational change also frequently occurs in biological
systems, for example in the signal transduction carried out by
G protein-coupled receptors,44,45 and has been implicated in
the protein misfolding and aggregation associated with some
forms of amyloidosis.46 The study of conformational changes
in synthetic model systems can therefore give insight into the
forces that govern these important cellular and extracellular
processes, and inform future therapeutic strategies.
Results and discussion
Treatment of aniline 2 (prepared in a convergent manner from
2,6-dinitroaniline and methyl-2-iodobenzoate)39,51 with iso-
nicotinoyl chloride afforded the desired switch 1 in 65% yield
(Scheme 1). The corresponding control compounds 3 and 4
The diphenylacetylene motif is well-suited to the investi-
gation of conformational equilibria since the low barrier for
rotation about the acetylene allows rapid interchange between
conformers.47 Building on the seminal work of Kemp,48,49 we
have previously demonstrated that 2,6-bis(amido)-2′-alkyl-
benzoates are competent molecular balances, with the relative
H-bond donor ability of the two amides dictating the confor-
mational preference, and that this conformation can be per-
turbed by changes in pH or halide concentration.50–52 We
postulated that isonicotinamide 1 would be susceptible to con-
formational change under the influence of Lewis acids. Upon
binding to the basic pyridine nitrogen an enhancement of
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, UK. E-mail: sam.thompson@chem.ox.ac.uk,
andrew.hamilton@chem.ox.ac.uk; Tel: +44 (0)1865 275978
†Electronic supplementary information (ESI) available. CCDC 993562. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4ob01556h
Fig. 1 Conformational switching of diphenylacetylenes upon appli-
cation of a stimulus: (a) Brønsted acid; (b) an anion; (c) Lewis acids.
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Fig. 2 1H NMR spectral comparison of 1 (bottom) and 1·BF3 (top) in
b
CDCl3. Ha
(
(
), Hc ( ) and Hd
(
■
●
) are indicated. Black markers indi-
▼
), H
cate unmodified 1, blue corresponds to 1·BF3.
Hd experienced a downfield shift consistent with withdrawal of
electron density when the pyridine lone pair is acting as a
Lewis base. When the corresponding shifts in the control com-
pounds 3 and 4 are considered, this equates to a 4 : 1 bias of
switch 1 in favour of hydrogen bonding to Ha. These com-
pounds are taken to define the chemical shift of Ha in the
extreme cases where it is not hydrogen bonded (3, 0%
control), and is entirely hydrogen bonded (4, 100% control) to
the methyl ester acceptor,54 and that the position of the con-
formational equilibrium is well-approximated by the chemical
shift of Ha relative to these extremes.51,55
Given the well-known propensity of pyridines to bind zinc(II)
porphyrins,56 we were intrigued as to whether the addition of
5 would elicit conformational change in our system. Zinc(II)
porphyrin 5, prepared from 3,5-di-tert-butylbenzaldehyde,
pyrrole and zinc(II) acetate, was added to a solution of switch 1
in CDCl3.57 Both amide (Ha and Hb) and pyridine (Hc and Hd)
hydrogens experienced a significant upfield shift due to their
proximity to the porphyrin ring current (Fig. 3). Whilst these
shifts are diagnostic of zinc : pyridine binding, analysis of the
conformational behaviour (with reference to controls 3 and 4)
shows minimal change (a ratio change from 2 : 1 to 7 : 3). This
is likely due to unfavourable steric repulsion between the ester
and porphyrin in the conformer of complex 1·5 when the iso-
nicotinoyl amide hydrogen bond is engaged. Such behaviour
Scheme 1 (A) synthesis of 1. (B) X-ray crystal structure of 1 shown from
two perspectives. The intramolecular N–H⋯O bond distance and di-
hedral angle between the carbonyl group and pyridine ring are indi-
cated. (C) structures of control molecules
dimethylaminopyridine, rt = room temperature.
3 and 4. DMAP = 4-
were generated in an analogous manner (see ESI† for full
experimental detail).
In the absence of an external stimulus, solution-phase data
suggested that diphenylacetylene 1 exhibits a 2 : 1 bias in
favour of hydrogen bonding to the isonicotinamide N–H
(vide infra), consistent with its single crystal X-ray structure
which displays an N–H⋯O bond distance of 2.2 Å (Scheme 1).‡
Congruent with previous studies,51 hydrogen bonding to the
ester causes a steric clash, leading to a 52° twist of the pyridine
ring out of the plane of the diphenylacetylene.
Having demonstrated the conformational bias in the
absence of an applied stimulus we investigated the confor-
mational switching achieved upon recognition of Lewis acids.
The addition of BF3·OEt2 to a solution of 1 in CDCl3 led to two
discrete species observable in solution (see Fig. 2, middle spec-
trum: 0.5 eq.), as opposed to protonation studies on similar
systems in which rapid proton transfer led to a single, time-
averaged set of signals.51,53 The peak-broadening and small
chemical shift changes observed for 1 upon addition of a sub-
stoichiometric quantity of BF3 are indicative of slow exchange
between bound (1·BF3) and unbound (1) states on the NMR
time scale. Upon addition of one equivalent of the Lewis acid,
a downfield shift was observed in Ha, from 9.41 to 9.70 ppm,
whilst Hb moved upfield from 9.08 to 8.90 ppm (Fig. 2). Hc and
Fig. 3 1H NMR spectral conformational analysis of 1 by chemical shifts
b
c
of Ha
(
(
), H ( ) and Hd
(
■
●
) on the addition of 5 in CDCl3. The
▼
), H
‡The X-ray data for 1 has been deposited in the Cambridge Crystallographic
stoichiometry of 5 is calculated by integration relative to the pyrrole
C–H singlet.
Data Centre (CCDC 993562).
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ion enhances the adjacent amide as a hydrogen bond donor,
leading to a conformational preference for the rotamer in
which this N–H⋯O hydrogen bond is maintained. Switching
molecules of this kind have fascinating potential applications
in stimulus-responsive medicines and materials, and the
ability to sense both Brønsted- and Lewis acids provides a
powerful tool for further investigations.
Experimental details
For full experimental details for the synthesis of 2, and for
control compounds 3 and 4 by analogous routes to that
described for 1, please refer to the ESI.†
Fig. 4 1H NMR spectral conformational analysis of switch 1 by chemical
b
shifts of Ha
(
(
), Hc ( ) and Hd
(
■
●
) on the addition of TFA in CDCl3.
▼
), H
Synthetic procedures
The stoichiometry of TFA is calculated precisely by integration relative to
an internal 1H NMR standard.58
Methyl 2-((2-benzamido-6-(isonicotinamido)phenyl)ethynyl)
benzoate (1)‡. Thionyl chloride (139 μL, 1.6 mmol) was added
to a solution of isonicotinic acid (100 mg, 0.81 mmol) in
dichloromethane (3 mL). A drop of dimethylformamide was
added, causing the reaction mixture to bubble vigorously for
several minutes. After gas evolution had ceased (ca. 10 min)
the reaction mixture was concentrated under a stream of nitro-
gen gas. The solid residue was taken up as a suspension in
dichloromethane (2 mL) and pyridine (130 μL, 1.6 mmol) was
added. The supernatant solution was removed via syringe and
added to a stirred suspension of 2 (100 mg) and 4-dimethyl-
aminopyridine (0.5 mg) in dichloromethane (2 mL). All solids
were observed to dissolve immediately upon addition of the
acid chloride solution. After 30 min the reaction mixture was
diluted (dichloromethane, 25 mL) and water (10 mL) was
added. The layers were separated and the aqueous layer was
extracted with dichloromethane (3 × 10 mL). The combined
organic extracts were washed with brine, dried, filtered and
concentrated in vacuo. The residue was purified by flash
column chromatography (1 : 1 petrol–ethyl acetate) to give
1 (83 mg, 65%) as a white powder. X-ray diffraction quality
crystals were grown by vapour diffusion (chloroform–hexane);
δH (CDCl3, 500 MHz) 9.41 (1H, br s, H17), 9.07 (1H, br s, H22),
8.78 (2H, d, J 6.0, H21), 8.41 (1H, d, J 8.8, H13/H15), 8.35 (1H,
d, J 8.2, H13/H15), 8.09 (1H, d, J 7.9, H4), 7.99 (2H, d, J 7.3,
H25), 7.83–7.80 (2H, m, H20), 7.60–7.57 (3H, m, H6, H7 &
H27), 7.54–7.45 (4H, m, H5, H14 & H26), 3.44 (3H, s, H1);
δC (CDCl3, 126 MHz) 165.8 (C23), 165.3 (C2), 164.9 (C18), 150.4
(C21), 142.6 (C19), 140.0 (C12/C16), 139.7 (C12/C16), 135.1
(C24), 132.9 (C6/C7), 132.6 (C6/C7), 132.0 (C27), 131.2 (C5),
131.1 (C4), 130.2 (C3), 129.0 (C5), 128.7 (C26), 127.4 (C25),
122.9 (C8), 121.8 (C20), 115.5 (C13 & C15) 103.1 (C9), 102.5
(C11), 85.6 (C10), 52.1 (C1); νmax (neat): 3398, 2952, 1719, 1684,
1583, 1487, 1469, 1304, 695; HRMS (ESI): found 498.1417;
C29H21N3NaO4 [M + Na]+ requires 498.1424; MP: 197–199 °C
(chloroform/hexane).
reinforces the hypothesis that hydrogen bond donor strength
is not the sole determinant of conformation, and that other
non-covalent interactions must be considered during the
design stages.55
Given our previous work with conformational switching of
diphenylacetylene-based compounds in the presence of a
Brønsted acid stimulus we were intrigued to see whether the
pyridyl system would undergo analogous behaviour. Accord-
ingly trifluoroacetic acid (TFA) was titrated into a solution of 1
in CDCl3, and the position of the 1H peak corresponding to
N–Ha was examined as a function of the TFA equivalence.58 An
▼
immediate downfield shift in Ha
(
) was observed upon the
addition of TFA, concomitant with an upfield shift in Hb ( ),
and consistent with an increased bias towards the conformer
in which Ha is hydrogen-bonded to the methyl ester. To assess
the extent to which the change in shift was due to confor-
mational change, as opposed to acidification alone, the titra-
tion experiment was performed on controls 3 and 4. As the
concentration of TFA is increased, the 1H shift of Ha tends
towards that of the 100% control 4, consistent with a confor-
mational change in favour of the isonicotinoyl amide. Prior to
the addition of the acid, the conformation lies slightly in
favour of this side, whereas upon addition of 3 eq. of TFA, the
bias is increased to 4 : 1. This result suggests a comparable
conformational bias with that obtained with Lewis acids. Both
■
proton chemical shifts on the pyridine (Hc and Hd; and
●
respectively) also move markedly downfield (from 7.82 to
8.28 ppm, and 8.78 to 8.87 ppm respectively) supporting the
postulate that the pyridine nitrogen is undergoing protonation
(Fig. 4).59
Conclusions
We have demonstrated that the conformational equilibrium of
Zinc(II) tetra(3,5-di-tert-butyl)phenylporphyrin (5). Based on
an isonicotinamide diphenylacetylene switch can be biased in a literature procedure,60 pyrrole (83 μL, 1.3 mmol) was added
response to a range of stimuli. This process is mediated remo- to
a solution of 3,5-di-tert-butylbenzaldehyde (250 mg,
tely at the pyridine nitrogen atom; the resulting pyridinium 1.15 mmol) in propionic acid (15 mL), and the resulting
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mixture was heated to reflux. After 3 h the reaction was given concentration of 5 was determined in an analogous
allowed to cool to room temperature and was concentrated manner to that described for the BF3-mediated switching.
in vacuo. Residual propionic acid was removed by azeotrope
with toluene (3 × 25 mL), and the resulting brown solid was
taken up in dichloromethane, triethylamine (0.25 mL) was
added and the mixture was stirred for 30 min. The solution
Acknowledgements
The authors would like to thank The University of Oxford for
financial support, and Dr Amber L. Thompson for assistance
with X-ray crystallography.
was then passed twice through a plug of silica (eluent: dichlor-
omethane) to remove polymeric impurities. The purple residue
was concentrated in vacuo and re-dissolved in chloroform
(40 mL), and a solution of zinc(II) acetate dihydrate (0.25 g,
1.15 mmol) in methanol (5 mL) was added in one portion. The
reaction mixture was stirred for 2 h then concentrated in vacuo
and re-dissolved in dichloromethane–petrol (1 : 1 v/v). This
solution was passed over a plug of silica (1 : 1 dichloro-
methane–petrol) and concentrated in vacuo to afford a purple
solid. This was dissolved in chloroform (3 mL) and triturated
by layering with methanol (3 mL) to give 5 (88 mg, 27%) as a
lustrous purple crystalline solid. δH (CDCl3, 400 MHz) 9.02
(8H, s), 8.11 (8H, d, J 1.7), 7.79 (4H, t, J 1.8), 1.53 (72H, s).61
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1
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(see ESI† for full details).
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