Isomer-Specific Hydrogen Bonding as a Design Principle for Bidirectionally Quantitative and Redshifted Hemithioindigo Photoswitches

Article abstract of DOI:10.1021/jacs.7b04448

A new class of bidirectionally quantitative photoswitches based on the hemithioindigo (HTI) scaffold is reported. Incorporation of a pyrrole hydrogen-bond donor leads to a bathochromic shift allowing for quantitative bidirectional isomerization. Additionally, extending conjugation from the electron-rich pyrrole results in quantitative visible-light photoswitches, as well as photoswitches that isomerize with red and near-infrared light. The presence of the hydrogen bond leading to the observed redshift is supported by computational and spectroscopic evidence.

Full text of DOI:10.1021/jacs.7b04448

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Communication
Isomer-Specific Hydrogen Bonding as a Design Principle for
Bidirectionally Quantitative and Redshifted Hemithioindigo Photoswitches
Joshua E. Zweig, and Timothy R. Newhouse
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 27 Jul 2017
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Isomer-Specific Hydrogen Bonding as a Design Principle for Bidirec-
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Joshua E. Zweig and Timothy R. Newhouse*
Department of Chemistry, Yale University, 275 Prospect Street, New Haven, Connecticut 06520-8107, United States
Supporting Information Placeholder
ABSTRACT: A new class of bidirectionally quantitative phoꢀ
toswitches based on the hemithioindigo scaffold is reported. Inꢀ
corporation of a pyrrole hydrogenꢀbond donor leads to a bathoꢀ
chromic shift allowing for quantitative bidirectional isomerizaꢀ
tion. Additionally, extending conjugation from the electronꢀrich
pyrrole results in quantitative visibleꢀlight photoswitches, as well
as photoswitches that isomerize with red and NIR light. The presꢀ
ence of the hydrogen bond leading to the observed redshift is
supported by both computational and spectroscopic evidence.
Small molecule photoswitches have recently seen a surge of interꢀ
est as a means for controlling biological systems at the molecular
Figure 1. a) Small molecule E/Z photoswitches b) arylpyrrole heꢀ
mithioindigo photoswitches show isomerꢀspecific hydrogen bonding
level. These compounds, which undergo geometric changes upon
irradiation with light, have been used in the study of photopharmacolꢀ
ogy, peptide tertiary structure and function, and other macromolecular
applications.1 In order to optimally apply this technology to therapeuꢀ
tic development, a photoswitch should display quantitative photoconꢀ
version between its isomers using nearꢀinfrared light (650 – 900 nm)
to allow for maximum tissue penetration.2 Additionally, photoswitchꢀ
es that operate via double bond isomerization are needed for many
biological applications in which large endꢀtoꢀend distance changes are
required to sufficiently modulate protein binding or other biochemical
interactions.1,3
irradiation with an appropriate wavelength of light should lead to
selective and quantitative photoisomerization of either isomer. Furꢀ
thermore, incorporation of an electronꢀrich pyrrole ring to the heꢀ
mithioindigo core should lead to a redshift of both E- and Z- isomers.
Several recent examples have effectively utilized modification of
photoswitch core structures to increase bathochromic shifts by perꢀ
turbing the energies of the relevant molecular orbitals through elecꢀ
tronic substituent effects or by enforcing geometric distortions.7ꢀ11 For
example, azobenzene (1) has been modified with orthoꢀfluoro, subꢀ
stituents7c,h,j which results in the stabilization of the nonꢀbonding
However, obtaining quantitative photoisomerization remains a
challenge across many classes of E/Z photoswitches (1ꢀ3).4 As double
bond isomerization does not intrinsically change the extent of πꢀ
conjugation, significant overlap in the absorption spectra of the two
isomers often renders selective irradiation of either one unattainable.
While their endꢀtoꢀend distance changes and photostability make
hemithioindigos (3) an attractive class of E/Z photoswitches for use in
biological systems,5 application has been limited in part as a result of
the drawback of incomplete photoisomerization, generally 80ꢀ90%.6
Derivatization of hemithioindigos has not overcome this limitation or
led to therapeutically applicable nearꢀinfrared photoswitches. Herein,
structural modifications to the hemithioindigo scaffold that enable
selective bidirectional photoisomerization using red and nearꢀinfrared
light are described.
molecular orbitals of the cisꢀisomer and results in
a larger
bathchromic shift. Heteroazobenzenes with ‘ortho’ subsitutents8 and
cyclic azobenzenes9 have also been shown to undergo selective phoꢀ
toisomerizations due to their distorted geometries.
Electronꢀdonating substituents have also been used to dramatically
redshift the absorbance of azobenzenes.7 Introduction of amino
groups para and methoxy substituents ortho to the diazo functionality
results in azobenzenes that can be isomerized with red light.7a,b Altꢀ
hough susceptible to hydrolysis, a strong intramolecular Lewisꢀ
acid/Lewisꢀbase interaction using a boron substituent has also been
employed to redshift the absorbance of azobenzenes (up to 730 nm
light).10 On acylhydrazone scaffolds (2),11 use of substituents, heteroꢀ
cycles, and πꢀextended systems was capable of producing phoꢀ
toswitches with absorption maxima between 400–425 nm.11b Periphꢀ
eral substitution of the hemithioindigo core has similarly been effecꢀ
tive:6f,h Z→E photoisomerization has been reported with 505 nm light
(80% E) and E→Z isomerization with up to 625 nm (89% Z).
It was hypothesized that the absorbance spectra of hemithioindigo
isomers could be differentiated by replacement of the phenyl group of
the hemithioindigo stilbene core with a hydrogenꢀbond donating hetꢀ
erocycle (Figure 1). In the Eꢀisomer of such a modified hemithioindiꢀ
go (E-4), the pyrrole NꢀH would donate an intramolecular hydrogen
bond to the benzothiophenone ketone, resulting in a bathochromic
shift of the Eꢀisomer. With a sufficiently large bathochromic shift,
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To validate our hypothesis that a heterocyclic NꢀH group could
participate as a hydrogen bond donor, we conducted DFT studies on
2ꢀpyrrolyl hemithioindigo 5 (Figure 2).12 Two isomers were investiꢀ
gated: E-5, which could possess an intramolecular hydrogen bond,
and Z-5 where such an interaction is not possible. The calculated
geometry of E-5, with an O…H distance of 1.75 Å and a C=O…H
angle of 117°, is also characteristic of intramolecular hydrogen bondꢀ
ing.13 These geometric features are in good agreement with crystal
structures that have been obtained of βꢀ(2ꢀpyrrolo)ꢀenones that adopt
a sevenꢀmembered cyclic geometry.14 Furthermore, NBO analyses of
both 5 and 6 show an O…H Wiberg bond index of 0.08 and 0.07 reꢀ
spectively,15 which indicates a hydrogenꢀbond strength comparable to
sixꢀmembered O–H…O systems such as 1,3ꢀdicarbonyls.16
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In the E-isomer, where a hydrogen bond is geometrically feasible, a
weaker C=O bond would be expected if the carbonyl serves as a hyꢀ
drogen bond acceptor. Indeed, the calculated IR spectra indicate that
the presence of a hydrogen bond decreases the stretching frequency
by 52 cmꢀ1. This hydrogen bond is expected to stabilize the LUMO
leading to a smaller HOMOꢀLUMO gap for the E-isomer, thereby
increasing the bathochromic shift between E- and Z-isomers.
TDꢀDFT studies were then conducted to elucidate the effect of the
intramolecular hydrogen bond on the absorption spectra of hemithioꢀ
indigos. It was predicted that 2ꢀpyrrolyl hemithioindigo (5) and 2ꢀ
imidazolyl hemithioindigo (6) would have bathochromic shifts of 39
nm and 47 nm, respectively, surpassing a predicted shift of 29 nm for
the parent carbocyclic system (3). Smaller bathochromic shifts were
predicted for other heterocyclic hemithioindigos which lacked a hyꢀ
drogen bond (7ꢀ8).
With theoretical support for the efficacy of the proposed hydrogen
bond, several heterocyclic photoswitches were synthesized (see Supꢀ
porting Information for details). We were pleased to discover that 5
displayed an improved bathochromic shift of 44 nm in CH2Cl2 soluꢀ
tion, exceeding the 11 nm shift of parent hemithioindigo 3. The imidꢀ
azole analog, 6, displayed a smaller bathochromic shift (35 nm) and
was similarly less selective in its EꢀZ photoisomerization.17 In
agreement with calculations, thiophene and furan hemithioindigos 7
and 8 displayed bathochromic shifts comparable to that of the parent
hemithioindigo, 19 and 15 nm, respectively. This suggests that the
large bathochromic shift of 5 is not merely a general property of the
electronꢀrich systems or a function of the sterics of introducing a fiveꢀ
membered heterocycle, but that the hydrogen bond is responsible for
the increased bathochromic shift.
Further supporting our hypothesis, a 20 cmꢀ1 reduction of the C=O
stretching frequency of E-5 relative to Zꢀ5 was observed experimenꢀ
tally. The proximity of the NꢀH and carbonyl in E-5 is additionally
supported by the observed properties of an Nꢀmethylated analog of 5.
This analog proved to be an exceptionally poor photoswitch – in fact,
its E-isomers could not be generated in sufficient quantities to definiꢀ
tively ascertain its λmax. Presumably, the same geometric constraints
that place the heterocyclic NꢀH in position to hydrogen bond to the
ketone result in a steric clash between the Nꢀmethyl group and ketone,
disfavoring relaxation from the photoexcited state to the Eꢀisomer.
Figure 2. a) Intramolecular hydrogen bonding predicts increased bathoꢀ
chromic shifts. (B3LYP/6ꢀ31G*) b) Pyrrole hemithioindigo (6) has an
increased bathochromic shift and improved photostationary state (PSS)
selectivity. c) Comparison of phenyl and pyrrole photoswitches (ca. 30
µM in CH2Cl2). Solid lines = Z-isomers. Dashed lines = E-isomers.
the arylpyrrole hemithioindigos could be obtained as single isomers
by precipitation and trituration. In its entirety, this sequence comprisꢀ
es five steps from commercial materials and requires one chromatoꢀ
graphic purification for most substrates.
To further redshift the absorbance of the pyrrole hemithioindigos
the πꢀextended series 4 was synthesized (Scheme 1) by coupling the
fully elaborated aldehydes 11 and benzothiophenone 13.6d The arꢀ
ylpyrroles 10 were synthesized via a Suzuki coupling with boronic
acid 9 and the corresponding aryl bromides.18 The resultant Nꢀ
protected biaryls were then deprotected using NaOMe before regioseꢀ
lective formylation under VilsmeierꢀHaack conditions. Simply treatꢀ
ing thiophenoxyacetic acid (12) with excess TfOH19 provided imꢀ
proved yields of 15 relative to the reported AlCl3ꢀmediated proceꢀ
dures. As an added benefit, material prepared by the TfOH protocol
was less susceptible to oxidative decomposition. Synthesis of the
arylpyrrole hemithioindigos was completed by treatment of the aldeꢀ
hydes 11 and benzothiophenone 13 with DBU in refluxing toluene.
Apart from 4i, which was purified by silica gel chromatography, all
Arylation at the 5’ position (4a) redshifted the peak absorbance of
the Z-isomer from 459 nm to 491 nm. Extension the πꢀsystem also
intensified the photochromicity of the photoswitches, increasing the
bathochromic shift from 44 nm (5) to a maximum of 67 nm (4g) (Figꢀ
ure 3). This property is readily observed in the color of the phoꢀ
toswitch solution before and after irradiation: in CH2Cl2 solution, Z-
4g is pink, while E-4g is violet in color. This photochromicity is parꢀ
tially responsible for the nearly isomerically pure photostationary
states. Regardless of substitution, all of these arylpyrrole hemithioinꢀ
digos can be quantitatively isomerized to their E- isomers, and E→Z
photoisomerization proceeds with >97% conversion for most memꢀ
bers of the library.
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Scheme 1. Convergent Assembly of Arylpyrrole-Hemithioindigo Photoswitches
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aReagents and conditions: (a) ArBr (1.0 equiv), 11 (1.5 equiv), Pd(OAc)2 (2 mol %), XPhos (4 mol %), K3PO4 (2.0 equiv), nꢀBuOH, 23 °C, 2 h; (b)
NaOMe (1.1ꢀ1.5 equiv), THF, 23 °C, 30 min; (c) POCl3 (1.05 equiv), DMF (1.2 equiv), then 3 M NaOH (aq.)/THF (1:1 v:v), 23 °C, 42 – 81% over three
steps; (d) TfOH (5.0 equiv), CH2Cl2, 40 °C, 9 h, 66%; (e) DBU, PhMe, 110 °C, 2 h, 44 – 97%.
Following the same trend as carbocyclic hemithioindigos,6,20 subꢀ
stituents such as –CN (4b) and –F (4c) resulted in observable (2ꢀ3
nm), but small blue shifts to the peak absorbance. The effects of elecꢀ
tron donating substituents were much larger: Z-4d displayed a peak
absorbance at 501 nm, and E-4d was sufficiently redshifted such that
its E→Z isomerization could be induced with 623 nm light. Introducꢀ
tion of additional oxygen substituents meta to the pyrrole (4e-f) did
not further redshift the absorbance of the photoswitches, but led to an
increase in the selectivity of the E→Z photoisomerization. The redꢀ
shifting effect was significantly larger for Nꢀsubstituted compounds
4gꢀi which displayed peak absorbance at as long as 559 nm for Z-4i.
As a result, quantitative Z→E isomeration was possible with up to
567 nm light for switches 4h and 4i. For 4g-i, E→Z isomerization was
most effective with irradiation in the nearꢀinfrared window (660 nm).
Furthermore, a photostationary state comprised of greater than 60% of
Z-4i was obtained under irradiation with infrared 740 nm light. In
toluene solution, the Eꢀisomers of 4a-i are more stable than their corꢀ
responding Z-isomers, and at 80 ˚C, compounds 4a-f possess halfꢀ
lives between 5ꢀ9 h and aminoꢀsubstituted compounds 4g-i possess
halfꢀlives between 0.3ꢀ2 h (see Table S1 in the Supporting Inforꢀ
mation for details).
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Photoswitch 4d was investigated in greater detail as a representaꢀ
tive example. The quantum yield for the photoisomerization of Zꢀ4d
to Eꢀ4d with 405 nm light was measured to be 0.13. In 1:1
DMSO:phosphate buffer, 10 ꢁm reduced glutathione and 5 ꢁm TCEP,
no detectable reduction of 4d was observed over a sixꢀhour period.
This reduction pathway is a wellꢀestablished obstacle for the introducꢀ
tion of azobenzene chromophores in certain biological applications.7
Additionally, 4d displayed no discernible signs of photobleaching in
CH2Cl2 over 20 irradiation cycles using 460 nm and 590 nm light;
more electron rich photoswitches such as 4g-i displayed loss of abꢀ
sorbance between 1ꢀ5% per cycle. Quantitative photoisomerization of
4d could also be observed in solvents with a wide range of dielectric
constants (e.g. >97% in both directions for CCl4 and MeCN). While
switching was effective in isopropanol, photoswitching in aqueous
media was less selective (see Table S2 in the Supporting Information
for details).
In conclusion, the combined redshifting from an intramolecular hyꢀ
drogen bond, electronꢀrich heterocycle, and extension of the πꢀsystem
with an electronꢀrich arene allow for photoisomerization within the
optimal window for therapeutic applications (660ꢀ740 nm). The use
of isomerꢀselective hydrogen bonding to create large bathochromic
shifts and thus quantitative isomerization may have utility in other
contexts. The properties of these photoswitches: quantitative phoꢀ
toisomerization, red and nearꢀinfrared absorbance, and resistance to
photoꢀ and biodegradation suggest that these photoswitches may serve
as tools for the construction of lightꢀcontrolled systems in biological
tissues, and numerous other applications.
Figure 3. a) Properites of substituted arylpyrrole hemithioindigos. b)
UV/Vis spectra. (ca. 30 µM in CH2Cl2) Solid lines = Z-isomers. Dashed
lines = E-isomers.
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Konieczny, M. T.; Konieczny, W. Heterocycles, 2005, 65, 451–464. (j)
Wiedbrauk, S.; Dube, H. Tetrahedron Lett. 2015, 56, 4266–4274.
ASSOCIATED CONTENT
(7) For substituted azobenzenes, see: (a) Sadovksi, O.; Beharry, A. A.;
Zhang, F.; Woolley, G. A. Angew. Chem. Int. Ed. 2009, 48, 1484–1486.
(b) Beharry, A. A.; Sadovski, O.; Woolley, G. A. J. Am. Chem. Soc. 2011,
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A.; Sadovski, O.; McCormick, T. M.; Babalhavaeji, A.; Tropepe, V.;
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Babalhavaeji, A.; Dong, M. X.; Woolley, G. A. Angew. Chem. Int. Ed.
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K.; Seferos, D. S.; Woolley, G. A. Chem. Commun. 2013, 49, 10314–
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Brouwer, A. M.; Saalfrank, P.; Hecht, S.; Bléger, D. Chem. – Eur. J. 2014,
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lmán, L.; Woolley, G. A. Chem. Commun. 2015, 51, 12981–12984. (i)
Castellanos, S.; GouletꢀHanssens, A.; Zhao, F.; Dikhtiarenko, A.; Pustovaꢀ
renko, A.; Hecht, S.; Gascon, J.; Kapteijn, F.; Bléger, D. Chem. – Eur. J.
2016, 22, 746–752. (j) Konrad, D. B.; Frank, J. A.; Trauner, D. Chem. –
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Chem. Soc. Rev. 2012, 41, 1809. (l) Beharry, A. A.; Woolley, G. A. Chem.
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Supporting Information. Experimental procedures and spectroscopic
data for all new compounds, including 1Hꢀ and 13CꢀNMR spectra,
UV/Vis spectra, and details of HPLC and computational experiments.
Halfꢀlives, solvent effects, quantum yield. The Supporting Inforꢀ
mation is available free of charge on the ACS Publications website at
DOI:
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Timothy R. Newhouse: 0000ꢀ0001ꢀ8741ꢀ7236
AUTHOR INFORMATION
timothy.newhouse@yale.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
(8) For heteroazobenzenes, see: (a) Wendler, T.; Schütt, C.; Naẗher, C.;
Yale University and the NSF (GRF to J.E.Z.) are acknowledged for
financial support.
Herges, R. J. Org. Chem. 2012, 77, 3284−3287. (b) Weston, C. E.; Richꢀ
ardson, R. D.; Haycock, P. R.; White, A. J. P.; Fuchter, M. J. J. Am.
Chem. Soc. 2014, 136, 11878–11881. (c) Weston, C. E.; Richardson, R.
D.; Fuchter, M. J. Chem. Commun. 2016, 52, 4521–4524. (d) Calbo, J.;
Weston, C. E.; White, A. J. P.; Rzepa, H. S.; ContrerasꢀGarcía, J.; Fuchter,
M. J. J. Am. Chem. Soc. 2017, 139, 1261–1274. (e) Coelho, P. J.; Carꢀ
valho, L. M.; Fonseca, A. M. C.; Raposo, M. M. M. Tetrahedron Lett.
2006, 47, 3711–3714.
(9) For examples of bridged azobenzenes, see: (a) Siewertsen, R.;
Neumann, H.; BuchheimꢀStehn, B.; Herges, R.; Näther, C.; Renth, F.;
Temps, F. J. Am. Chem. Soc. 2009, 131, 15594–15595. (b) Sell, H.;
Näther, C.; Herges, R. Beilstein J. Org. Chem. 2013, 9, 1–7. (c) Hamꢀ
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(10) For introduction of Lewisꢀacid substituents to azobenzenes, see:
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Am. Chem. Soc. 2017, 139, 1037–1040.
(11) For acylhydrazone photoswitches, see: (a) Vantomme, G.; Hafezi,
N.; Lehn, J. M. Chem. Sci. 2014, 5, 1475–1483. (b) van Dijken, D. J.;
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Phys. Chem. A. 2006, 110, 5665–5673. (b) Cordes, T.; Schadendorf, T.;
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(13) For a relevant review on hydrogenꢀbond interactions, see: Etter,
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