Synthesis of photocaged diamines and their application in photoinduced self-assembly

Article abstract of DOI:10.1002/poc.3935

The photochemical cleavage of covalent bonds is an important strategy in protection group chemistry, as well as for the triggering of chemical events posterior to the application of the physicochemical stimulus. Photocages allow the arresting and traceles

Full text of DOI:10.1002/poc.3935

Received: 12 October 2018
DOI: 10.1002/poc.3935
Revised: 23 December 2018
Accepted: 31 December 2018
R E S E A R C H A R T I C L E
Synthesis of photocaged diamines and their application in
photoinduced self‐assembly
Tomas Barra1 | Lily Arrue1,3 | Esteban Urzúa1 | Lars Ratjen1,2
1 Center for Bioinformatics and Integrative
Abstract
Biology (CBIB), Facultad de Ciencias
The photochemical cleavage of covalent bonds is an important strategy in pro-
tection group chemistry, as well as for the triggering of chemical events poste-
rior to the application of the physicochemical stimulus. Photocages allow the
arresting and traceless liberation of a chemical entity, which can be broadly
applied as a functional control element in materials chemistry and the life sci-
ences in general. Among the best studied and most versatile light‐sensitive
protecting groups known to date rank the o‐nitrobenzyl derivatives, entities
which are easily introduced to amines, thiols, and alcohols. Their photolability
relies on a phototautomerisation‐induced cleavage mechanism, a phenomenon
largely dependent on the substitution pattern of the aromatic ring in the
o‐nitrophenyl‐moiety. Although well described and studied in detail for the
protection of amino groups of different nature, the photocaging of aliphatic
diamines has not been described in detail to date. Because of their interesting
properties as synthons in supramolecular and polymer chemistry alike, we
wish to describe the efficient photocaging of diamines with o‐nitrobenzyl deriv-
atives, their photocleavage behavior over time, as well as their application in a
photoinduced templated self‐assembly reaction towards cyclic imines.
Biológicas, Universidad Andrés Bello,
Santiago, Chile
2 Fundación Fraunhofer Chile Research,
Centro de Biotecnología de Sistemas
(FCR‐CSB), Huechuraba, Santiago, Chile
3 Doctorado en Fisicoquímica Molecular,
Facultad de Ciencias Exactas, Universidad
Andrés Bello, Santiago, Chile
Correspondence
Lars Ratjen, Fundación Fraunhofer Chile
Research, Centro de Biotecnología de
Sistemas (FCR‐CSB), Av. del Cóndor 844,
Piso 3, Huechuraba, Santiago, Chile.
Email: lars.ratjen@fraunhofer.cl
Funding information
CONICYT, Fondecyt Iniciación en
Investigación, Grant/Award Number:
11140476; Innova‐Chile CORFO, Grant/
Award Number: FCR‐CSB 09CEII‐6991
KEYWORDS
diamines, imine formation, photocaging, photochemistry, physicochemical stimuli, self‐assembly
1 | INTRODUCTION
cleavages) and reversible transformations (eg, light‐
induced isomerizations).[3] Whereas reversible reactions
The exploitation of light energy as a driving force for
chemical transformations is of exceptional utility, since
it allows for the spatiotemporal control of reactivity on‐
demand, resulting in triggerable chemical reactions
and their associated functions.[1] Many light sources
offer the exact control of their emitted wavelengths,
discrete operational areas, and highly exact exposure
times, rendering them perfect tools for applications in
organic chemistry, material sciences, and medicine
alike.[2] Photochemical organic reactions can basically
be distinguished as irreversible (eg, photochemical bond
are commonly applied in complex systems chemistry,
dynamic materials, biomedical gating processes, and
photopharmacology,[4] irreversible reactions are more
common in light‐controlled polymerizations or as
photocleavable protection groups.[5] o‐Nitrobenzyl deriva-
tives are among the most common irreversibly light‐
cleaved molecules, and their invention is dating back to
reports by Barltrop et al,[6] and since then, they were
widely applied, greatly improved, and mechanistically
studied by various laboratories.[7] The simplicity and
straightforward synthetic manipulation render them
J Phys Org Chem. 2019;e3935.
wileyonlinelibrary.com/journal/poc
© 2019 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/poc.3935

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BARRA ET AL.
perfect for photoprotection in organic chemistry or as
highly efficient control elements in on/off and off/on pro-
cesses.[8] The mechanism involved in their photocleavage
relies on a phototautomerism (see Scheme 1), initiated by
(i) a light‐induced hydrogen transfer from the benzylic
substituent in o‐position to the NO2‐group, resulting in
(ii) an aci‐nitro‐intermediate in Z‐ or E‐form, with the
(iii) E‐aci‐nitro species cyclizing irreversibly into a
5‐membered ring. This bicyclic intermediate finally ring
opens into a transient nitroso‐alcohol, releasing the
previously protected molecule from the benzylic position,
resulting in the deprotected entity and an o‐nitroso-
benzaldehyde as a by‐product.[9]
patterns are abbreviated as follows: singlet (s), doublet
(d), multiplet (m), and broad singlet (bs). UV/VIS spectra
were recorded using quartz cuvettes on a Varian Cary 50
spectrophotometer, equipped with a thermostated cell
holder at 25
0.1°C. For irradiation experiments,
ThorLabs LEDs (365 and 405 nm) were applied, coupled
with a collimator and optical fiber to direct and
concentrate light beams onto the sample solutions.
Ultraperformance liquid chromatography coupled to
mass spectrometry detection (UPLC‐MS) was performed
with a Waters Alliance system (gradient mixture of
acetonitrile/water) equipped with Acquity UPLC col-
umns. The Waters system consisted of a Waters Separa-
tions Module 2695, a Waters Diode Array Detector 996,
an LCT Premier XE mass spectrometer, and a Waters
Mass Detector ZQ 2000.
Therefore, it is no surprise that electron‐donating sub-
stituents in the aromatic ring facilitate the reaction, and
the most commonly applied o‐nitrobenzyl derivatives
bear the 4,5‐MeO‐substitution pattern or other electron
rich groups (see Scheme 1, right hand side).[10]
Despite the fact that the photochemical properties,
quantum yields, and reactivities of differently substituted
o‐nitrobenzyl derivatives are well studied,7a we were
intrigued by their application towards the photocaging
of diamines, as they are representing viable substrates in
polymerizations and self‐assembly reactions alike.[11]
2.1.1 | 2‐Nitrobenzyl(4‐nitrophenyl)
carbonate
4.28 g (1.3 Eq, 21.23mmol) 4‐nitrophenyl chloroformate
was dissolved in 100 mL dry THF and subsequently cooled
to 0°C. Then, 1.71 mL (1.3 Eq, 21.23mmol) pyridine was
added to the solution dropwise and the mixture left stir-
ring for 30 minutes. Subsequently, 2.50 g (1.0 Eq,
16.33mmol) of 2‐nitrobenzyl alcohol dissolved in 50 mL
dry THF was added over 10 minutes and the resulting mix-
ture left stirring for 16 hours at room temperature. Then,
100 mL CH2Cl2 was added to the mixture and then trans-
ferred to a separation funnel and washed with 1M HCl
(3 × 50 mL) and brine (1 × 80 mL). The aqueous layer
was reextracted with CH2Cl2 (2 × 50 mL) and the unified
organic phases dried over MgSO4. The solvent was
removed in vacuo and the crude product purified by
recrystallization from a mixture of ethyl acetate/petrol
ether 40‐60 and washed with cold petrol ether, giving
4.54 g (14.23mmol, 87% yield) of an off‐white solid. Analyt-
2 | EXPERIMENTAL
2.1 | Materials and apparatus
Solvents (anhydrous and nonanhydrous) and commercial
starting materials were used as received. Reactions were
monitored by thin layer chromatography (TLC) carried
out on silica gel plates (Merck 60F‐254) using UV light
for visualization. Column chromatography was carried
out with standard silica gel on normal phase (Merck 60,
particle size 0.040 to 0.063 mm). Nuclear magnetic reso-
nance (NMR) spectra were recorded on a Bruker DPX
1
1
300 (300 MHz for H, 75 MHz for 13C) spectrometer at
ics: H‐NMR (300 MHz, CDCl3) δ [ppm]: 5.74 (s, 2H,
25°C using residual protonated solvent signals as internal
standards for 1H and 13C spectra (1H: δ (CDCl3) =
7.26 ppm, 13C: δ (CDCl3) = 77.16 ppm). The splitting
―CH2O―), 7.42 (d, 2H, 3J = 9.2 Hz, Ar‐H), 7.55‐7.62 (m,
1H, Ar‐H), 7.71‐7.77 (m, 2H, Ar‐H), 8.20 (d, 1H,
3
3J = 8.8 Hz), 8.29 (d, 2H, J = 9.2 Hz, Ar‐H). 13C‐NMR
SCHEME 1 Photochemical cleavage of o‐nitrobenzyl derivatives with transient species; most efficiently cleaved o‐nitrobenzyl derivative
because of electron‐donating substitutions (box on right hand side)

BARRA ET AL.
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(75 MHz, CDCl3) δ [ppm]: 67.5, 121.9, 125.5, 125.7, 129.2,
129.7, 130.7, 134.3, 145.7, 147.5, 152.2, 155.5. UV‐VIS
(λmax): 265 nm.
―CH2O―), 6.83 (s, 1H, Ar‐H). 13C‐NMR (75 MHz,
CDCl3) δ [ppm]: 56.4, 61.3, 61.6, 62.6, 106.9, 130.0,
138.4, 142.1, 147.0, 155.8.
2.1.2 | 4,5‐Dimethoxy‐2‐nitrobenzyl(4‐
nitrophenyl)carbonate
2.1.4 | 3,4,5‐trimethoxy‐2‐nitrobenzyl(4‐
nitrophenyl)carbonate
3.07 g (1.3 Eq, 15.24mmol) 4‐nitrophenyl chloroformate
was dissolved in 100 mL dry THF and subsequently
cooled to 0°C. Then, 1.23 mL (1.3 Eq, 15.24mmol) pyri-
dine was added to the solution dropwise and the mixture
left stirring for 30 minutes. Subsequently, 2.50 g (1.0 Eq,
11.73mmol) of 4,5‐dimethoxy‐2‐nitrobenzyl alcohol dis-
solved in 50 mL dry THF was added over 10 minutes
and the resulting mixture left stirring for 16 hours at
room temperature. Then, 100 mL CH2Cl2 was added to
the mixture and then transferred to a separation funnel
and washed with 1M HCl (3 × 50 mL) and brine
(1 × 80 mL). The aqueous layer was reextracted with
CH2Cl2 (2 × 50 mL) and the unified organic phases dried
over MgSO4. The solvent was removed in vacuo and the
crude product purified by recrystallization from a mixture
of ethyl acetate/petrol ether 40‐60 and washed with cold
petrol ether, giving 3.43 g (9.07mmol, 77% yield) of a
slightly yellow solid. Analytics: 1H‐NMR (300 MHz,
CDCl3) δ [ppm]: 3.98 (s, 3H, CH3O―), 4.02 (s, 3H,
CH3O―), 5.71 (s, 2H, ―CH2O―), 7.10 (s, 1H, Ar‐H),
1.2 g (1.3 Eq, 6.41mmol) 4‐nitrophenyl chloroformate was
dissolved in 30 mL dry THF and subsequently cooled to
0°C. Then, 0.52 mL (1.3 Eq, 6.41mmol) pyridine was
added to the solution dropwise and the mixture left stir-
ring for 30 minutes. Subsequently, 1.20 g (1.0 Eq,
4.94mmol) of 3,4,5‐trimethoxy‐2‐nitrobenzyl alcohol dis-
solved in 20 mL dry THF was added over 10 minutes
and the resulting mixture left stirring for 16 hours at
room temperature. Then, 100 mL CH2Cl2 was added to
the mixture and then transferred to a separation funnel
and washed with 1M HCl (3 × 20 mL) and brine
(1 × 40 mL). The aqueous layer was reextracted with
CH2Cl2 (2 × 30 mL) and the unified organic phases dried
over MgSO4. The solvent was removed in vacuo and the
crude product purified by column chromatography over
silica gel with ethyl acetate/petrol ether 40‐60 mixtures
(5:1 to 1:1), resulting in the product in quantitative
1
amounts as a slightly yellow solid. Analytics: H‐NMR
(300 MHz, CDCl3) δ [ppm]: 3.91 (s, 3H, CH3O―), 3.94
(s, 3H, CH3O―), 4.00 (s, 3H, CH3O―), 5.30 (s, 2H,
3
3
7.41 (d, 2H, J = 9.2 Hz, Ar‐H), 7.77 (s, 1H, Ar‐H), 8.29
―CH2O―), 6.80 (s, 1H, Ar‐H), 7.38 (d, 2H, J = 9.3 Hz,
3
(d, 2H, J = 9.2 Hz, Ar‐H). 13C‐NMR (75 MHz, CDCl3) δ
Ar‐H), 8.27 (d, 2H, 3J = 9.3 Hz, Ar‐H). 13C‐NMR
(75 MHz, CDCl3) δ [ppm]: 56.6, 61.3, 62.6, 66.5, 107.7,
121.9, 123.0, 125.5, 126.3, 143.3, 145.6, 147.2, 152.2,
155.4, 155.5. UV‐VIS (λmax): 265 nm, 340 nm.
[ppm]: 56.6, 56.7, 67.8, 108.5, 110.7, 121.9, 125.2, 125.5,
140.1, 145.6, 148.9, 152.2, 153.8, 155.5. UV‐VIS (λmax):
246 nm, 343 nm.
2.1.3 | (3,4,5‐trimethoxy‐2‐nitrophenyl)‐
methanol
2.1.5 | Bis(4,5‐dimethoxy‐2‐nitrobenzyl)
((ethane‐1,2‐diylbis (oxy))bis (ethane‐2,1‐
diyl))‐di‐carbamate
3.0 g (1.0 Eq, 11.06mmol) methyl‐3,4,5‐trimethoxy‐2‐
nitrobenzoate were dissolved in 50 mL dry toluene under
an atmosphere of argon and cooled to −20°C (ice‐NaCl
mixture). Subsequently, a solution of DIBAL‐H in toluene
(1.2M, 1.25 Eq, 13.27mmol, 11.06 mL) was added slowly
over 10 minutes. The reaction was left stirring for 2 hours
at room temperature, after which the mixture was treated
with MeOH, diluted with H2O, and transferred to a sepa-
ration funnel. The reaction was extracted with ethyl ace-
tate (3 × 100 mL) and the unified extracts dried over
MgSO4, filtered, and evaporated to dryness. The resulting
crude material was purified by column chromatography
(ethyl acetate/petrol ether 40‐60, 1:3), resulting in a yel-
54.2 mg (55 μL, 0.366mmol, 1.0 Eq) 2,2’‐(ethane‐1,2‐
diylbis‐(oxy))‐diethanamine and 304.6 mg (0.805mmol,
2.2 Eq) 4,5‐dimethoxy‐2‐nitrobenzyl‐(4‐nitrophenyl)‐car-
bonate were dissolved in 19 mL dry CH3CN. Subse-
quently, 104.1 mg (137 μL, 0.805mmol, 2.2 Eq) DIPEA
were added and the resulting mixture stirred at reflux
overnight. The solvent was evaporated to dryness and
purified by column chromatography on SiO2 (cyclohex-
ane/ethyl acetate 1:1), giving the title compound in quan-
titative amounts as a slight yellow solid. Analytics:
1H‐NMR (300 MHz, CDCl3) δ [ppm]: 3.38‐3.42 (m, 4H,
―CH2―), 3.56‐3.58 (m, 4H, ―CH2―), 3.61 (bs, 4H,
―CH2―), 3.93 (s, 6H, CH3O―), 3.95 (s, 6H, CH3O―),
5.46 (bs, 6H, ―CH2O― and ―NH―), 6.97 (s, 2H, Ar‐
H), 7.66 (s, 2H, Ar‐H). 13C‐NMR (75 MHz, CDCl3) δ
1
low solid (1.55 g, 6.37mmol, 58% yield). Analytics: H‐
NMR (300 MHz, CDCl3) δ [ppm]: 3.89 (s, 3H, CH3O―),
3.93 (s, 3H, CH3O―), 3.90 (s, 3H, CH3O―), 4.62 (s, 2H,

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BARRA ET AL.
[ppm]: 41.0, 56.5, 63.7, 70.1, 70.4, 108.2, 110.6, 128.0,
140.0, 148.2, 153.6, 156.1. MS (ESI+) m/z: 627.214
(M + H+), calcd. 610.215. UV‐VIS (λmax): 346 nm.
2.1.8 | Bis(4,5‐dimethoxy‐2‐nitrobenzyl)
(oxybis (ethane‐2,1‐diyl))dicarbamate
49.0 mg (50 μL, 0.471mmol, 1.0 Eq) 2,2’‐oxydiethanamine
and 391.6 mg (1.035mmol, 2.2 Eq) 4,5‐dimethoxy‐2‐
nitrobenzyl‐(4‐nitrophenyl)‐carbonate were dissolved in
24 mL dry CH3CN. Subsequently, 133.8 mg (176 μL,
1.035mmol, 2.2 Eq) DIPEA were added and the resulting
mixture stirred at reflux overnight. The solvent was evap-
orated to dryness and purified by column chromatogra-
phy on SiO2 (cyclohexane/ethyl acetate 1:1), giving
257 mg (0.441mmol, 94 % yield) of the title compound
2.1.6 | Bis(2‐nitrobenzyl)((ethane‐1,2‐
diylbis (oxy))bis (ethane‐2,1‐diyl))
dicarbamate
54.2 mg (55 μL, 0.366mmol, 1.0 Eq) 2,2′‐(ethane‐1,2‐
diylbis (oxy))‐diethanamine and 256.3 mg (0.805mmol,
2.2 Eq) 2‐nitrobenzyl‐(4‐nitrophenyl)‐carbonate were dis-
solved in 20 mL dry CH3CN. Subsequently, 104.1 mg
(137 μL, 0.805mmol, 2.2 Eq) DIPEA were added and the
resulting mixture stirred at reflux overnight. The solvent
was evaporated to dryness and purified by column chro-
matography on SiO2 (cyclohexane/ethyl acetate 1:1), giv-
ing 159 mg (0.314mmol, 86 % yield) of the title
1
as a slight yellow solid. Analytics: H‐NMR (300 MHz,
DMSO) δ [ppm]: 3.16‐3.20 (m, 4H, ―CH2―), 3.42‐3.44
(m, 4H, ―CH2―), 3.86 (s, 6H, CH3O―), 3.88 (s, 6H,
CH3O―), 5.31 (s, 4H, ―CH2O―), 7.16 (s, 2H, Ar‐H),
7.49‐7.51 (m, 2H, ―NH―), 7.67 (s, 2H, Ar‐H). 13C‐NMR
(75 MHz, DMSO) δ [ppm]: 56.1, 56.2, 62.4, 68.9, 108.1,
110.5, 127.9, 139.2, 147.7, 153.3, 155.8. MS (ESI+) m/z:
583.187 (M + H+), calcd. 583.189. UV‐VIS (λmax): 346 nm.
1
compound as a slight yellow solid. Analytics: H‐NMR
(300 MHz, CDCl3) δ [ppm]: 3.38‐3.41 (m, 4H, ―CH2―),
3.56‐3.59 (m, 4H, ―CH2―), 3.61 (bs, 4H, ―CH2―),
5.47‐5.53 (m, 6H, ―CH2O― and ―NH―), 7.42‐7.45 (m,
2H, Ar‐H), 7.55‐7.57 (m, 2H, Ar‐H) 7.59‐7.62 (m, 2H,
Ar‐H),8.05 (d, J = 8.2 Hz, 2H). 13C‐NMR (75 MHz,
CDCl3) δ [ppm]: 41.0, 63.4, 70.0, 70.4, 125.0, 128.6,
128.9, 133.7, 147.4, 156.0. MS (ESI+) m/z: 524.16
(M + H2O), 507.14 (M + H+). UV‐VIS (λmax): 265 nm.
3 | RESULTS AND DISCUSSION
The incorporation of photocaged molecules into a
system designed to self‐assemble renders light an ideal
trigger to start the chemical reaction, or more general,
to trigger the associated event. To introduce the
o‐nitrobenzyl group to amines, the most common strategy
leads through the corresponding p‐nitrophenyl‐(PNP)‐
carbonates, since the PNP‐group represents an excellent
leaving group upon nucleophilic attacks.[12] To pursue
our endeavors, we synthesized different (mainly
electron‐rich) candidates from commercially available
o‐nitrobenzyl alcohols and p‐nitrophenyl chloroformate.
This simple one‐pot procedure with pyridine as an acti-
vating agent gave the corresponding products 1‐3 in good
to excellent yields (see Figure 1, left side). Since we were
intrigued by the results of Cummings and Krafft[13] on
the virtual unreactivity of the 3,4,5‐MeO‐substituted
o‐nitrobenzyl‐group, we synthesized the related carbon-
ate 3 in two steps from the ester as well (see Figure 1,
top right) to gain more insight into these molecules.[14]
First, we studied the synthesized carbonates by UV‐
spectroscopy (in CH3CN as a solvent) to corroborate the
aforementioned reactivity trends. The unsubstituted car-
bonate 1 shows an absorption maximum at λ = 265 nm,
and the 4,5‐MeO‐substituted 2 two maxima at λ = 246
and 343 nm, respectively, with a curve fading further into
the 400 nm range. The 3,4,5‐MeO‐derivative 3 shows a
maximum at λ = 265 nm and a slightly wider shoulder into
the 400 nm range as compared with 1, nevertheless with
much lower intensities than 2 (at equal concentration in
2.1.7 | Bis(3,4,5‐trimethoxy‐2‐nitrobenzyl)
((ethane‐1,2‐diylbis (oxy))bis (ethane‐2,1‐
diyl))di‐carbamate
54.2 mg (55 μL, 0.366mmol, 1.0 Eq) 2,2’‐(ethane‐1,2‐
diylbis‐(oxy))‐diethanamine and 304.6 mg (0.805mmol,
2.2 Eq) 4,5‐dimethoxy‐2‐nitrobenzyl‐(4‐nitrophenyl)‐car-
bonate were dissolved in 20 mL dry CH3CN. Subse-
quently 104.1 mg (137 μL, 0.805mmol, 2.2 Eq) DIPEA
were added and the resulting mixture stirred at reflux
overnight. The solvent was evaporated to dryness and
purified by column chromatography on SiO2 (cyclohex-
ane/ethyl acetate 1:1), giving 245 mg (0.358mmol, 98 %
yield) of the title compound as a slight yellow solid. Ana-
1
lytics: H‐NMR (300 MHz, CDCl3) δ [ppm]: 3.33‐3.36 (m,
4H, ―CH2―), 3.52‐3.54 (m, 4H, ―CH2―), 3.58 (bs, 4H,
―CH2―), 3.87 (s, 6H, CH3O―), 3.89 (s, 6H, CH3O―),
3.95 (s, 6H, CH3O―), 5.07 (s, 4H, ―CH2O), 5.38 (bs,
2H, NH―), 6.72 (s, 2H, Ar‐H). 13C‐NMR (75 MHz,
CDCl3) δ [ppm]: 41.0, 56.4, 61.3, 62.5, 70.0, 70.4, 107.5,
125.4, 139.0, 142.5, 146.7, 155.2, 155.9. MS (ESI+) m/z:
704.24 (M + H2O), 687.24 (M + H+). UV‐VIS (λmax):
255 nm, 360 nm.

BARRA ET AL.
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FIGURE 1 Synthesis of differently substituted o‐nitrobenzyl‐(PNP)‐carbonates 1‐3 and their corresponding UV‐spectra
CH3CN). Considering these absorption spectra, it was no
surprise that 1 and 2 also performed substantially better
in photocleavage experiments when irradiated with a
365 nm LED light under constant reaction control. Car-
bonate 2 was the most efficiently cleaved candidate as
indicated by the initial spectral change, whereas 3 showed
virtually no change even after 30 minutes of irradiation at
a wavelength of 365 nm, very much in line with the previ-
ous results reported by Cummings and Krafft.[13]
Considering our goal of the implementation of a pho-
toinduced templated self‐assembly reaction of iminoid
macrocycles, we turned our attention to the development
of a synthetic protocol for the photoprotection of different
aliphatic diamines. We deemed the commercially avail-
able 2,2′‐(ethane‐1,2‐diylbis‐(oxy))‐diethanamine as the
most appropriate for the templated self‐assembly of
macrocycles following different reports by Haussmann
et al,[15] although we synthesized photocaged ethyle-
nediamine and 2,2′‐oxydiethaneamine as well. Oxygen‐
containing diamines are generally more favorable for
templated self‐assembly reactions, since they add multiple
coordination sites for metal centers into a system. The syn-
thetic protocol we developed involves the corresponding
p‐nitrophenyl‐carbonates 1‐3 and the respective diamines,
using Hünig's base (DIPEA) as a base, under refluxing con-
ditions in acetonitrile. This protocol gave us the resulting
products 4‐6 in good to excellent yields (see Figure 2).
From the respective UV absorption spectra, it became
very clear that candidate 5 is the most viable for photoin-
duced release applications, since it shows a strong absorp-
tion maximum at λ = 346 nm. As expected from previous
studies and our own results, the 3,4,5‐MeO‐substituted
derivate 6 did not show any significant absorption maxi-
mum in the UV/VIS range. In the photocleavage experi-
ments of the corresponding photocaged diamines, we
compared their light‐induced photo deprotection over
time (see Figure 3). It was no surprise that 4 and 5 per-
formed significantly better than 6 (see Figure 3, top vs
bottom right), with candidate 5 being superior to 4 as
shown by the faster initial spectral change rate, indicating
a more efficient liberation of the diamine and better avail-
ability for a following self‐assembly reaction in the tenta-
tive supramolecular assembly application. The absorption
spectrum of 5 and its fading into the 400 nm range possi-
bly opens up the photocleavage in the visible light range,
a theory we could actually prove by using a 405 nm LED
light in the photo uncaging experiment (see Figure 3, bot-
tom left). This fact is especially interesting for applica-
tions in medicine, where light of longer wavelengths is
vital for its application in tissue, allowing for a deeper tis-
sue penetration as a function of longer wavelengths.[16]
With these results in hand, we turned our attention
towards the application of photocaged diamines in
photoinduced self‐assembly reactions with dialdehydes
in a reversible condensation fashion. We chose an experi-
mental setup with commercially available 2,6‐pyridi-
nedialdehyde,[17] our photoprotected diamine 5, and Zn
(OTf)2 as a templating metal source, since it is easily avail-
able and compatible with in situ NMR experiments. As a
first reaction, we carried out a control experiment to
exclude the existence of background reactions of any type.
For this purpose, we mixed the 2,6‐pyridinedialdehyde,

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BARRA ET AL.
FIGURE 2 Synthesis of different photocaged diamines 4‐6 and corresponding UV‐spectra
FIGURE 3 Photocleavage of caged diamines 4,5, and 6 over time and at different wavelengths (365 vs 405 nm)
photocaged diamine 5, and Zn(OTf)2 in equimolar
amounts in a 1:1 mixture of CDCl3/CD3CN at 0.2M con-
centration. The resulting 1H‐NMR spectrum virtually
resembles the reactants, without additional aldehyde or
aromatic peaks indicative for any significant background
reaction (see Figure 4a).
The next experiment we carried out was the stoichiomet-
ric mixture of 2,6‐pyridinedialdehyde, free 2,2’‐(ethane‐1,2‐
diylbis (oxy))‐diethanamine, and Zn(OTf)2 in equimolar
amounts in a 1:1 mixture of CDCl3/CD3CN at 0.2M concen-
tration. After heating this mixture to 60°C for equilibration
of the reversible reaction, we obtained a 1H‐NMR‐spectrum

BARRA ET AL.
7 of 8
FIGURE 4 A photoinduced self‐assembly reaction featuring (a) background reaction of dialdehyde, photocaged diamine 5, and Zn (OTf)2;
(b) reaction of dialdehyde, noncaged diamine, and Zn (OTf)2; and (c) dialdehyde, photocaged diamine 5, and Zn (OTf)2 after irradiation with
UV light of λ = 365 nm
of a mixture of two major species. These peaks are likely
indicative for [n + n]‐macrocycles, and the clean nature of
the NMR‐spectrum shows that the reaction mixture is
approaching to or had reached an equilibrium state (see
Figure 4b).
4 | CONCLUSIONS
In summary, we demonstrated the potential of o‐nitro-
benzyl derivatives as photosensitive protection groups for
synthetically important diamines. Our utilization of these
molecules in self‐assembly reactions triggered by light is
showcasing only one possible application of photocaged
diamines. Many other diamines of aromatic and aliphatic
nature are important building blocks in systems chemistry
and materials, thus rendering the application of light per-
fect to trigger these systems. Although we did focus on reg-
ular o‐nitrobenzyl derivatives in this study, the fact that
photocages cleavable at longer wavelengths are developed
regularly enables the application of photocaged diamines
in life sciences for the future.
Finally, in an experiment otherwise identical to the
one reported in Figure 4a, we irradiated the corresponding
sample with an LED of λ = 365 nm for 200 minutes, then
equilibrated the mixture at 60°C for 1 hour, and subse-
quently analyzed the 1H‐NMR‐spectrum. We were pleased
to find a clean and virtually identical spectrum of one of
the species observed in the spectrum of Figure 4b.
Although we were not able to clearly identify whether a
[1 + 1]‐ or a [2 + 2]‐macrocycle was formed, previous
reports on similar molecules indicate that strain renders
formations of [2 + 2]‐macrocycle more likely.15a In any
case, it became quite clear that the effect of diamine
photocaging was beneficiary for an ordered formation of
dialdehyde/diamine adducts. One can presume that the
consecutive liberation of the diamine leads through path-
ways involving Zn‐coordinated intermediates.
ACKNOWLEDGEMENTS
We gratefully acknowledge funding from CONICYT,
Fondecyt Iniciación en Investigación Program No.
11140476. We thank Prof. Dr. Stefan Hecht, the research

8 of 8
BARRA ET AL.
[6] a) J. A. Barltrop, P. Schofield, Tetrahedron Lett. 1962, 3, 697.
b) J. A. Barltrop, P. J. Plant, P. Schofield, Chem. Commun.
1966, 822.
lab at the Laboratory of Organic Chemistry and Func-
tional Materials in the Department of Chemistry, and
the Humboldt‐Universität zu Berlin, Germany for gener-
ous support and collaboration during the conduct of
experiments and analytics, as well as for helpful sugges-
tions during the preparation of this manuscript. Further-
more, we thank CORFO for basic funding, Proyecto
Fraunhofer Chile Research, Innova‐Chile CORFO (FCR‐
CSB 09CEII‐6991).
[7] a) P. Klán, T. Šolomek, C. G. Bochet, A. Blanc, R. Givens, M.
Rubina, V. Popik, A. Kostikov, J. Wirz, Chem. Rev. 2013, 113,
119. b) J. W. Walker, G. P. Reid, J. A. McCray, D. R. Trentham,
J. Am. Chem. Soc. 1988, 110, 7170. c) R. W. Yip, D. K. Sharma,
Res. Chem. Intermed. 1989, 11, 109.
[8] C. P. Ramil, Q. Lin, Curr. Opin. Chem. Biol. 2014, 21, 89.
[9] Y. V. Il'ichev, M. A. Schwörer, J. Wirz, J. Am. Chem. Soc. 2004,
126, 4581.
ORCID
[10] C. A. DeForest, K. S. Anseth, Angew. Chem. Int. Ed. Engl. 2012,
51, 1816.
Lars Ratjen https://orcid.org/0000-0001-7739-6371
[11] a) X.‐G. Li, M.‐R. Huang, W. Duan, Y.‐L. Yang, Chem. Rev. 2002,
102, 2925. b) D. Pingen, J. P. Schwaderer, J. Walter, J. Wen, G.
Murray, D. Vogt, S. Mecking, ChemCatChem 2018, 10, 3027. c)
S. Yagai, A. Kitamura, Chem. Soc. Rev. 2008, 37, 1520.
REFERENCES
[1] a) J.‐M. Lehn, Angew. Chem. Int. Ed. 2015, 54(11), 3276. b) D.
D. Young, W. F. Edwards, H. Lusic, M. O. Lively, A. Deiters,
Chem. Commun. 2008, 462.
[12] I.‐H. Um, E. Y. Kim, H.‐R. Park, S.‐E. Jeon, J. Org. Chem. 2006,
71, 2302.
[13] R. T. Cummings, G. A. Krafft, Tetrahedron Lett. 1988, 29, 65.
[2] a) D. Phillips, Photochem. Photobiol. Sci. 2010, 9, 1589. b) M.‐M.
Russew, S. Hecht, Adv. Mater. 2010, 22, 3348.
[14] M. V. R. Reddy, B. Akula, S. C. Cosenza, C. M. Lee, M. R.
Mallireddigari, V. R. Pallela, D. R. C. Venkata Subbaiah, A.
Udofa, E. P. Reddy, J. Med. Chem. 2012, 55, 5174.
[3] a) X. Bai, Z. Li, S. Jockusch, N. J. Turro, J. Ju, Proc. Natl. Acad.
Sci. 2003, 100, 409. b) A. A. Beharry, G. A. Woolley, Chem. Soc.
Rev. 2011, 40, 4422. c) R. Schmidt, D. Geissler, V. Hagen, J.
Bendig, J. Phys. Chem. A 2007, 111, 5768.
[15] a) P. C. Haussmann, S. I. Khan, J. F. Stoddart, J. Org. Chem.
2007, 72, 6708. b) S. Ulrich, J.‐M. Lehn, J. Am. Chem. Soc.
2009, 131, 5546. c) L. Ratjen, G. Vantomme, J.‐M. Lehn, Chem.
– Eur. J. 2015, 21, 10070.
[4] a) M. Banghart, K. Borges, E. Isacoff, D. Trauner, R. H.
Kramer, Nat. Neurosci. 2004, 7, 1381. b) M. M. Lerch, M. J.
Hansen, G. M. van Dam, W. Szymanski, B. L. Feringa, Angew.
Chem. Int. Ed. 55, 2016, 10978. c) M. Kathan, S. Hecht, Chem.
Soc. Rev. 2017, 46, 5536. d) C.‐Y. Huang, A. Bonasera, L.
Hristov, Y. Garmshausen, B. M. Schmidt, D. Jacquemin, S.
Hecht, J. Am. Chem. Soc. 2017, 139, 15205.
[16] A. M. Smith, M. C. Mancini, S. Nie, Nat. Nanotechnol. 2009, 4, 710.
[17] M. Albrecht, Y. Yulia, A. Exarchos, P. Nachev, R. Fröhlich,
Dalton Trans. 2009, 7421.
How to cite this article: Barra T, Arrue L, Urzúa
E, Ratjen L. Synthesis of photocaged diamines and
their application in photoinduced self‐assembly. J
Phys Org Chem. 2019;e3935. https://doi.org/
10.1002/poc.3935
[5] a) F. Bella, R. Bongiovanni, J. Photochem. Photobiol.
C
Photochem. Rev. 2013, 16, 1. b) C. Chang, B. Niblack, B. Walker,
H. Bayley, Chem. Biol. 1995, 2, 391. c) C. G. Bochet, J. Chem.
Soc. Perkin Trans. 2002, 125. d) H. Zhao, E. S. Sterner, E. B.
Coughlin, P. Theato, Macromolecules 2012, 45, 1723.