Uncaging Alcohols Using UV or Visible Light Photoinduced Electron Transfer to 9-Phenyl-9-tritylone Ethers

Article abstract of DOI:10.1021/acs.orglett.5b02924

The clean and efficient photorelease of primary and secondary alcohols is reported from the deprotection of a new photoremovable protecting group, the 9-phenyltritylone (PTO) group. Deprotection is initiated by 350 nm excitation of the PTO chromophore in the presence of triethylamine or using 447 nm light in the presence of a visible light absorbing photocatalyst and triethylamine. Laser flash photolysis results are reported in support of a proposed deprotection mechanism for the release of alcohols on a ca. 20 μs time scale.

Full text of DOI:10.1021/acs.orglett.5b02924

Letter
pubs.acs.org/OrgLett
Uncaging Alcohols Using UV or Visible Light Photoinduced Electron
Transfer to 9‑Phenyl-9-tritylone Ethers
Derek M. Denning, Nichole J. Pedowitz, Matthew D. Thum, and Daniel E. Falvey*
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
S
* Supporting Information
ABSTRACT: The clean and efficient photorelease of primary and
secondary alcohols is reported from the deprotection of a new
photoremovable protecting group, the 9-phenyltritylone (PTO) group.
Deprotection is initiated by 350 nm excitation of the PTO
chromophore in the presence of triethylamine or using 447 nm light
in the presence of a visible light absorbing photocatalyst and triethylamine. Laser flash photolysis results are reported in support
of a proposed deprotection mechanism for the release of alcohols on a ca. 20 μs time scale.
nterest in spatiotemporal control of molecular concentrations
has motivated the development of photoremovable protecting
absorbing step from the bond-breaking chemistry allowing for
broad spectral response (UV and visible light). Successful
examples include phenacyl19 and NAP groups,20 triplet
sensitized nitrophenyl groups,21 and phenethyl alcohol sys-
tems.22 This report describes the simple release of alcohols in
good yields under 350 or 447 nm light. Laser flash photolysis and
product analysis experiments help identify intermediates and
products driving the mechanism proposed for the photochemical
deprotection of alcohols using the PTO group.
I
groups (PPGs).1 Photorelease strategies have found applications
in several areas: synthesis of complex molecules,2 photo-
lithography,3 time-resolved studies of enzymatic and cellular
processes,4 controlled release of drugs,5 optogenetics,6 photo-
imaging,7 and the development of light driven self-assembly of
supramolecular structures.8,20b Recent developments include the
coumaryl group,9 BODIPY derivatives,10 phenacyl groups,11
fluorescein analogues,12 and meta-substituted arylmethyl
groups.13
ΔGET ≈ 23.06(Eox − Ered) − E00 − S
(1)
All of these PPGs provide excellent options for the protection
and photorelease of relatively good leaving groups such as
phosphates, sulfonates, carboxylates, etc. In the case of less labile
leaving groups such as alcohols, there are fewer options. One
approach is to protect the OH group as a mixed carbonate ester
and rely on the spontaneous decarboxylation of the mono-
carbonic ester to release the alcohol.9a−c Other avenues for
alcohol release include photoisomerization and intramolecular
cyclization of silyl14a and cinnamate14b derivatives, photo-
enolization,15 naphthylenyl derivatives,16 and the direct
photolysis of trityl ethers.17
The PTO-ethers, shown in Scheme 1, were prepared through
acid-catalyzed condensation of 9-hydroxy-9-phenyltritylone 1
with the corresponding alcohols. As with previous reports, we
Scheme 1. Synthesis and Scope of PTO-Ethers
While photorelease of alcohols can be effected using ultraviolet
(UV) light, there is particular interest in the development of
PPGs capable of using visible or near-infrared light. High
wavelengths are particularly valuable in situations where the OH
group is part of a structure that contains other chromophores.
For example, 55 (36.7%) of the top 150 small molecule
pharmaceutical products (2012 retail sales)18 contain primary or
secondary OH groups. In contrast, the CO2H group, which has
dominated PPG development, is only observed in 16.7% of that
group. Additionally, of the 55 primary and secondary OH
containing drugs, 49 had aromatic rings or α,β-unsaturated
carbonyl moieties capable of absorbing UV. Thus, the develop-
ment of new PPGs for alcohols utilizing high wavelength light is
an important endeavor.
Herein, is described the 9-phenyl-9-tritylone (PTO) group,
which releases alcohols via photoinduced electron transfer
(PET). PET systems provide a means for decoupling the light-
Received: October 8, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02924
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
find that primary alcohols are most readily protected in the best
yields, whereas secondary alcohols are less reactive and provide
lower yields of PTO-ether. We, and previous investigators,23
were unsuccessful in attempts to protect tertiary alcohols.
While the PTO group has been previously described as a
protecting group for alcohols,24 the behavior of the PTO-ethers
toward PET has not been reported. Using previously reported25
reduction potentials for PTO-ethers (Ered = −1.30 to 1.36 V vs
Ag/AgCl), and assuming PTO has the same triplet state energy
as benzophenone,26 eq 1 predicts that PET from triethylamine
(TEA, Eox = +1.15 V vs SCE)27 to the PTO-ethers is exergonic by
ca. 13 kcal/mol.28 It was further anticipated that the resulting
PTO radical anion would undergo C−O bond-breaking leading
to the deprotection and recovery of the alcohol. The photolysis
experiments summarized in Table 1 confirm this hypothesis.
Table 2. Relative Yields of 1-Octanol in the 60 min Photolysis
at 350 nm of 2a and a Donor in Various Solvents
c
[2a], mM
donor
[donor], mM
solvent
MeOH
relative yield
11.3
11.3
11.3
TEA
TEA
TEA
TEA
DMA
DBU
anisole
TEA
TPA
TEA
TEA
28.7
14.3
5.65
27.0
28.4
29.5
27.3
28.7
28.7
28.7
28.7
32.6
1.00 1.00
0.98 0.65
0.84 1.80
0.38 0.21
0.40 0.27
0.64 1.08
0.79 2.19
0.63 0.55
0.37 0.76
0.98 3.26
0.52 0.53
0.59 0.46
MeOH
MeOH
a
10.4
MeOH
b
10.4
MeOH
10.4
10.4
10.8
11.0
11.8
10.9
10.0
MeOH
MeOH
1,4-dioxane
1,4-dioxane
MeCN
benzene
tert-BuOH
TEA
a
b
Purged with O2. Average of two runs; peaks of donor and ROH not
Table 1. Yield of Released Alcohols Following 240 min of 350
nm Irradiation As Analyzed by GC
c
well resolved. Photolysis reactions were performed in triplicate.
b
c
transfers from the oxidized donor. The bicyclic structure of DBU
inhibits proton transfer from DBU+•. Indeed DBU provides a
lower yield, suggesting that such proton transfers play a role in
the release mechanism. Finally, product yields can be inhibited
using a triplet quencher (ground state O2). We attribute this
decrease in photochemical efficiency to triplet energy transfer
from excited state PTO competing with the desired PET
pathway.
ether
[ether], mM [TEA], mM
solvent(s)
MeOH
MeOH
% yield
2a
11.4
2.80
8.99
11.8
11.9
7.24
5.75
21.5
5.38
26.9
21.5
21.5
17.9
17.9
91.0 1.82
82.3 1.56
92.2 1.59
31.6 0.63
82.3 3.63
63.7 1.68
77.4 5.12
a
2b
2c
2d
2e
2f
MeOH/dioxane
MeOH/dioxane
MeOH/dioxane
MeOH/dioxane
2g
MeOH/dioxane
These results above imply that formation of the PTO anion
radical 3 is sufficient for the desired C−O bond scission. Thus, it
should be possible to initiate the reaction using visible light
absorbing sensitizers as outlined in Scheme 2. In this case, rather
a
b
25 min photolysis; analyzed by HPLC. 1,4-Dioxane (25% v/v except
ether 2d where 12.5% was used) added to help solubilize ether at
concentrations used. Photolysis reactions were performed in
triplicate.
c
Scheme 2. Proposed Mechanism for the Release of Alcohols
under (a) Direct UV Irradiation, (b) Oxidative, and (c)
Reductive Visible Light Irradiation
Photolysis of ethers 2a−g at 350 nm in the presence of TEA
cleanly releases the alcohol. 3′-O-Acetylthymidine, benzyl
alcohol, cyclohexanol, benzhydrol, and cholesterol were all
released in satisfactory yields. A potential limitation of this
process is illustrated by the low yield of 4-(4′-methyoxyphenyl)-
1-butanol from 2d. In this case the readily oxidized anisyl group
can act as an electron donor, competing with TEA for reduction
of the triplet state PTO group. Apparently, undesired products
resulting from intramolecular PET limit the yield from 2d under
UV conditions. However, when visible light is used (see below),
the yield increases to 66%. This supports the notion of
intramolecular PET acting as a nonproductive pathway.
To understand how solvent and donors affect the overall
deprotection process, ether 2a was photolyzed under various
conditions (Table 2). These experiments were carried out at
modest conversions (ca. 70% under standard conditions) so that
small changes in yields or photolysis rates would be apparent.
Yields of 1-octanol are normalized to entry 1 conditions which
facilitated the best deprotection results.
The best yields are obtained in polar solvents (MeOH,
MeCN), while increasing the donor concentration above 15 mM
had no significant effect on the yield or efficiency. Two donors,
N,N-dimethylaniline (DMA) and N,N,N-triphenylamine (TPA),
provided lower yields of the alcohol. This can be attributed to
competing light absorption in the 320−380 nm range by the
donor (see Supporting Information, SI). In principle, excited
singlet amines should be able to donate electrons to ground state
PTO. However, this process is expected to be of lower efficiency
due to the short lifetimes of the amine singlet states. A
bridgehead amine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
was examined to determine the importance of secondary proton
than using UV light to excite the PTO group, two photocatalysts,
fac-(tris(2,2′-phenylpyridine))iridium(III) (fac-Ir(ppy)3) and
tris(bipyridine)ruthenium(II) chloride ([Ru(bpy)3]Cl2), were
excited using visible light (CW diode laser, 1 W, 447 nm). As
indicated in Figure 1, with added TEA both photocatalysts
trigger photorelease of 2a and 2b with a ca. 50% yield of alcohol.
Release occurs through PET from TEA to the photocatalysts
+
generating either fac-Ir(ppy)32+ or [Ru(bpy)3]Cl2 . Both species
are strong reducing agents (Ered = −2.19 V29 and −1.33 V30 vs
SCE respectively) that are able to reduce the PTO group. Using
[Ru(bpy)3]Cl2 in comparison to fac-Ir(ppy)3 provided the ability
to monitor the photocatalyst during the photolysis reaction due
to its characteristic absorption band at 450 nm. Over the course
of the reaction a decrease in this band could be observed (see SI)
B
DOI: 10.1021/acs.orglett.5b02924
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
triplet state of the benzophenone chromophore.31 On the basis
of these observations, this species shown in the top of Figure 2 is
assigned to the triplet state of PTO.
When an electron donor (TEA) is added, two new transient
species are formed. Figure 2 shows spectra from LFP of 2c in the
presence of TEA in CH3CN. Immediately following the laser
pulse, two features appear: a broad band with an indistinct peak
near 620 nm and a sharper feature at 530 nm. The former decays
rapidly, leaving a longer-lived transient with a maximum at ca.
530 nm. The signal at 620 nm decays in a biexponential manner
having a rapid phase rate constant of 4.03 × 105 s−1 and a slower
phase of 4.75 × 104 s−1. This behavior is very similar to what has
been observed when benzophenone is excited in the presence of
amine donors.32 In that case the anion radical, which absorbs in
the 600−700 nm region, decays via protonation to form the
neutral ketyl radical, which absorbs at ca. 530 nm. On the basis of
that precedent, we attribute the 620 nm peak to the PTO anion
radical 3 and the 530 nm peak to the ketyl radical 4. While the
530 nm signal overlaps significantly with the signal assigned to
the triplet state, the two species can be distinguished on the basis
of their different lifetimes. Quenching of the signals assigned to 3
and 4 by O2 provides further support for these assignments.
Following the decay of 4 (530 nm) additional transient
absorptions in the 370−420 nm and 470−570 nm region are
seen (see SI). These persist, without detectable decay for >0.5 ms
following the laser pulse. Such long-lived signals are consistent
with what would be expected for the highly conjugated tritylonyl
radical 5. While additional work will be done to verify the
formation of 5, further evidence is provided by mass
spectrometry. Aerobic photolysis leads to an M + 1 peak
corresponding to peroxide 6. Alternatively, anaerobic photolysis
generates an M + 1 peak consistent with reduction product 7.
The above experiments demonstrate clean and rapid photo-
release of alcohols from photolysis of PTO-ethers under electron
transfer conditions. These conditions can be realized through UV
(350 nm) excitation of the PPG chromophore in the presence of
electron donors or through mediated electron transfer using
visible light (447 nm). LFP and product analysis studies present a
picture consistent with the mechanisms shown in Scheme 2.
Under direct UV irradiation, the triplet PTO chromophore
abstracts an electron from the TEA donor generating 3.
Subsequent proton transfer generates the ketyl species 4. The
latter releases alcohol on a 20 μs time scale generating the radical
5. Presumably under visible light conditions, the same
intermediates can be formed. However, the electron source for
the formation of anion radical 3 in these cases is reduced fac-
Ir(ppy)3 and [Ru(bpy)3]Cl2. Several details of the mechanism
such as (1) whether the C−O bond scission releases an alkoxide
anion or whether it is coupled to a proton transfer and (2)
whether 4 releases the alcohol directly or via 5 are not clearly
established with current data. Future efforts aim to elucidate the
details of the release mechanism, verify relevant intermediates,
optimize the chemical yields, and explore applications of this
protecting group with emphasis on visible light deprotection.
Figure 1. Photolysis of octyl ether 2a (∼10 mM), TEA (∼93 mM), and
fac-Ir(ppy)3 (∼200 μM) (top) and photolysis of 2b (0.832 mM), TEA
(0.108 mM), and [Ru(bpy)3]Cl2 (2.11 mM) (bottom). Both photolyses
done using a 447 nm 1 W laser.
suggesting degradation of photocatalyst as a reason why
moderate yields of alcohol are obtained under the visible light
conditions stated above.
Laser flash photolysis (LFP) experiments were conducted on
ether 2c to identify intermediates in the reaction. Figure 2 shows
Figure 2. Transient absorption spectrum of benzyl ether 2c in benzene
with decay profile monitored at 530 nm under N2 and O2 (top) and
MeCN with TEA under N2 (bottom).
transient spectra obtained at various times following 355 nm
pulsed laser excitation (355 nm, 10 mJ, 7 ns) of 2c in benzene, a
solvent presumed to be inert to H atom transfer reactions. Under
these conditions a short-lived band with λmax = 540 nm appears
immediately following the nanosecond laser pulse. This species
decays in a first-order manner with a rate constant of 2.63 × 106
s−1. This signal is quenched by O2, with the decay rate constant
increasing to 4.87 × 106 s−1 in an air-equilibrated sample. The
transient species observed under these conditions is similar to the
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02924.
Detailed synthetic procedures, characterization data,
photolysis methods, and laser studies (PDF)
C
DOI: 10.1021/acs.orglett.5b02924
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(19) Banerjee, A.; Falvey, D. E. J. Org. Chem. 1997, 62, 6245−6251.
(20) (a) Edson, J. B.; Spencer, L. P.; Boncella, J. M. Org. Lett. 2011, 13,
6156−6159. (b) Borak, J. B.; Lee, H. Y.; Raghavan, S. R.; Falvey, D. E.
Chem. Commun. 2010, 46, 8983−8985.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: falvey@umd.edu.
Notes
(21) Woll, D.; Walbert, S.; Stengele, K. P.; Albert, T. J.; Richmond, T.;
̈
Norton, J.; Singer, M.; Green, R. D.; Pfleiderer, W.; Steiner, U. E. Helv.
The authors declare no competing financial interest.
Chim. Acta 2004, 87, 28−45.
(22) Tu, W.; Floreancig, P. E. Org. Lett. 2007, 9, 2389−2392.
(23) Barnett, W. E.; Needham, L. L.; Powell, R. W. Tetrahedron 1972,
28, 419−424.
ACKNOWLEDGMENTS
■
The authors thank the American Chemical Society Petroleum
Research Fund (51429ND4) and the National Science
Foundation (CHE1112018).
(24) Barnett, W. E.; Needham, L. L. J. Chem. Soc. D 1971, 170−171.
(25) van der Stouwe, C.; Schafer, H. J. Tetrahedron Lett. 1979, 20,
̈
2643−2646.
(26) Leigh, W. J.; Arnold, D. R. J. Chem. Soc., Chem. Commun. 1980,
406−408.
REFERENCES
■
̌
(1) (a) Klan
́
, P.; Solomek, T.; Bochet, C. G.; Blanc, A.; Givens, R.;
(27) Meites, L.; Zuman, P. CRC Handbook Series in Organic
Electrochemistry, Vols. I−V; CRC Press, Inc.: Boca Raton, FL, 1977−
1982.
Rubina, M.; Popik, V.; Kostikov, A.; Wirz, J. Chem. Rev. 2013, 113, 119−
191. (b) Pelliccioli, A. P.; Wirz, J. Photochem. Photobiol. Sci. 2002, 1,
441−458.
(28) Rehm, D.; Weller, A. Isr. J. Chem. 1970, 8, 259−271.
(29) Nguyen, J. D.; D'Amato, E. M.; Narayanam, J. M. R.; Stephenson,
R. J. Nat. Chem. 2012, 4, 854−859.
(30) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013,
113, 5322−5363.
(31) Buettner, A. V.; Dedinas, J. J. Phys. Chem. 1971, 75, 187−191.
(32) (a) Inbar, S.; Linschitz, H.; Cohen, S. G. J. Am. Chem. Soc. 1981,
103, 1048−1054. (b) Devadoss, C.; Fessenden, R. W. J. Phys. Chem.
1990, 94, 4540−4549.
(2) (a) Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: Hoboken, NJ, 1999. (b) Pirrung, M. C. Chem.
Rev. 1997, 97, 473−488. (c) Guillier, F.; Orain, D.; Bradley, M. Chem.
Rev. 2000, 100, 2091−2157.
(3) Woll, D.; Lukzen, N.; Steiner, U. E. Photochem. Photobiol. Sci. 2012,
̈
11, 533−538.
(4) Ellis-Davies, G. C. R. Nat. Methods 2007, 4, 619−628.
(5) (a) Sun, Y.; Yan, Y.; Wang, M.; Chen, C.; Xu, H.; Lu, J. R. ACS Appl.
Mater. Interfaces 2013, 5, 6232−6236. (b) Lin, Q.; Huang, Q.; Li, C.;
Bao, C.; Liu, Z.; Li, F.; Zhu, L. J. Am. Chem. Soc. 2010, 132, 10645−
10647.
(6) Miller, G. Science 2006, 314, 1674−1676.
́
(7) Beecher, J. E.; Cameron, J. F.; Frechet, J. M. J. J. Mater. Chem. 1992,
2, 811−816.
(8) (a) Muraoka, T.; Cui, H.; Stupp, S. I. J. Am. Chem. Soc. 2008, 130,
2946−2947. (b) Matson, J. B.; Navon, Y.; Bitton, R.; Stupp, S. I. ACS
Macro Lett. 2015, 4, 43−47.
(9) (a) Givens, R. S.; Rubina, M.; Wirz, J. Photochem. Photobiol. Sci.
2012, 11, 472−488. (b) Hagen, V.; Kilic, F.; Schaal, J.; Dekowski, B.;
Schmidt, R.; Kotzur, N. J. Org. Chem. 2010, 75, 2790−2797. (c) Suzuki,
A. Z.; Watanabe, T.; Kawamoto, M.; Nishiyama, K.; Yamashita, H.; Ishii,
M.; Iwamura, M.; Furuta, T. Org. Lett. 2003, 5, 4867−4870. (d) Atta, S.;
Jana, A.; Ananthakirshnan, R.; Dhuleep, P. S. N. J. Agric. Food Chem.
2010, 58, 11844−11851.
(10) Goswami, P. P.; Syed, A. S.; Beck, C. L.; Albright, T. R.; Mahoney,
K. M.; Unash, R.; Smith, E. A.; Winter, A. H. J. Am. Chem. Soc. 2015, 137,
3783−3786.
(11) (a) Jagadesan, P.; Da Silva, J. P.; Givens, R. S.; Ramamurthy, V.
Org. Lett. 2015, 17, 1276−1279. (b) Givens, R. S.; Heger, D.; Hellrung,
B.; Kamdzhilov, Y.; Mac, M.; Conrad, P. G., II; Cope, E.; Lee, J. I.; Mata-
Segreda, J. F.; Schowen, R. L.; Wirz, J. J. Am. Chem. Soc. 2008, 130,
3307−3309.
̌
(12) Sebej, P.; Wintner, J.; Mueller, P.; Slanina, T.; Anshori, J. A.;
̈
́
Antony, L. A. P.; Klan, P.; Wirz, J. J. Org. Chem. 2013, 78, 1833−1843.
(13) (a) Wang, P.; Lu, W.; Devalankar, D. A.; Ding, Z. Org. Lett. 2015,
17, 2114−2117. (b) Perrotta, R. R.; Winter, A. H.; Falvey, D. E. Org. Lett.
2011, 13, 212−215. (c) Ruane, P. H.; Bushan, M.; Pavlos, C. M.; D’Sa,
R. A.; Toscano, J. P. J. Am. Chem. Soc. 2002, 124, 9806−9811.
(14) (a) Pirrung, M. C.; Fallon, L.; Zhu, J.; Lee, Y. R. J. Am. Chem. Soc.
2001, 123, 3638−3643. (b) Duan, X.-Y.; Zhai, B.-C.; Song, Q.-H.
Photochem. Photobiol. Sci. 2012, 11, 593−598.
(15) Konosonoks, A.; Wright, P. J.; Tsao, M.-L.; Pika, J.; Novak, K.;
́
Mandel, S. M.; Bauer, J. A. K.; Bohne, C.; Gudmundsdottir. J. Org. Chem.
2005, 70, 2763−2770.
(16) Kulikov, A.; Arumugam, S.; Popik, V. V. J. Org. Chem. 2008, 73,
7611−7615.
(17) (a) Zhou, L.; Yang, H.; Wang, P. J. Org. Chem. 2011, 76, 5873−
5881. (b) Yang, H.; Zhou, L.; Wang, P. Photochem. Photobiol. Sci. 2012,
11, 514−517.
(18) McGrath, N. A.; Brichacek, M.; Njardarson, J. J. Chem. Educ. 2010,
87, 1348−1349.
D
DOI: 10.1021/acs.orglett.5b02924
Org. Lett. XXXX, XXX, XXX−XXX