Visible Light Photorelease of Carboxylic Acids via Charge-Transfer Excitation of N-Methylpyridinium Iodide Esters

Article abstract of DOI:10.1021/acs.orglett.5b01490

Iodide contrast sensitization to direct irradiation of charge transfer salts incurs carboxylic acid release via visible light absorption. The photochemical reduction of N-methyl-4-pyridinium iodide esters to release carboxylic acids is examined using ¹H NMR analysis. Photolysis reactions are carried out under mild, biphasic solvent conditions using a household LED lamp. Carboxylic acid release is reported in high yields, and the viability of this method for synthetic chemistry is demonstrated through a macroscale reaction.

Full text of DOI:10.1021/acs.orglett.5b01490

Letter
pubs.acs.org/OrgLett
Visible Light Photorelease of Carboxylic Acids via Charge-Transfer
Excitation of N‑Methylpyridinium Iodide Esters
David J. Kunsberg, Allison H. Kipping, and Daniel E. Falvey*
Department of Chemistry, University of Maryland, College Park, Maryland 20742, United States
*
S Supporting Information
ABSTRACT: Iodide contrast sensitization to direct irradi-
ation of charge transfer salts incurs carboxylic acid release via
visible light absorption. The photochemical reduction of N-
methyl-4-pyridinium iodide esters to release carboxylic acids is
1
examined using H NMR analysis. Photolysis reactions are
carried out under mild, biphasic solvent conditions using a
household LED lamp. Carboxylic acid release is reported in
high yields, and the viability of this method for synthetic
chemistry is demonstrated through a macroscale reaction.
hotoreleasable protecting groups (PPGs), which are also
reactions can be carried out using household light sources,
which are readily available, inexpensive, and safer to operate
P
referred to as “photocages” or “phototriggers”, are light
sensitive molecular species that can be covalently linked to a
reactive functional group on a substrate molecule in a way that
masks its reactivity. Light is then used to release the PPG from
the substrate, restoring the latter to its active form. Applications
35−40
than UV sources.
However, one drawback of the electron
transfer approach is that the requirement for an external
sensitizer molecule (and/or reductants) can complicate the
subsequent isolation of the targeted molecule following the
photorelease procedure.
1
−3
of this technology include organic synthesis,
photolithog-
and optoge-
4
,5
6,7
8−10
raphy,
neurobiology,
drug release,
The current report describes investigations into the photo-
chemistry of iodide salts of NAP esters. Specifically it is
demonstrated that, in moderately polar solvents, ion pairing
leads to formation of charge transfer or Mulliken complexes
that absorb visible light. More significantly, excitation of these
ion pairs results in single electron transfer reactions that, in
turn, promote fragmentation of the ester C−O bond releasing
carboxylate anions. On the basis of these mechanistic findings, a
protocol for carboxylic acid deprotection was developed that
used visible light and eliminated the need for any separation of
the released carboxylic acid from the sensitizer, reductant, or
PPG residue.
1
1,12
netics.
One of the earliest and most commonly used types of PPG is
1
3,14
based on the 2-nitrobenzyl chromophore.
Subsequent
1
5−17
developments include (1) the 4-hydroxyphenacyl group,
which was designed to improve aqueous compatibility and
generate more benign byproducts from the photorelease step;
(
2) the coumarin-4-methyl group, which has an excellent cross
1
8−20
section for two-photon absorption;
(3) the use of
fluorescein or BODIPY chromophores, which allow for
2
1,22
photorelease using visible wavelengths;
and (4) other
groups which possess alternative mechanisms for photo-
2
3−26
release.
In a series of reports we have advocated the use of
The NAP ester iodide salts used in this study were prepared
32
using previously reported procedures. The corresponding
27−30
photoinduced electron transfer in the design of PPGs.
In
carboxylic acid is coupled with 4-picolylalcohol using N-N′-
dicyclohexylcarbodiimide (DCC) and then alkylated using
these systems, release of the protecting group is initiated by
electron transfer from an excited state sensitizer group to the
protecting group, rather that through direct light absorption.
For example, it is possible to effect photorelease of carboxylic
acids from N-alkyl-4-pyridinium (NAP) esters through
irradiation of excited state electron donor molecules. One
attractive feature of this approach is that it effectively decouples
the light absorption step from the bond-breaking step, allowing
both to be optimized independently of each other. And indeed,
if the correct donor is utilized, release can be triggered using
wavelengths that extend from the near-UV into the visible
CH I. In the earlier studies these iodide salts were subjected to
3
a metathesis reaction designed to replace the iodide counterion
with a tetrafluoroborate. In the current study this step is not
necessary.
The photochemical and spectroscopic investigations de-
scribed below were designed to test the mechanistic proposal
outlined in Scheme 1. Related pyridinium iodides have been
shown to exhibit a solvent-dependent charge-transfer absorp-
41
tion band in the visible region of the spectrum. This is
associated with promoting an electron from the iodide to the
31−34
region of the spectrum.
A high wavelength spectral
response is advantageous because (1) it can reduce side
products due to unintended light absorption by products and
other additives in the reaction mixture and (2) often such
Received: May 21, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01490
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Predicted Mechanism of NAP−Iodide Ester
Charge Transfer Excitation
K [I][NAPtotal]εCTCb
a
ACTC
=
1
+ K [I]
(1)
a
As seen in Figure 1, the charge transfer complexes formed in
CH CN have a tail absorption that extends into the low
3
wavelength part of the visible spectrum (>420 nm), implying
that the charge transfer reactions described in Scheme 1 could
be initiated using inexpensive visible light sources. To test this,
a 1.3 mM solution of 1a in 2.5 mL of CH CN/CHCl was
3
3
irradiated using an 18 W household LED lamp. Detection of
phenylacetic acid by HPLC determined that production of the
acid is rapid over the first 10 min and then slowly increases over
the remaining hour with an apparent limit of 50% under these
conditions (Figure S-3). The production of acid in this
experiment confirms the general predictions of Scheme 1,
namely that photolysis into the charge transfer absorption band
pyridium ion in the contact ion pair. Such an excitation in the
NAP ester iodides should generate the same pyridyl radical that
is formed from quenching excited state electron donors such as
−
initiates an electron transfer reaction from I to the NAP ester
3
2,42
leading to release of the corresponding carboxylic acid.
However, from a practical standpoint, yields of the latter are
not satisfactory.
BODIPY or arylamines.
As such, the resulting pyridyl
radical is expected to fragment generating a carboxylate ion,
along with the picolyl radical cation 4. The latter is of course
reactive, and previous work has shown that trapping this
intermediate with a good hydrogen atom donor is necessary in
order to obtain high yields of the targeted carboxylate anions.
To determine if intimate ion pairs possessing a visible charge
transfer band would form, the UV−visible spectra of various
pyridinium ions were determined in the presence of varying
concentrations of iodide. An example of these experiments is
The low yields can be attributed to two related effects. First,
C−O heterolysis of pyridyl radical 2 generates both the desired
carboxylate anion and radical cation 4, a highly reactive species
which, in the absence of efficient radical trapping pathways, can
initiate unintended radical reactions, and could degrade the
desired product. Similarly, the initial electron transfer generates
atomic I. While this species is expected to be less reactive than
−
+
−
radical cation 4, it is known to generate I3 (through
illustrated in Figure 1. In this case, 0 to 458 mM nBu N I was
4
−
combination with an additional atomic I and any added I ).
The latter has a strong absorption band in the near-UV region
of the spectrum and, thus, could serve as an inner filter,
occluding light from the NAP ester iodide. Figure 2 shows
+
−
Figure 1. Addition of nBu N I to 1.0 mM 1a to form a charge-
4
transfer complex. Inset: Increase in charge-transfer absorbance at 345
nm indicates an asymptotic binding curve. Calculated K of NAP−I
a
−1
complex formation is 11 M .
Figure 2. Spectra of various triiodide concentrations (dashed, legend is
−
[
I ]) overlaid with UV−vis spectra of photolysis spectrum (solid).
3
UV−vis spectra resulting from the photolysis of the CH CN/
3
added to a 1.0 mM solution of NAP ester 1a in CH CN.
Increasing [I ] results in the growth of a new absorption band
at 340 nm that does not appear in the UV−vis spectrum of the
corresponding perchlorate salt. This absorption band exhibits a
bathochromic shift in increasingly nonpolar solvents (NAP
3
CHCl solutions of 1a along with spectra measured from
−
3
−
preparing varying concentrations of I3 in the same solvent. As
is apparent from these data, the absorption of I3− dominates the
spectrum after relatively short photolysis times (in fact these
solutions visually develop a strong orange-red color as the
ester 1e λmax in H O: 331 nm, MeOH: 357 nm, MeCN: 360
2
photolysis proceeds).
The formation of I , while consistent with the proposed
−
nm, CHCl : 363 nm). This behavior is consistent with expected
3
3
4
3,44
formation of a charge-transfer or Mulliken complex.
The
mechanism, is an impediment to practical implementations of
these reactions in situations where recovery of the released acid
is desired. Adding reductants, such as ascorbate or starch,
directly to the photolysis solution could suppress I3− formation,
but at the expense of further complicating any subsequent
purification procedures. Therefore, we sought methods of
directly segregating reductants and byproducts from the
reactants and products.
absorbance at each concentration was modeled using eq 1. The
absorbance of the charge-transfer complex, ACTC, can be related
to the binding constant, K , molar attenuation coefficient, εCTC,
a
path length, b, the overall concentration of the iodide anion,
[
I], and the concentration of NAP ester, [NAPtotal]. The results
of this analysis, which provide an association constant of 11
−
1
M , are illustrated in the inset of Figure 1.
B
DOI: 10.1021/acs.orglett.5b01490
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Although the NAP-pyridinium iodide salts are charged, they
are, in most cases, sufficiently hydrophobic to partition
selectively into organic solvents (CHCl /CH CN). Likewise
3
3
the PPG residue, 1,4-dimethylpyridinium ion 5, and the
−
oxidized donor, I , are highly soluble in H O. Therefore, it
3
2
was reasoned that carrying out the photolysis under biphasic
solvent conditions would allow use of a sacrificial reductant (in
the aqueous phase) and provide for rapid segregation of the
byproducts from the product.
This scheme was realized using an immiscible mixture of
water and CHCl /CH CN (95/5 v/v). Under these conditions
3
3
the protected molecules 1a−1e selectively partition into the
organic phase. Photolysis of a rapidly stirred mixture containing
ascorbic acid, Na SO , and 1a in the organic phase (using a 100
mW 405 nm diode laser for 1 h or the broad-band output of a
household LED lamp for 8 h) produced nearly quantitative
yields of the acid in the organic layer (e.g., 92.6% of 6a using
2
4
Figure 3. Low conversion biphasic photolyses for 1a. Standard
conditions refer to a 30 min photolysis by 405 nm laser where 28 μmol
of NAP ester is solubilized in 1.5 mL of CDCl
/CD CN (95/5 v/v)
3
3
and 250 μL of D O (with 249 μmol of Na SO and 217 μmol of
2
2
4
ascorbic acid). Other conditions are modifications only of the
indicated chemical.
4
05 nm diode laser, and deuterated solvents to facilitate NMR
1
analysis) with no side products or byproducts detectable by H
NMR analysis in the organic layer.
Scheme 2 shows yields for photorelease of several other
carboxylic acids determined in a similar manner. Aside from the
balances in the organic layer were reduced from 95% to 70%.
This can be attributed to increased migration of ester 1a into
the aqueous layer when this salting out additive is omitted.
1
Scheme 2. Visible Light, Biphasic Photolysis of NAP-Esters
Indeed, H NMR analysis of the aqueous phase from these
experiments showed that significant amounts of 1a had
partitioned into the aqueous phase. Once in the aqueous
phase, photolysis is inhibited because this polar medium
prevents formation of the contact ion pairs required for
formation of the charge transfer complex.
Decreasing ascorbic acid concentration slightly improves the
apparent rate at which the deprotection occurs, at the expense
of a lower mass balance. Apparently ascorbic acid has a similar
effect to that of Na SO in that it inhibits ester partitioning into
2
4
the aqueous phase. While NaI has no discernible effect on the
mass balance, and presumably the partitioning ratio for the
ester, at very high concentrations (>100 mM in the aqueous) it
does appear to inhibit photolysis. This can be attributed to an
indirect inhibition of the reduction of I by ascorbic acid. The
2
anion I− with I2− is in equilibrium with I . Increasing
−
3
concentrations of I reduces the effective concentration of I ,
2
thus reducing the rate of reduction of the latter by ascorbate.
Finally, in order to assess the utility of these reactions for
preparative scale ester deprotection, photolysis for 24 h using
the 18 W household LED lamp was carried out on a 0.500 g
sample of 1a using the standard biphasic reaction conditions.
On this scale 0.140 g (76%) was isolated from the photolysis
mixture by separating the organic layer, removing the solvent
and recrystallization from petroleum ether.
acetate derivative, 1e, the yields are close to quantitative. In the
case of 1e, the acetic acid product is sufficiently soluble in the
aqueous phase that efficient segregation is not achieved and
only a 29.8% yield is detected in the organic layer. This example
illustrates a limitation to the biphasic photolysis procedure.
Carboxylic acids possessing a high aqueous solubility in their
protonated form are unlikely to be recovered in satisfactory
yields.
In conclusion, photolysis of NAP esters by charge-transfer
excitation is a facile method for catalyst-free carboxylic acid
deprotection triggered by visible light. Photolysis and
purification procedures allow this reaction to be performed
outside of photochemical laboratories. Protection of carboxylic
acids is achieved simply in a two-step process, and deprotection
is performed with room light and widely available chemicals
and solvents. Under the conditions above, photolysis of many
NAP esters could produce high yields. For individual cases,
these conditions can be optimized to achieve a near-
quantitative release. The byproducts of this reaction appear
to be generally nontoxic (5 is found in ranges of 5 to 25 mg/kg
in coffee extract) and nonreactive, a crucial component for
To determine the effect of the various additives, ester 1a was
photolyzed for 30 min using each of the conditions shown in
Figure 3 and the amounts of phenylacetic acid and unconverted
1
ester in the organic phase were determined by H NMR using
an internal standard. These photolyses were carried out to
incomplete conversions of 1a (ca. 50% under standard
conditions) so that modest differences in rates or yields
1
would be more apparent. In all cases, H NMR could detect
only 1a and phenylacetic acid in the organic phase. Reducing
4
5,46
the concentration of Na SO in the aqueous layer shows a
protecting groups to be used in biological systems.
These
2
4
negligible effect on the yield of product. However, the mass
characteristics suggest the provided method may be of use for
C
DOI: 10.1021/acs.orglett.5b01490
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Organic Letters
Letter
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ASSOCIATED CONTENT
Supporting Information
■
́
*
S
̌
̌
(
́
4
(
6
(
Full experimental procedure, additional release studies,
characterization data, and NMR spectra for all new compounds
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01490.
2
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AUTHOR INFORMATION
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National Science Foundation.
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