Time-resolved pH jump study of photochemical cleavage and release of carboxylic acids from α-keto amides

Article abstract of DOI:10.1016/j.tetlet.2004.11.167

Time-resolved pH jump experiments, using laser flash photolysis and bromocresol green as an indicator, showed that photochemical cleavage and release of carboxylic acids from various α-keto amides derivatives in aqueous media occurs on the microsecond tim

Full text of DOI:10.1016/j.tetlet.2004.11.167

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1045–1048
Time-resolved pH jump study of photochemical cleavage and
release of carboxylic acids from a-keto amides
*
Chicheng Ma, Mark G. Steinmetz, Erica J. Kopatz and Rajendra Rathore
Department of Chemistry, Marquette University, Milwaukee, WI 53201-1881, USA
Received 22 October 2004; revised 9 November 2004; accepted 9 November 2004
Available online 22 December 2004
Abstract—Time-resolved pH jump experiments, using laser flash photolysis and bromocresol green as an indicator, showed that
photochemical cleavage and release of carboxylic acids from various a-keto amides derivatives in aqueous media occurs on the
microsecond timescale (18–136 ls), depending on carboxylate leaving group ability.
Ó 2004 Elsevier Ltd. All rights reserved.
The photochemical reactions of a-keto amides have long
been thought to proceed via intermediates, which pos-
The rates of elimination of the leaving groups from zwit-
terionic intermediates such as 4 (Fig. 1) have not been
determined. One reason for this is that conventional
nanosecond laser flash photolysis experiments have re-
vealed no significant transient absorptions to monitor
for kinetic information about the reaction. An alternate
approach using time-resolved difference FT-IR spectro-
scopy seemed promising in this regard, because vibra-
tions specific to the released carboxylate anion could
be directly observed at pH 6 in buffer. This approach,
using a rapid scan technique, provided an upper limit
estimate of the release time of the c-amino acid GABA
1
,2
sess zwitterionic character. Recent studies have inves-
tigated the prospects for exploiting these zwitterionic
intermediates to effect heterolytic elimination of carboxy-
3
4
late and phenolate leaving groups as a strategy for
developing photoremovable protecting groups and cage
5
,6
compounds. For example, photolyses of N,N-diethyl
a-keto amides 1 with leaving groups LG ¼ CH CO ,
ꢀ
3
2
ꢀ
PhCH CO at the position a to the keto group result
2
2
in efficient cleavage and release of carboxylic acids in
essentially quantitative yields in aqueous media (Scheme
3
3
1
). The cleavage coproducts were found to be mainly
of 30ms. However, further studies to resolve the rate
the diastereomeric hemiacetal 2 and minor amounts of
methyleneoxazolidinone 3. In these cases the zwitter-
ionic intermediate 4 would be involved in the elimina-
tion step.
constants using a faster step scan technique proved
unfeasible due to the insensitivity of the method at
355 nm in the cases of our weakly absorbing a-keto
amides.
Given the above difficulties in determining release rates,
we have turned to a time-resolved pH jump method
using laser flash photolysis, which takes advantage of
the pronounced increases in acidity, which are observed
when the carboxylate derivatives of a-keto amides are
photolyzed in unbuffered aqueous media. The pH jumps
are sufficiently large to permanently change the color of
CH3
H
NEt
CH3
H
NEt
O
7
hν
O
O
LG
NEt2
+
-
-
-
LG CH3
+
O
H
HO
O
O
1
2
3
-
Leaving groups LG :
an added pH indicator, bromocresol green (pK 4.90,
a
-
-
-
-
CH CO , PhCH CO , BocNHCH(CH )CO , 4-NCC H CO
3
2
2
2
3
2
6
4
2
(
BocAla)
HO
HO
Scheme 1.
LG
NEt
LG
NEt
+
O
O-
Keywords: a-Keto amide; Photocleavage; Zwitterion; pH jump.
Corresponding author. Tel.: +1 414 288 3535; fax: +1 414 288
7066; e-mail: mark.steinmetz@marquette.edu
4
*
Figure 1. Intermediate with zwitterionic character.
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.167

1046
C. Ma et al. / Tetrahedron Letters 46 (2005) 1045–1048
8
a
2
0 °C ). In this letter we report the rate constants for
conditions. For 0.04–0.05 M 1 with various carboxylate
leaving groups (LG ¼ CH
ꢀ
ꢀ
bleaching of the 620nm band of this dye, which allow
us to establish the mechanism for the loss of the carboxyl-
ate leaving groups that occurs in the rate determining
step via zwitterionic intermediates 4.
3 2
CO , PhCH CO , BocAla,
2
4-NCC H CO ) in 50% aqueous CH CN the magnitude
2
ꢀ
6
4
2
3
of the observed change in pH was 2.6–3.3 units starting
from a pH of 6.1–6.6. When photolyses with bromocre-
sol green were monitored by absorption spectroscopy,
the 620nm band of the anionic form of the pH indicator
was observed to decrease in intensity, and a new absorp-
tion at 420nm was observed to increase.
Steady-state photolyses (k > 300 nm) were conducted
with N,N-diethyl a-keto amides 1 substituted with vari-
ous carboxylate leaving groups LG (Scheme 1) follow-
ing previously described procedures. In 50% aqueous
acetonitrile, photocleavage was observed in all cases
and resulted in formation of the corresponding carbox-
3
,4
The kinetics of the pH jumps, as reflected by the bleach-
ing of the 620nm absorption band of 20 lM bromocre-
sol green, were studied by 355 nm nanosecond laser flash
3
ylic acid and the diastereomeric hemiacetal 2, which
3
,4
10
was accompanied by a minor product 3. The yields
are given in Table 1. Quantum yields of reaction (k
photolyses of 0.1–0.2 M 1 in air-saturated 50% H O in
2
CH CN at pH ca. 6 (unbuffered). The flowed samples
3
ꢀ
ꢀ
2
3
10nm) for each LG
3
were as follows: CH CO ,
were subjected to 10–20 3 mJ shots of a Nd-YAG laser
at 30or 60s intervals. The summed DOD versus time
plots in each case gave a satisfactory fit to a monoexpo-
nential function, which afforded the time constant for
the bleaching kinetics of the bromocresol green. A rep-
3
ꢀ
3
U = 0.31; PhCH
2
CO , U = 0.36; BocAla, U = 0.35;
CO , U = 0.32.
2
ꢀ
9
4
-NCC
6
H
4
2
Prior to conducting the laser flash photolysis studies, we
examined the pH jumps under steady-state photolysis
resentative kinetic plot (Fig. 2A) is shown for 1
ꢀ
(
LG ¼ PhCH CO ), along with bleaching of the dye
2
2
at time intervals (Fig. 2B). Control experiments with
a-keto amide 1 (LG = H, no leaving group) showed no
bleaching. The bleaching rate constants are summarized
in Table 1.
Table 1. Yields of photoproducts from steady-state photolyses of
various a-keto amides, and rate constants for bleaching of bromo-
cresol green
ꢀ
a
3
k, 10 s
ꢀ1c
LG
Yield, %
For 1 the rate constants follow the order of leaving
group ability, CH CO < PhCH CO , <Boc-alanine,
2
3 2
ꢀ
ꢀ
b
LG-H
2
3
1
2
ꢀ
ꢀ
< 4-NCC
ꢀpK of the released acid is 0.74 ± 0.07 (R 0.9919).
6 4
H CO (Table 1), and a plot of log k versus
8b,c
CH3CO2
82
86
81
75
66
78
85
4.5
19
7.33
2
2
ꢀ
d
PhCH2CO2
BocAla
1012
018
18.0
31.8
54.9
a
ꢀ
e
4
-NCC6H4CO2
nd
013
The pronounced leaving group effects on the rate con-
stants for bleaching of bromocresol green in the case
of 1 are consistent with rate determining elimination
of the carboxylate groups in the unstable zwitterionic
intermediate 4. Subsequent proton release would be con-
sidered to occur mainly in a non-rate determining step
along pathway a, which leads to the principal cleavage
coproduct, diastereomeric 2 (Scheme 2). An inverse
a
Yields determined by NMR spectroscopy with DMSO, DMF, or
glycine as standards in 50% D O in CD CN.
2
3
b
c
Unreacted at end of photolysis.
The average error was <5%.
Yields taken from Ref. 3.
d
e
1
Not determined due to overlap with starting material in the H NMR
spectrum.
0
0
.1
.0
0.010
laser
A
B
0.005
0.000
-0.005
-
0.1
0
.0
-0.1
-
-
0.2
-0.2
0
.0
0.1
time, ms
0.2
0.3
-
5
00
550
600
650
700
0.5
0.0
time, ms
0.5
wavelength, nm
ꢀ
2
2
CO (15 laser shots summed); inset
Figure 2. (A) Kinetics of bleaching of bromocresol green at 620nm upon laser flash photolysis of 1, LG ¼ PhCH
shows the fit to a single exponential decay function made after the transient spike due to cuvette luminescence. (B) Spectral response at time intervals
for one shot at each wavelength.

C. Ma et al. / Tetrahedron Letters 46 (2005) 1045–1048
1047
OH
CH3
OH
References and notes
H
CH3 H O
H
H
2
-H
CH3
HO
HO
O
+
± H+
-
LG-
4
N
N
1. Chesta, C. A.; Whitten, D. G. J. Am. Chem. Soc. 1992,
N
+
Et path a
Et
Et
1
. (a) Aoyama, H.; Sakamoto, M.; Kuwabara, K.; Yoshida,
14, 2188–2197.
O
5
O
6
O
7
2
K.; Omote, Y. J. Am. Chem. Soc. 1983, 105, 1958–1964;
(
b) Aoyama, H.; Sakamoto, M.; Omote, Y. J. Chem. Soc.,
Perkin Trans. 1 1981, 1357–1359; (c) Aoyama, H.;
Hasegawa, T.; Omote, Y. J. Am. Chem. Soc. 1979, 101,
path b
H+
± H+
-
3
2
5343–5347; (d) Zehavi, U. J. Org. Chem. 1977, 42, 2821–
2825; (e) Johansson, N. G.; Akermark, B.; Sjoberg, B.
Scheme 2.
Acta Chem. Scand. B 1976, 30, 383–390.
. Ma, C.; Steinmetz, M. G.; Cheng, Q.; Jayaraman, V. Org.
Lett. 2003, 5, 71–74.
. Ma, C.; Steinmetz, M. G. Org. Lett. 2004, 6, 629–
632.
5. (a) Marriott, G. In Methods in Enzymology; Academic:
San Diego, 1998; Vol. 291; (b) Kahl, J. D.; Greenberg, M.
M. J. Am. Chem. Soc. 1999, 121, 597–604; (c) Pirrung, M.
C.; Fallon, L.; Lever, D. C.; Shuey, S. W. J. Org. Chem.
3
4
solvent isotope effect of 0.74 ± 0.02 is observed, which
would be consistent with the enolate group of 4 being
a stronger base in D O than in H O such that elimina-
2
2
1
1
tion occurs more rapidly in the deuterated solvent.
1
996, 61, 2129–2136; (d) Lloyd-Williams, P.; Albericio,
F.; Giralt, E. Tetrahedron 1993, 49, 11065–
1133.
Proton release via path a would involve addition of
1
2
water to imminium ion 5 to produce enol 6. Pseudo
first-order rate constants for hydration of imminium
1
6
. (a) Morrison, J.; Wan, P.; Corrie, J. E. T.; Papageorgiou,
G. Photochem. Photobiol. Sci. 2002, 1, 960–969; (b)
Givens, R. S.; Lee, J.-I. J. Photosci. 2003, 10, 37–48; (c)
Rajesh, C. S.; Givens, R. S.; Wirz, J. J. Am. Chem. Soc.
2000, 122, 611–618; (d) Cheng, Q.; Steinmetz, M. G.;
Jayaraman, V. J. Am. Chem. Soc. 2002, 124, 7676–7677;
6
8
ions range from 10 to 10 s for the few examples re-
ꢀ1
1
3,14
ported.
The remaining steps along path a, such as
1
5
tautomerization and cyclization to give hemiacetal
diastereomers 2, would be slow acid-catalyzed reactions
of relatively stable compounds that are considered to
have no bearing on the bleaching rates.
(
e) Corrie, J. E. T.; Barth, A.; Munasinghe, V. R. N.;
Trentham, D. R.; Hutter, M. C. J. Am. Chem. Soc. 2003,
25, 8546–8554.
. (a) Barth, A.; Corrie, J. E. T. Biophys. J. 2002, 83, 2864–
871; (b) Choi, J.; Hirota, N.; Terazima, M. J. Phys.
1
Deuterium labeling studies support two mechanistically
distinct pathways in the formation of 2 and 3. In the
case of diastereomers 2 deuterium is incorporated into
the methyl group a to the carboxamide group, consis-
7
2
Chem. 2001, 105, 12–18; (c) Viappiani, C.; Bonetti, G.;
Carcelli, M.; Ferrari, F.; Sternieri, A. Rev. Sci. Instrum.
3
tent with a prior tautomerization step (path a). No deu-
terium is incorporated into the methylene group of the
1
998, 69, 270–276; (d) Walker, J. W.; Reid, G. P.;
McCray, J. A.; Trentham, D. R. J. Am. Chem. Soc.
1988, 110, 7170–7177; (e) Gutman, M.; Huppert, D.;
Pines, E. J. Am. Chem. Soc. 1981, 103, 3709–3713; (f)
Clark, J. H.; Shapiro, S. L.; Campillo, A. J.; Winn, K. R.
J. Am. Chem. Soc. 1979, 101, 746–748.
. (a) CRC Handbook of Chemistry and Physics, 76th ed.;
Lide, D. R., Ed.; CRC: Boca Raton, 1995–1996; pp 8–17;
(b) pK values: Rappoport, Z. In CRC Handbook of
a
Tables for Organic Compound Identification, 3rd ed.;
double bond of 3, which rules out a tautomerization
4
mechanism for the formation of this product. The ab-
sence of deuterium in 3 shows that it is not formed via
2. In addition, a control experiment shows that diaste-
reomers 2 are not formed from 3, which is stable in
8
the presence of CH CO D at pD 2.8 in 50% D O in
3
2
2
CD CN for >14 d.
3
Weast, R. C., Ed.; CRC: Cleveland, 1967; pp 429–433;
In summary, the photoelimination of carboxylic acids
from a-keto amides results in a rapid, permanent change
in pH sufficient to cause bleaching of the 620nm absorp-
tion band of the pH indicator, bromocresol green. In the
case of N,N-diethylamides 1 the time constants for
bleaching span 18–136 ls, depending on carboxylate
leaving group ability, which is consistent with a rate
determining elimination step in the photogenerated
ground state zwitterionic intermediates.
(
9. (a) The detailed procedures used for quantum yield
a
c) BocAla, pK = 4.02, CA 15761-38-3.
9
b
9c
determinations
and ferrioxalate actinometry
were
described previously; (b) Steinmetz, M. G.; Luo, C.; Liu,
G. J. Org. Chem. 1999, 64, 2057–2065; (c) Hatchard, C.
G.; Parker, C. A. Proc. R. Soc. London 1956, 235,
5
18.
0. High concentrations of 1 were required because the molar
1
1
ꢀ1
ꢀ1
at the
extinction coefficients were <10L mol cm
55 nm photolysis wavelength. For each experiment the
absorbance at 355 nm was 0.5–0.7.
3
1. (a) An inverse solvent isotope effect usually signifies the
existence of a preequilibrium protonation step that is
Acknowledgements
1
1b,c
followed by a rate determining step.
Since the pH
rapidly changes in our unbuffered experiments, significant
protonation of 4 in competition with elimination could
result in complicated kinetics and non-monoexponential
bleaching. We suspect the isotope effect could be due to
We thank Ms. Elizabeth Vissat for assistance with the
synthesis of 1 (LG = BocAla). Acknowledgement is
made to the donors of the Petroleum Research
Fund, administered by the American Chemical Society
2 2
weaker solvation of the intermediate in D O than H O; (b)
(
M.G.S.) and to the National Science Foundation
Keefe, J. R.; Jencks, W. P. J. Am. Chem. Soc. 1983, 105,
265–279; (c) Keefe, J. R.; Jencks, W. P. J. Am. Chem. Soc.
1981, 103, 2457–2459.
for a Career Award (R.R.) for support of this
research.

1048
C. Ma et al. / Tetrahedron Letters 46 (2005) 1045–1048
1
1
2. An approximately planar imminium ion 5 would have four
combinations of s-cis and s-trans conformers. For brevity
only one is shown in Scheme 2.
3. (a) Eldin, S.; Digits, J. A.; Huang, S.-T.; Jencks, W. P.
J. Am. Chem. Soc. 1995, 117, 6631–6632; (b) Eldin, S.;
Jencks, W. P. J. Am. Chem. Soc. 1995, 117, 4851–4857.
14. In Ref. 4 on photochemical release of phenolic groups
from a-keto amides, intermediate 6 should have been
included in the mechanism for formation of the
hemiacetals.
15. Chiang, Y.; Kresge, A. J.; Santaballa, J. A.; Wirz, J.
J. Am. Chem. Soc. 1988, 110, 5506–5510.