PH Dependent Photodeprotection of Formaldehyde: Homolytic C-C Scission in Acidic Aqueous Solution versus Heterolytic C-C Scission in Basic Aqueous Solution

Article abstract of DOI:10.1021/acs.joc.6b02756

The photodeprotection of formaldehyde was investigated for 3-(1-hydroxypropan-2-yl)benzophenone (3-HPBP) with ultrafast time-resolved spectroscopy. The femtosecond transient absorption results indicated the singlet excited state of 3-HPBP transformed efficiently into its triplet state by a fast intersystem crossing. In acidic (pH = 0) and basic (pH = 12.5) aqueous solutions, the triplet intermediate was a key precursor for the deprotection of formaldehyde via two different pathways. However, little photodeprotection was observed in neutral (pH = 7) aqueous solution where the triplet intermediate appeared to undergo a proton coupled electron transfer process to form a ketyl radical transient. The important benzylic biradical intermediates seen in the acidic and basic aqueous solutions were identified by time-resolved resonance Raman spectra whose vibrational frequency patterns were consistent with DFT calculation results for the benzylic biradical intermediate. The results here indicate that the β-carbon alcohol group of the triplet state 3-HPBP is deprotonated in basic aqueous solutions and this leads to a heterolytic C-C bond cleavage to deprotect formaldehyde and produce the benzylic carbanion triplet state species, whereas protonation of the carbonyl moiety of the triplet state 3-HPBP leads to direct generation of a benzylic biradical intermediate and the deprotection of formaldehyde in acidic aqueous solutions via a homolytic C-C bond cleavage.

Full text of DOI:10.1021/acs.joc.6b02756

Subscriber access provided by UB + Fachbibliothek Chemie | (FU-Bibliothekssystem)
Article
pH Dependent Photodeprotection of Formaldehyde:
Homolytic C-C Scission in Acidic Aqueous Solution Versus
Heterolytic C-C Scission in Basic Aqueous Solution
Mingyue Liu, Wenjian Tang, Ming-De Li, and David Lee Phillips
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02756 • Publication Date (Web): 22 Feb 2017
Downloaded from http://pubs.acs.org on February 24, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
pH Dependent Photodeprotection of Formaldehyde: Homolyt-
ic C-C Scission in Acidic Aqueous Solution Versus Heterolyt-
ic C-C Scission in Basic Aqueous Solution
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
* 1,3
*, 1
Mingyue Liu , Wenjian Tang , Ming-De Li , and David Lee Phillips
1
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong S.A.R., P. R.
China
2
School of Pharmacy, Anhui Medical University, Hefei 230001, P. R. China
Department of Chemistry, Shantou University, Guangdong 515063, P. R. China.
3
KEYWORDS: Phototrigger, Formaldehyde, Time-resolved resonance Raman, Transient absorption,
Benzophenone
O
OH
Phototrigger Release
of Formaldehyde
3
-HPBP
OH-
O
H
O
•
•
Heterolysis
H+
O
Cleavage (pH=12.5)
OH+
T1
on
+ CH2
O
Homolysis
Cleavage (pH=0)
OH
Benzylic Carbanion
OH
T1OH
OH
•
Hydrogen
Abstraction (pH=7)
+ CH2O
Off
×
benzylic biradical 1
Ketyl radical
ABSTRACT: The photodeprotection of formaldehyde was investigated for 3-(1-hydroxypropan-2-
yl)benzophenone (3-HPBP) with ultrafast time-resolved spectroscopy. The femtosecond transient ab-
sorption results indicated the singlet excited state of 3-HPBP transformed efficiently into its triplet state
by a fast intersystem crossing. In acidic (pH=0) and basic (pH=12.5) aqueous solutions, the triplet in-
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 21
termediate was a key precursor for the deprotection of formaldehyde via two different pathways. How-
ever little photodeprotection was observed in neutral (pH=7) aqueous solution where the triplet interme-
diate appeared to undergo a proton coupled electron transfer process to form a ketyl radical transient.
The important benzylic biradical intermediates seen in the acidic and basic aqueous solutions were iden-
tified by time-resolved resonance Raman spectra whose vibrational frequency patterns were consistent
with DFT calculation results for the benzylic biradical intermediate. The results here indicate that the β-
carbon alcohol group of the triplet state 3-HPBP is deprotonated in basic aqueous solutions and this
leads to a heterolytic C-C bond cleavage to deprotect formaldehyde and produce the benzylic carbanion
triplet state species whereas protonation of the carbonyl moiety of the triplet state 3-HPBP leads to di-
rect generation of a benzylic biradical intermediate and the deprotection of formaldehyde in acidic
aqueous solutions via a homolytic C-C bond cleavage.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
INTRODUCTION
A number of benzophenone (BP) compounds after photoexcitation to produce an electronic singlet
excited state can then undergo highly efficient intersystem crossing (ISC) to produce triplet state
1-6
intermediates.
Different subsequent photochemical reactions can occur from these triplet
7
-12
13-17
intermediates and example reactions include hydrogen abstraction,
photodecarboxylation,
1
8-20
21-23
photohydration,
and photoredox
reactions. Thus, BP and its derivatives are compounds that can
provide a rich platform to design molecules for a wide range of applications. Among BP derivatives,
some BP alcohols have recently attracted interest for their intriguing pH dependent photochemical
1
4, 24-26
reaction behavior in aqueous solutions.
Photoexcitation of 3-(hydroxymethyl)benzophenone that
contains an alcohol moiety at the -carbon in the meta position on a phenyl group was observed by Wan
2
6
and co-workers
to undergo a photoredox in aqueous (pH<3) solution that produced 3-
2
ACS Paragon Plus Environment

Page 3 of 21
The Journal of Organic Chemistry
formylbenzhydrol as a final product. This reaction involved an intramolecular process for the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
6
photoredox and is an interesting illustration of a meta effect in photochemistry. Further work by Wan
and co-workers discovered that an alcohol group substituent on the -carbon attached at meta on the
1
4, 24
phenyl group underwent a photo-retro-aldol reaction.
They demonstrated that an aldehyde group
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
was photodeprotected from the BP structure and suggested a potential mechanism (see Scheme 1 below)
which hypothesized the benzoyl part of BP may be a strong electronic withdrawing moiety that drives a
1
4,24
C-C heterolysis to produce a benzyl carbanion that became a photo-activated leaving moiety.
This
process could be the driving force initiating the photo-release of formaldehyde in the reaction.
Furthermore, Wan and coworkers reported a related photo-retro-aldo reaction for a nitrobenzyl alcohol
compound in which water molecules and hydroxide ions appeared involved in facilitating the release of
2
7
formaldehyde. Although a number of experiments were carried out using transient absorption
spectroscopy and/or product analysis to investigate the reaction mechanism(s), it is still unclear how
these photo-activated aldehyde release reactions occur. More work is needed to clearly identify and
directly characterize the reaction intermediates to gain further insight into the mechanism(s) for these
1
4,24
intriguing photo-activated aldehyde release reactions.
In this report, time-resolved spectroscopies included nanosecond time-resolved resonance Raman
3
(
ns-TR ) and femtosecond time-resolved transient absorption (fs-TA) were utilized to investigate the
photochemical reactions of 3-(1-hydroxypropan-2-yl)benzophenone (3-HPBP) over femtoseconds to
microseconds so as to directly detect the intermediates associated with the photo-release of
3
formaldehyde in aqueous solutions with varying pH values (see Scheme 1). Fs-TA sand ns-TR results
found that 3-HPBP readily undergoes base- or acid-assisted retro-aldol reactions after 266 nm excitation
to give efficient and clean production of an ethylbenzophenone product and release of formaldehyde.
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 21
Scheme 1. A possible mechanism proposed in reference 14 and an overview of reaction mechanisms
proposed in this work for release of formaldehyde from 3-HPBP after photolysis in strongly basic
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(pH=12.5) and acidic (pH=0) aqueous solutions.
Prior Work:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
This Work:
RESULTS
Release of formaldehyde for 3-HPBP in a basic aqueous solution through a heterolytic C-C bond
cleavage reaction
In a strong basic aqueous solution on the ultrafast time scale, 3-HPBP exhibits a BP-like conversion
from its S state to its T state. Figure 1 (a-c) displays the time evolution of the 3-HPBP spectra after
1
1
photoexcitation. Within 1 ps (see spectra shown in Figure 1a) 267 nm light excited 3-HPBP to an
excited singlet state and the maximum absorbance shifts from 329 nm up to 338 nm and then it experi-
ences an internal conversion (IC) from S to the S state which leads to the appearance of a new peak at
n
1
1
3, 28
5
80 nm from 0.8 ps to 3.5 ps.
Therefore, the strong transient absorption at 338 nm and weak broad
transient absorption at 580 nm are assigned to the first singlet excited state of 3-HPBP. We note the tran-
sient absorption of the first singlet excited state of BP and other BP derivatives also have a similar weak
1
3,25
broad transient absorption around 580 nm.
Next, (see Figure 1b), the S transient decays and
1
3
transforms into its triplet species ( [3-HPBP]) that have a peak at around 325 nm and a wide feature
4
ACS Paragon Plus Environment

Page 5 of 21
The Journal of Organic Chemistry
located at 525 nm. The two time constants for the S decrease in intensity (9.3±0.9 ps) and the T
1
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
increase in intensity (9.1±0.6 ps) further indicates the second transient is produced by the first singlet
excited state of 3-HPBP. The ISC time constant for 3-HPBP is about the same observed for BP in
29
acetonitrile and indicates the substituent has little effect on this process. In Figure 1c, the triplet
species decays slightly and can be easily observed up to 3 ns.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
.8 p s
1 .4 p s
.6 p s
1 .7 p s
.5 p s
0.1 ps
0.2 ps
0.3 ps
0.4 ps
0.55 ps
0.8 ps
b
338
3
3 8
a
1
3
6 .1 p s
9 .6 p s
1 5 .1 p s
5
2 5
3
3 .1 p s
3
29
50
350
400
4 50
50 0
550
600
3
400
450
500
550
600
650
wavelength/nm
w a v e le n g th /n m
3
3.1 ps
c
3099 ps
d
525
3
38 nm
5
25 nm
350
400
450
500
550
600
650
0
20
40 2500
delay time/ ps
3000
wavelength/nm
Figure 1 (a-d). Fs-TA spectra of 3-HPBP in MeCN:H O=1:1 (volume ratio) solution where sodium
2
hydroxide added to get a pH=12.5 and acquired subsequent to 267 nm excitation over the delay times
indicated by the inset delay time values and time dependent kinetics of 338 nm and 525 nm are shown.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
0 ns
Page 6 of 21
a
3
28 nm
b
500
500
3
29 nm
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5
0 ns
200 ns
6
05 nm
A
B
6
05 nm
3
00
400
600
700
2
74 nm
633 nm
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
00 350 400 450 500 550 600 650 700 750
3
00
400
600
700
wavelength/nm
Wavelength / nm
Figure 2. (a) Ns-TA spectra of 3-HPBP obtained after 266 excitation in basic (pH=12.5)
MeCN:H O=1:1 (volume ratio) solution. (b) Comparison of (A) the ns-TA spectrum observed at 0 ns
2
delay time and (B) the TD-DFT calculated absorption spectrum of triplet state benzylic carbanion
species intermediate.
Figure 2 shows nanosecond transient absorption (ns-TA) data for 3-HPBP in the basic (pH=12.5)
aqueous solution with MeCN:H O=1:1 (volume ratio). The transient has a strong absorption band at 329
2
nm and a wide feature at 605 nm and the kinetics were fit with exponential time constants of 76 ns at
3
29 nm and 80 ns at 605 nm (see Figure S1). The almost identical time constants reveal that only one
transient was detected by the ns-TA instrument. Consideration of the results from an earlier study of a
decarboxylation reaction of ketoprofen in a phosphate buffered solution, this intermediate can be readily
associated with the triplet state benzylic carbanion species (structure shown in Scheme 1) whose
2
1
absorption bands and kinetics are similar with that found after similar photolysis of ketoprofen. In
order to further verify the transient observed by ns-TA, TD-DFT computations were done for the triplet
state benzylic carbanion and a comparison of the results (Figure 2a ) indicate that the experimental ns-
TA spectrum obtained at 0 ns delay time is in good agreement with the predicted absorption spectrum of
the triplet state benzylic carbanion intermediate shown in Scheme 1. This demonstrates that the
6
ACS Paragon Plus Environment

Page 7 of 21
The Journal of Organic Chemistry
intermediate generated at early delay times with its characteristic absorption bands of 329 nm and 605
nm may be attributed to the triplet state benzylic carbanion intermediate.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
It is noted that there is a very weak shoulder feature at 525 nm around 0 ns, this transient absorption
3
band is likely a contribution from the [3-HPBP] intermediate that was seen in the femtosecond transient
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
absorption (fs-TA) spectra. The triplet benzylic carbanion appeared to be made at the expense of the
3
3
triplet [3-HPBP] species so that within several nanoseconds, the transient absorption of [3-HPBP]
quickly disappears in the ns-TA spectra.
3
Figure 3 shows the ns-TR spectra of 3-HPBP acquired in a pH=12.5 aqueous solution and two
transients are observed over 0 ns to 3 µs with the first intermediate having strong Raman bands at 957
-1
-1
-1
3
cm , 1222 cm and 1539 cm that can be attributed to the [3-HPBP] species since the 0 ns spectrum is
2
about the same as the spectrum of the triplet state of BP obtained under the same conditions. Second, in
3
Figure 3 (b), the DFT calculated normal Raman spectra of [3-HPBP] comparison with the experimental
resonance Raman spectrum at 0 ns shows good correlation between their vibrational frequencies. The
relative intensities differ somewhat since there is resonant enhancement of the experimental spectrum
3
whereas the computed one is not resonantly enhanced. The [3-HPBP] is the precursor of the second
species that starts to become distinguishable around 10 ns and grows in with its largest Raman bands
-1
-1
-1
located at 982 cm , 1518 cm and 1578 cm and can be attributed to the benzylic biradical 1 (structure
shown in Scheme 1) intermediate based on two reasons. First, a benzylic biradical 1 structure species
DFT predicted normal Raman spectrum shown in Figure 3c displays a good correlation of the
vibrational frequencies with the experimental 70 ns delay time resonance Raman spectrum and also with
the 80 ns delay time resonance Raman spectrum of a ketoprofen benzylic biradical 1 intermediate
(displayed in the center of Figure 3d) seen in decarboxylation reaction investigations of ketoprofen
1
3,30
photochemistry.
The benzylic biradical 1 can be obtained from a hydrogen shift of the triplet state
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 21
3
benzylic carbanion that is not seen in the ns-TR spectra since its transient absorption band ~600 nm is
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
30
far from the 319.9 nm probe wavelength utilized in the ns-TR experiment .
a
b
9
57
3
s
* *
1
078 1169 1222
1539
*
1 s
700 ns
500 ns
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
00 ns
2
1
00 ns
50 ns
8
00 1000 1200 1400 -11600 1800
Raman Shift/ cm
1
515
1
20 ns
9
7
0 ns
0 ns
c
1578
9
82
1515
9
82
*
50 ns
30 ns
20 ns
10 ns
1
222
1578
0
ns
1
169
9
57
1539
8
00 1000 1200 1400 -11 600 1800
Raman Shift (cm )
800 1000 1200 1400 1600 1800
-
1
Raman Shift/ cm
3
Figure 3. (a) 3-HPBP ns-TR spectra acquired in basic (pH=12.5) MeCN:H O=1:1 (volume ratio)
2
solution using 266 nm excitation and a 319.9 nm probe wavelength for different time delays. The
experimental resonance Raman spectrum of 3-HPBP at 0 ns (b) is compared to the DFT predicted
3
spectrum (c, bottom spectrum) for [3-HPBP]. The experimental 70 ns time delay resonance Raman
spectrum of 3-HPBP (c) acquired in a pH=12.5 basic MeCN:H O=1:1 solution is compared to an
2
experimental 80 ns delay time resonance Raman spectrum of the ketoprofen benzylic biradical 1
reported (c, middle spectrum) in reference 30 and the DFT predicted spectrum for the benzylic biradical
1
(c, bottom spectrum). Dotted lines indicate the correspondence between the computed and
experimental Raman features.
Release of formaldehyde in a strongly acidic aqueous solution by a C-C bond homolytic scission
reaction
8
ACS Paragon Plus Environment

Page 9 of 21
The Journal of Organic Chemistry
The photo-retro-aldo process to deprotect formaldehyde also occurs in strongly acidic (pH=0)
1
2
aqueous solutions. Figure 4 (a-d) displays transient absorption spectra and corresponding kinetics of
selected characteristic absorption features of 3-HPBP in strongly acidic (pH=0) aqueous solution. Three
separated sets of spectra for different time ranges are shown in Figures 4a to 4c. Figure 4a indicates the
S1 state 339 nm feature decreases in intensity and shifts to 334 nm and concurrently a 525 nm feature
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
increases in intensity at the expense of the S state over 1.2 ps to 31.1 ps. This new transient having 334
1
3
nm and 525 nm absorption features is attributed to the [3-HPBP] intermediate because of the similarly
of these results to the analogous results found in basic aqueous solutions discussed in the previous
section. Figure 4b shows the 525 nm feature decays whereas the 334 nm feature increases in intensity
and changes to 330 nm over 195 ps to 1850 ps and an isobestic point observed at 339 nm suggests the
triplet transforms into a new intermediate than can be attributed to a benzylic biradical 1 based on its
very similar changes in the fs-TA spectra for ~324 nm feature also observed on the same time scale for
3
1
the acid assisted photo-decarboxylation of ketoprofen under the analogous conditions. The kinetics at
selected different wavelengths are shown in Figure 4d and the triplet species feature at 525 nm decrease
in intensity can be fit by a 954±180 ps time constant that appears correlated with the growth of the
benzylic biradical 1 species time constant of 814±147 ps at 330 nm (within the uncertainty of the
measurements). In the later nanosecond time range, the transient absorption band at long wavelength
shifts down from 525 nm to 520 nm (see Figure 4c) which is consistent with the blue-shift of the
3
1
transient absorption of the ketoprofen biradical intermediate. The corresponding kinetics at each of
these wavelengths were also measured and are shown in Figure S2. The decay kinetics are about the
same with 345 ns for 329 nm and 347 ns for 520 nm, indicating these two features come from the same
intermediate of the benzylic biradical 1 intermediate. Additional support for this species being assigned
to a benzylic biradical 1 intermediate comes from the similarity of these results with those observed in a
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 21
previous ns-TA study for ketoprofen in similar acidic aqueous solutions of a benzylic biradical 1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
1
species.
1.2 ps
1.9 ps
4.1 ps
8.1 ps
14.6 ps
31.1 ps
330
3
194.6 ps
549.6 ps
799.6 ps
1849.6 ps
338
a
b
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
39
525
525
334
3
50
400
450
500
550
600
650
350
400
450
500
550
600
650
wavelength/ nm
wavelength/ nm
0 ns
329
d
c
300 ns
600 ns
1200 ns
3
30 nm
5
25 nm
39 nm
3
520
0
500 1000 1500 2000 2500 3000
3
50
400
450
500
550
600
650
delay time/ ps
wavelength/ nm
Figure 4. (a-d) 3-HPBP transient absorption spectra obtained in acidic (pH=0), MeCN:H O=1:1 (volume
2
ratio) solution using 267 nm excitation. The 330 nm, 339 nm and 525 nm kinetics of the spectra are
also shown.
3
Ns-TR data were done to find vibrational spectra of the intermediates generated in the photochemical
process of 3-HPBP in acidic pH=0 aqueous solution. Figure 5 indicates only one predominant transient
3
was observed in the ns-TR data. Compared to the behavior of 3-HPBP in basic aqueous solutions, a
3
quicker process occurs in acidic aqueous solutions since no Raman features of the [3-HPBP] transient
10
ACS Paragon Plus Environment

Page 11 of 21
The Journal of Organic Chemistry
3
precursor was seen in the early delay time of the ns-TR data in the strongly acidic aqueous solution.
This behavior is consistent with the transient absorption data for 3-HPBP in strongly acidic aqueous
solution as the formaldehyde release reaction occurs within a nanosecond. The transient is seen to decay
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-1
-1
-1
over 1 microsecond and has characteristic Raman bands at 982 cm , 1518 cm and 1578 cm
associated with similar Raman bands of the benzylic biradical 1 intermediate calculated for the normal
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Raman spectrum shown in Figure 3 (right lower panel, bottom spectrum). Compared with the spectra
3
that are observed in basic aqueous solutions, the ns-TR data observed in acidic aqueous solutions are
-1
-1
-1
much stronger so that smaller features at 959 cm , 1104 cm and 1175 cm can be more easily detected.
9
8
8
1
7
5
5
9
985
7
5
1
5
1
1
104
1
1
1
s
*
5
00ns
150ns
5
0ns
0ns
2
0ns
800
1000
1200
1400
1600
1800
-
1
Raman Shift (cm )
3
Figure 5. 3-HPBP ns-TR data in acidic pH=0, MeCN:H O of 1:1 (volume ratio) obtained using 266 nm
2
and a 319.9 nm probe at different indicated time delays.
Production of ketyl radicals in a neutral aqueous solution
In aqueous solutions of pH=12.5 and 0, irradiation of 3-HPBP leads to release of formaldehyde via
its reactive triplet state to first generate triplet state benzylic carbanion or benzylic biradical 1
intermediates respectively. Intriguingly, no benzylic biradical 1 species was seen in a neutral aqueous
solution. However, generation of ketyl radicals were observed presumably by proton coupling electron
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 21
transfer (PCET) process found for similar generation of a ketyl radical intermediate for BP and some BP
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
,32
derivatives after ultraviolet excitation in neutral MeCN:H O=1:1 (volume ratio) mixed solutions.
2
Usually, the carbonyl group of the triplet state of BP and BP derivatives will undergo a hydrogen
abstraction to produce a ketyl radical in a strong hydrogen donor solvent, such as isopropanol., However,
the carbonyl group of the triplet state of BP and BP derivatives can also produce a ketyl radical in aque-
ous solutions via an alternative PCET process even though water is a very weak hydrogen donor and
water is not easy to undergo the hydrogen abstraction reaction to generate a ketyl radical in aqueous so-
lutions. This PCET process involves the carbonyl group first being protonated and then undergo an elec-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
,32
tron transfer to produce the keyl radical species in aqueous solutions. The reader is referred to refer-
ence 32 for more details about how ketyl radicals are generated by hydrogen abstraction in strong hy-
drogen donor solvents such as isopropanol and by PCET in aqueous solutions from BP and some BP
derivatives. In Figure S3, the ns-TA spectra clearly show 325 nm and 525 nm transient absorption
2
features characteristic of a triplet intermediate much like that of the BP triplet. These features decay
with time constants of 394 ns (at 325 nm) and 368 ns (at 525 nm) and Figure S3 displays the kinetics
2
3
and fits to the data. Figure 6 displays the ns-TR data of 3-HPBP recorded in a neutral aqueous mixed
solution. Two intermediates were detected similar to the results for BP in the same kind of neutral
1
-1
-1
-1
aqueous solution . The first transient has Raman features at 963 cm , 1157 cm , 1222 cm and 1539
-1
cm that decrease in intensity over 0 ns to 30 ns and concurrently, a second transient starts to grow in
-1
-1
that has Raman features at 984 cm and 1581 cm that may be observed up to several microseconds.
-1
The characteristic Raman feature at 1539 cm can be attributed to a BP-like n,π* triplet transient and
-1
the diagnostic feature at 1581 cm can be attributed to a ketyl radical produced from PCET process with
3
,32
water by the preceding intermediate.
These data show there is no appreciable nucleophilic
substitution occurring to deprotect formaldehyde and also no appreciable protonation of the ketone is
observed to facilitate the release of formaldehyde in a neutral aqueous solution. Unlike the results seen
12
ACS Paragon Plus Environment

Page 13 of 21
The Journal of Organic Chemistry
3
in the strongly basic and acidic aqueous solutions, PCET reaction appears to cause the [3-HPBP]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
intermediate to mainly make a ketyl radical transient in the neutral MeCN:H O=1:1 mixed aqueous
2
3,32
solution examined here similar to BP and some other BP derivatives under similar conditions.
1581
9
84
5 s
2 s
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1.5 s
700 ns
500 ns
3
00 ns
00 ns
50 ns
20 ns
2
1
1
70 ns
50 ns
30 ns
20 ns
10 ns
0 ns
9
63
1
175 1222
1539
8
00 1000 1200 1400 1600 1800
-
1
Raman Shift (cm )
3
Figure 6. 3-HPBP ns-TR acquired in neutral MeCN:H O=1:1 (volume ratio) solution using 266 nm
2
excitation and a 319.9 nm probe wavelength are displayed with delay times indicated.
DISCUSSION
The pH value can serve as a switch that can turn off or turn on the photo-release of formaldehyde
following ultraviolet excitation of 3-HPBP in aqueous solutions. In neutral aqueous solutions, a ketyl
3
radical species produced from a PCET process of the [3-HPBP] and water analogous to BP (and some
BP derivatives) and water molecules under similar neutral aqueous solution conditions (see Scheme
3,32
2
). On the other hand, in the strong basic and acidic aqueous solutions; however, photolysis results in
3
the release of formaldehyde. The ns-TR and ns-TA data found in strong basic and acidic aqueous
solutions provide vibrational spectral data and associated dynamics of key transient species. These data
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 21
in conjunction with DFT computational results suggest in basic aqueous solution the hydroxide ion and
in acidic aqueous solutions protonation are involved to assist 3-HPBP to release formaldehyde. In basic
aqueous solutions, the observation of the triplet benzylic carbanion directly supports that heterolytic C-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
C bond occurs and is likely induced by a nucleophilic substitution in which OH reacts with the photo-
activated β-carbon sited alcohol through a S 2 path (leading to deprotonation) to give the deprotection
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
of formaldehyde.
A mechanism is proposed in Scheme 2 in which 266 nm photolysis in basic aqueous solution takes
the 3-HPBP ground state to a singlet excited state that then forms its triplet by ISC. The -carbon sited
3
alcohol hydrogen on the [3-HPBP] side chain first reacts with the hydroxide ion (that is stabilized by
the nearby water molecules leading to deprotonation) and then induces a heterolytic C-C bond scission
via nucleophilic substitution reaction so that the BP moiety forms a triplet state benzylic carbanion and
the formaldehyde is deprotected. Surprisingly, a release of formaldehyde occurs via a different pathway
in the strongly acidic aqueous solutions. This appears due in part to the carbonyl group of triplet state of
1,18
BP will be protonated under strong acid conditions. The observation of the benzylic biradical 1 shows
3
protonation of the [3-HPBP] ketone moiety appears to increase the reactivity of the β-alcohol through a
meta effect that gives rise to homolytic C-C bond scission to deprotect formaldehyde. We propose
protonation takes place because of the presence of the higher concentration of protons in a strongly
acidic environment and the carbonyl of the triplet BP group can be readily protonated to become a
reactant complex predisposed for structural rearrangement and further reaction as found in BP and
25,26
3
similar BP derivatives in strongly acidic aqueous solutions.
The protonated [3-HPBP] could then
undergo intramolecular charge transfer (the proton to the benzene ring) with molecule reforming so the
triplet electron pair separate into two radicals (benzylic biradical cation) via a meta effect to go to the
14
ACS Paragon Plus Environment

Page 15 of 21
The Journal of Organic Chemistry
3
2
benzene ring. The benzylic biradical cation likely directly undergoes the C-C homolytic cleavage to
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
form benzylic biradical 1 and to release the radical form of methanol (details are given in Scheme 2).
Scheme 2. Shown are the excited states and critical intermediates with their transient absorption and
resonance Raman bands and a possible mechanism in this work for pH dependent photochemical reac-
tion of 3-HPBP after photolysis in different aqueous solutions.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CONCLUSIONS
We studied an interesting photon induced reaction which is easily controlled by adjusting the pH
value of the aqueous solution, either turn-on in pH=12.5 and 0 conditions or turn-off near neutral pH=7
conditions. These intriguing pH dependent photo-release of formaldehyde reactions of HPBP have been
investigated utilizing time-resolved spectroscopic techniques in aqueous solutions. In a strong basic
aqueous solution (pH=12.5), the nucleophilic substitution reaction appears to occur via a hydroxide ion
reaction to cause a deprotonation that induces the release of formaldehyde via a photo-activated β-
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 21
carbon heterolytic C-C cleavage that directly generated a benzylic carbanion (the transient absorbing at
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
6
05 nm detected in the ns-TA experiments). The benzylic biradical 1 species observed by ns-TR is a
structure obtained through an excited state hydrogen shift with the triplet state benzylic carbanion.
Surprisingly, in a strong acid (pH=0) aqueous solution, it is thought that protonation of the carbonyl of
3
-HPBP takes place and a meta effect of the protonated triplet state of 3-HPBP will lead to release of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
formaldehyde via a β-carbon homolytic C-C cleavage pathway. The benzylic biradical 1 directly formed
3
3
by homolytic C-C cleavage was also observed in ns-TR spectra. However, the [3-HPBP] species
appears to undergo a PCET process to produce a ketyl radical rather than release a formaldehyde in
neutral (pH=7) or near neutral aqueous solutions similar to the parent BP molecule and some other BP
3
,32
derivatives.
EXPERIMENT AND COMPUTATIONAL SECTION
3-(1-hydroxypropan-2-yl)benzophenone (3-HPBP) was prepared using commercially available
3
3
1
13
ketoprofen and employing a procedure detailed in the literature and characterized by H and C NMR
spectra presented in the supporting information. For the experiments, the sample was recrystallized with
acetonitrile and water and then utilized to make a solution with a volume ratio of 1:1. The pH values of
the sample aqueous solutions were prepared using sodium hydroxide and perchloric acid to make
solutions with approximate pH values of 12.5 to 0 respectively for the basic and acidic aqueous samples.
The fs-TA experiments used 3-HPBP sample solutions with a 266 nm absorbance of 1 using a 2 cm
3
thick quartz cell while the ns-TR experiments samples used a concentration of 1.5 mM. The fs-TA, ns-
3
13
TA and ns-TR experimental apparatus and procedures have been detailed previously and a brief
account is provided in the supporting information.
Density Function Theory (DFT) computations using the (U)B3LYP/6-311G(d, p) method and basis set.
were employed to find the optimized geometries, vibrational modes and the vibrational frequencies for
16
ACS Paragon Plus Environment

Page 17 of 21
The Journal of Organic Chemistry
the different species of interest in this work (please see supporting information for more details). All of
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
4
the calculations were done using a commercially available program suite.
SUPPORTING INFORMATION
The 3-HPBP ns-TA kinetics determined at 329 and 605 nm in basic aqueous [pH=12.5, mixed
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MeCN:H O=1:1 (volume ratio)] solution and also at 329 nm (a) and 520 nm (b) and 660 nm (c) in an
2
acidic aqueous [pH=0, mixed MeCN:H O=1:1 (volume ratio)] solution are provided. 3S (a, b). Shown
2
are 3-HPBP ns-TA kinetics obtained at 325 and 525 in [pH=7, mixed aqueous MeCN:H O=1:1 (volume
2
ratio)]. 3-HPBP ns-TA data of in neutral aqueous solution of [pH=7, MeCN:H O=1:1 (volume ratio)]
2
are also given. The UB3LYP/6-311G(d, p) computational results for the Cartesian coordinates, sum of
electronic and thermal free energies for the optimized geometry of the intermediates of interest are pro-
1
13
vided. The H and C NMR spectra of 3-HPBP are given. A brief description of the experimental appa-
3
ratus and procedures used for the fs-TA, ns-TA and ns-TR experiments are provided.
AUTHOR INFORMATION
Corresponding Authors
*
mdli@stu.edu.cn and *phillips@hku.hk
Notes
The authors declare no competing financial interest
ACKNOWLEDGMENT
This work was supported by a grant from the Research Grants Council of Hong Kong (HKU 17301815)
to DLP and partial support from the University Grants Committee of Hong Kong Areas of Excellence
Scheme (AoE /P-03/08) and a Special Equipment Grant (SEG-HKU-07) as well as an University
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 21
Development Fund grant for the “New Ultrafast Spectroscopy Experiments for Shared Facilities“ from
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the University of Hong Kong.
REFERENCES
(1) Du, Y.; Xue, J.; Li, M. D.; Phillips, D. L.J. Phys. Chem. A 2009, 113, 3344-3352.
(2) Du, Y.; Ma, C.; Kwok, W. M.; Xue, J.; Phillips, D. L. J. Org. Chem.2007,72, 7148-7156.
(3) Li, M. D.; Huang, J.; Liu, M.; Li, S.; Ma, J.; Phillips, D. L. J. Phys. Chem. B 2015, 119, 2241-2252.
(4) Matinez, L. J.; Scaiano, J. C. J. Am. Chem. Soc. 1997, 119, 11066-11070.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(5) Laferriere, M.; Sanrame, C. N.; Scaiano, J. C. Org. Lett. 2004, 6, 873-875.
(6) Lukeman, M.; Scaiano, J. C. J. Am. Chem. Soc. 2005, 127, 7698-7699.
(7) Tahara, T.; Hamaguchi, H.; Tasumi, M. Chem. Phys. Lett. 1988, 152, 135-139.
(8) Tahara, T.; Hamaguchi, H.; Tasumi, M. J. Phys. Chem. 1990, 94, 170-178.
(
(
(
(
9) Yabumoto, S.; Sato, S.; Hamaguchi, H. Chem. Phys. Lett. 2005, 416, 100-103.
10) Du, Y.; Xue, J.; Ma, C.; Kwok, W. M.; Phillips, D. L. J. Raman Spectrosc. 2008, 39, 503-514.
11) Moore, W. M.; Hammond, G. S.; Foss, R. P. J. Am. Chem. Soc. 1961, 83, 2789-2794.
12) Pitts, J. N. Jr.; Letsinger, R.L.; Taylor, R. P.; Patterson, J. M.; Recktenwald, G.; Martin, R. B. J. Am.
Chem. Soc. 1959, 81, 1068-1077.
13) Li, M. D.; Ma, J.; Su, T.; Liu, M. Y.; Yu, L. H.; Phillips, D. L. J. Phys. Chem. B 2012, 116, 5882-
887.
(14) Xu, M.; Wan, P. Chem. Commun. 2000, 2147-2148.
15) Li, M. D., Du, Y.; Chuang, Y. P.; Xue, J.; Phillips, D. L. Phys. Chem. Chem. Phys. 2010, 12, 4800-
808.
(16) Borsarelli, B. C.; Braslavsky, S.; Sortino, E. S.; Marconi, G.; Monti, S. Photochem. Photobiol.
000, 72, 163-171.
(
5
(
4
2
18
ACS Paragon Plus Environment

Page 19 of 21
The Journal of Organic Chemistry
(
17) Sobczak, M.; Wagner, P. J. Org. Lett., 2002, 4, 379-382.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(18) Ramseier, M.; Senn, P.; Wirz, J. J. Phys. Chem. A 2003, 107, 3305-3315.
(19) Li, M.-D.; Du, Y.; Yeung, C. S.; Phillips, D. L. J. Phys. Chem. A 2009, 113, 12215-12224.
(
(
(
20) Zimmerman, H. E. J. Am. Chem. Soc. 1995, 117, 8988-8991.
21) Basaric, N.; Mitchell, D.; Wan, P. Can. J. Chem. 2007, 85, 561-571.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
22) Ma, J.; Su, T.; Li, M. D.; Du, W.; Huang, J.; Guan, X.; Phillips, D. L. J. Am. Chem. Soc. 2012, 134,
1
4858-14868.
(23) Lukeman, M.; Xu, M.; Wan, P. Chem. Comm. 2002, 2, 136-137.
(
24) Xu, M.; Lukeman, M.; Wan, P. J. Photochem. Photobiol. A: Chem. 2009, 204, 52-62.
25) Ma, J.; Li, M. D.; Phillips, D. L.; Wan P. J. Org. Chem. 2011, 76, 3710-3719.
(
(26) Mitchell, D.; Lukeman, M.; Lehnherr, D.; Wan, P. Org. Lett. 2005, 7, 3387-3389.
(27) Wan, P.; Muralidharan, S. J. Am. Chem. Soc. 1988, 110, 4336-4345.
(28) Li, M. D.; Li, W.; Ma, J.; Su, T.; Liu, M.; Du, Y.; Phillips, D. L. J. Phys. Chem. A 2011, 115, 14168-
14174.
29) Aloïse, S.; Ruckebusch, C.; Blanchet, L.; Rehault, J.; Buntinx, G.; Huvenne, J. P. J. Phys. Chem. A
008, 112, 224-231.
30) Li, M. D.; Su, T.; Ma, J.; Liu, M.; Liu H.; Li, X.; Phillips, D. L. Chem. Eur. J. 2013, 19, 11241-
1250.
(31) Li, M. D.; Yeung, C. S.; Guan, X.; Ma, J.; Li, W.; Ma C.; and Phillips, D. L. Chem. Eur. J. 2011, 17,
0935-10950.
32) Zhang, X.; Ma, J.; Li, S.; Li, M. D.; Guan, X.; Lan, X.; Zhu, R.; Phillips, D. L. J. Org. Chem.,
2016, 81, 5330–5336
33) Mahindroo, N.; Connelly, M. C.; Punchihewa, C.; Kimura, H.; Smeltzer, M. P.; Wu, S.; Fujii, N. J.
Med. Chem. 2009, 52, 4277-4287.
(
2
(
1
1
(
(
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 21
(
34) Frisch, J. N.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Mont-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
gomery, J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C. et al. Gaussian 09 Revision A.1,; Gaussian, Inc.:
Wallingford, CT, 2009.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
20
ACS Paragon Plus Environment

Page 21 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
21
ACS Paragon Plus Environment