Regioselectivity of Hydroxyl Radical Reactions with Arenes in Nonaqueous Solutions

Article abstract of DOI:10.1021/acs.joc.8b03188

The regioselectivity of hydroxyl radical addition to arenes was studied using a novel analytical method capable of trapping radicals formed after the first elementary step of reaction, without alteration of the product distributions by secondary oxidation processes. Product analyses of these reactions indicate a preference for o- over p-substitution for electron donating groups, with both favored over m-addition. The observed distributions are qualitatively similar to those observed for the addition of other carbon-centered radicals, although the magnitude of the regioselectivity observed is greater for hydroxyl. The data, reproduced by high accuracy CBS-QB3 computational methods, indicate that both polar and radical stabilization effects play a role in the observed regioselectivities. The application and potential limitations of the analytical method used are discussed.

Full text of DOI:10.1021/acs.joc.8b03188

Subscriber access provided by University of Glasgow Library
Article
Regioselectivity of Hydroxyl Radical Reactions
with Arenes in Nonaqueous Solutions
Lee C. Moores, Devinder Kaur, Mathew D Smith, and James S. Poole
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03188 • Publication Date (Web): 19 Feb 2019
Downloaded from http://pubs.acs.org on February 20, 2019
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 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 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.
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 26
The Journal of Organic Chemistry
1
2
3
4
5
6
Regioselectivity of Hydroxyl Radical Reactions with Arenes in Nonaqueous
Solutions
7
8
9
Lee C. Moores,1 Devinder Kaur,1 Mathew D. Smith1 and James S. Poole2*
1Department of Chemistry, Ball State University, Muncie IN 47306
2Current address: Department of Chemistry and Biochemistry, St. Cloud State University, St Cloud MN 56301
jspoole@stcloudstate.edu
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Received Date: TBD
Title Running Head: Hydroxyl Radical Reaction with Arenes
Corresponding Author Footnote: *Author to whom correspondence should be addressed.
TOC Graphic:
1.60
ortho
1.20
0.80
0.40
0.00
-0.40
meta
para
-OCH
3
Z
-CH
3
+
HO
-Cl
MeCN or C6H6
298K
-H
-CF3
8.00
8.50
9.00
9.50
10.00
Ionization Potential (eV)
Abstract
The regioselectivity of hydroxyl radical addition to arenes was studied using a novel analytical method
capable of trapping radicals formed after the first elementary step of reaction, without alteration of the
product distributions by secondary oxidation processes. Product analyses of these reactions indicate a
preference for o- over p- substitution for electron donating groups, with both favored over m-addition. The
observed distributions are qualitatively similar to those observed for the addition of other carbon-centered
radicals, although the magnitude of the regioselectivity observed is greater for hydroxyl. The data,
reproduced by high accuracy CBS-QB3 computational data, indicate that both polar and radical
stabilization effects play a role in the observed regioselectivities. The application and potential limitations
of the analytical method used are discussed.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 26
1
2
3
4
Introduction
5
6
7
8
Hydroxyl radical (HO•) is an important member of the class of compounds collectively known as
reactive oxygen species (ROS). The gas phase1 and aqueous2 reactivity of this species has been extensively
studied, largely driven by the importance of this reactive intermediate in both biological3-5 and
environmental6‐10 processes, and a considerable degree of effort has been expended to identify quantitative
structure-reactivity relationships for hydroxyl radical in the gas,11-13 nonaqueous14-16 and aqueous17-18
phases.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Previous laser flash photolysis (LFP) studies of the reactivity of hydroxyl radical with substituted arenes
in acetonitrile14-15 determined that the observed rate coefficient for reaction with arenes was more sensitive
towards the nature of the substituents than those observed in aqueous solutions. Nonaqueous reactivity data
exhibited a relatively poor correlation with aqueous data, which may have relevance to environmentally
and synthetically19-20 useful processes involving HO• that occur at interfaces21-23 and other non-isotropic
environments such as aerosols,24-25 soils26-28 and emulsions.29-31 A state correlation analysis, analogous to
that utilized by Fischer and Radom for radical additions to alkenes in solution,16, 32 provided a structure-
reactivity relationship characteristic of reactions involving electrophilic species where there is significant
+ †
charge transfer (in this case [HO----arene• ] ) character in the transition state. We were interested in
determining if the lowered reactivity and greater structural sensitivity of HO• reactions in nonaqueous
phases affects the observed regioselectivity of reaction.
In principle, substituents on the ring can enhance or retard the reactivity of the ring and may exert a
degree of regioselectivity in the reaction outcomes. A great deal of emphasis has been placed on reactivity,
the measurement and prediction of overall rate coefficients, rather than selectivity. Much of the data in
water have been obtained via pulse radiolysis techniques,2, 33-34 which provide an overall rate coefficient,
but do not typically provide branching ratios. LFP14-16, 35-36 suffers from similar limitations. Some partial
selectivity data may be gleaned from judicious isotopic substitution and determining the magnitude of the
kinetic isotope effect.14 The difficulty in correlating observed rate coefficients with widely used substituent
parameters (such as Hammett parameters)37 arises from the fact that any such attempt is predicated on the
ACS Paragon Plus Environment

Page 3 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
notion that the selectivity of the overall reaction remains fundamentally the same. HO• is an electrophilic
radical, and the differing directing effects of substituents on aryl rings with respect to non-radical
electrophiles are well known to organic chemists. We therefore wished to probe the degree to which
directing effects apply in these systems.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Product studies may be used to probe the selectivity of hydroxyl radical oxidation of arenes. However,
these studies have a potential limitation in that intermediates may be diverted into other oxidative pathways
(such as trapping by O2),38-40 and that many of the primary oxidation products (hydroxylated arenes) may
potentially exhibit greater reactivity than the starting material, and secondary oxidation is possible. In some
circumstances the substrates may be exhaustively oxidized. Thus, it may be difficult to unambiguously
assign branching ratios based on a complex (or even incomplete) product distribution. The ability to “trap”
the products of the first reaction step between HO and arenes and to inspect the trapped product
distributions may be instructive in this regard.
In this contribution, we describe such a product distribution study of hydroxyl radical reactivity towards
substituted benzenes, intended to determine whether:
(a)
selectivity observed in non-aqueous media mirror those observed in aqueous media to the degree
that reliable predictions may be made from aqueous data, and
(b)
substituents on aromatic rings exert directing effects similar in nature (if not in magnitude) towards
electrophilic HO, as they do toward “classical” electrophiles.
To this end, we have developed an analytical protocol involving the “trapping” of carbon-centered radical
intermediates from the first addition of hydroxyl radical to arenes that utilizes the chemistry of persistent
aminoxyl radicals such as 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO). GC/MS analysis of the product
distributions obtained has allowed us to determine relative rate coefficients and branching ratios for
hydroxyl radical attack on a series of arenes substituted by electron-donating and -withdrawing groups.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 26
1
2
3
4
Results and Discussion
5
6
7
8
Hydroxyl radical is generated thermally by the decomposition of azohydroperoxide 1, formed by the
autoxidation of acetone tert-butyl hydrazone (of the order of 0.01 moldm-3) in benzene (Scheme 1).41-42 The
decomposition is carried out in approximately equimolar mixtures of substrate and benzene (or in the case
of anisole 0.3-0.5 moldm-3 in benzene), so that a large excess of aromatic substrate (relative to peroxide) is
present. In acetonitrile, concentrations of 0.8 – 1.0 moldm-3 of both substrate and benzene are used. In each
case 2.3 – 2.5 molar equivalents (relative to peroxide) of TEMPO is used.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Decomposition of Azohydroperoxide in the presence of TEMPO
O2

+
+
+
HO
O
N2
HN N
N N
benzene
OOH
TEMPO
X
(1)
TEMPO
TEMPO =
(2)
N
N
O
O
TEMPO is known to couple selectively with carbon-centered radicals at close to diffusion-limited rates (1-
2 × 109 M-1s-1).43 There is evidence to suggest that TEMPO will react with oxygen-centered radicals such
as HO•,44 but under the conditions of this study such a reaction will not successfully compete with reactions
on arenes. Thus, the formed tert-butyl radical is rapidly scavenged by TEMPO to generate 2, leaving the
HO• free to react with the substrate. Aminoxyl radicals such as TEMPO are known to induce peroxide
decomposition,45 but this does not appear to affect the outcome of this experiment and the anticipated
nitrone was not detected.
Addition of HO• to a functionalized arene leads to the formation of stabilized cyclohexadienyl radicals,
which may couple with TEMPO to yield alkoxylamines, or undergo disproportionation to yield phenols
and the reduced species TEMPOH (Scheme 2). The former reaction is likely to be readily reversible –
ACS Paragon Plus Environment

Page 5 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
thermal reversibility of coupling with resonance stabilized allylic and benzylic radicals has been observed
at moderate temperatures,46-47 and the latter reaction has been reported in studies of free radical initiated
oligomerization of styrene.42, 48 Fragmentation/disproportionation of O-cumyl derivatives of TEMPO to
yield alkenes via more stable alkyl radicals has also been reported in the literature.49 The disproportionation
reaction is less likely to be reversible, due to the stability of the formed phenols, and the fact that TEMPOH
may be readily re-oxidized to TEMPO.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Possible Reaction Paths for Cyclohexadienyl Radicals with TEMPO
X
TEMPO
+
+
HO
X
X
N
OH
HO
HO
(TEMPOH)
TEMPO
OH
X
or
N
O
N
O
X
OH
The presence of excess TEMPO in the product mixtures induces a significant degree of
paramagnetic broadening in the NMR spectra of these mixtures, which precludes the integration of the
resonance peaks as a direct measure of product yields. In addition, there is a degree of spectral overlap in
the 1H NMR spectra of isomeric phenols which may limit the selectivity of this method for some substrates.
Instead, the mixture of products was isolated and subjected to GC/MS (or GC/FID) analysis; to assist
analysis, the phenols were silylated using N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA). Given the
reversibility of coupling between TEMPO and carbon-centered radicals at high temperatures (such as those
used in the inlet port or transfer line of the GC/MS instrument), it is important to note that the analytical
method is blind to certain reaction types, such as ipso-attack and hydrogen abstraction by HO• from side
chains. Previous LFP-based kinetic isotope effect studies suggest that at least for simple alkyl groups, the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 26
1
2
3
4
5
6
7
8
9
latter is not a dominant reaction. In some cases, a degree of chromatographic interference necessitated the
use of extracted, rather than total, ion chromatograms. Standard curves were constructed to determine the
appropriate instrument response factors for isomeric compounds having the same fragments, but differing
fragmentation patterns. The obtained product distributions for a sampling of monosubstituted benzene rings
with both electron-withdrawing and -donating groups are shown in Table 1. Reaction of isomeric xylenes
with hydroxyl radical in the presence of TEMPO will generate a series of isomeric dimethylphenols
(Scheme 3), and the product distributions for xylenes are summarized in Table 2.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Proposed Outcomes for Reactions of Xylenes with HO/TEMPO
(1) HO
+
(2) TEMPO
HO
OH
o-xylene
3,4-dimethylphenol
2,3-dimethylphenol
OH
(1) HO
+
+
(2) TEMPO
OH
OH
m-xylene
2,4-dimethylphenol
3,5-dimethylphenol
2,6-dimethylphenol
(1) HO
(2) TEMPO
OH
p-xylene
2,5-dimethylphenol
In general terms there is a degree of agreement within the dataset for monosubstituted arenes (Table
1 and Supplementary Information). The method denoted method 2 in Table 1 differs only in the aminoxyl
used (in this case 1,1,3,3-tetramethylisoindolin-N-oxyl, TMIO) and the analytical technique used (GC/FID,
rather than GC/MS). The selectivity data obtained for toluene by both methods are consistent, but the
reactivity relative to benzene is significantly different, and this may be a consequence of the product
analyses: the instrument response factors used in the GC/FID analyses are based on “effective carbon
number” approaches.50
ACS Paragon Plus Environment

Page 7 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Where measured, the relative rates of substrate and benzene towards HO in acetonitrile are consistent
with those calculated from LFP data, although the relative rate of anisole in benzene is approximately twice
to thrice that observed from LFP in acetonitrile. With respect to this observation, it may be germane to
note that in all cases, the GC/MS instrument response factors were assumed to be linear in concentration
for all TMS ethers. There is some indication that this may not apply to the TMS ethers of methoxyphenols.
The temperature ranges employed were dictated by the initiator – kinetic studies found that the rate of
decomposition of 1 is substantially accelerated in more polar solvents such as acetonitrile and chloroform.
Attempts to carry out the autoxidation of acetone tert-butyl hydrazone in these solvents led to significant
decomposition in situ. Thus, for the acetonitrile studies, 1 was generated as a concentrated solution in
benzene and injected into thermally pre-equilibrated solutions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The measured reactivities and product distributions in all cases show little change over the
temperature ranges studied, and exhibit modest variations with solvent, where such variation could be
measured. In some cases, there are distinctions between observed regioselectivities and those previously
reported in the literature.40, 51-55 The origin of these differences is not entirely clear, but we note that in
previous product studies, the yields of formed products are often low, suggesting the possibility of
secondary oxidation. Others involve photochemical conditions where it is possible that primary
photoproducts may undergo secondary photolysis. If this is so, we are not yet able to determine whether
any reactivity bias exists for the primary oxidation products that would enhance or decrease their presence
in the final product mixture. There is a great deal of variation in the observed product distributions for water
alone: the product distributions are dependent on the manner of hydroxyl radical generation, and the
environment this species finds itself in – in a number of these studies, reactions are believed to proceed at
surfaces,54-55 rather than in homogeneous solution.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 26
1
2
3
4
Table 1. Observed Product Distributions for Hydroxyl Radical Attack on Substituted Arenesa
5
6
7
8
Temp. co-solvent Methodb
(K)
Prod. ratiosd
subs : benz
15.4 ± 1.2
Product ratiosd
o- : m- : p-
(16.5 ± 0.8) : 1 : (5.2 ± 0.2)
% Prod. dist. Branching ratiose
c
group
benz/subs
o- : m- : p-
o- : m- : p-
-OCH3
318
benzene
1
50 - 75
(0.3-0.5M)
73 : 4 : 23
34 : 1.8 : 21
298
none
none
water
water
benzene
none
benzene
acetonitrilei
water
photf
photg
Fentonh
photh
1
3.1 : 0 : 1
5.2 : 0 : 1
16 : 1 : 3
76 : 0 : 24
84 : 0 : 16
79 : 5 : 15
75 : 11 :14
65 : 16 : 19
64 : 17 : 19
65 : 17 : 19
61 : 18 : 21
48 : 23: 28
57 : 14 :29
38 : 23 : 39
53 : 36 : 11
71 : 9 : 20
70 : 11 : 19
43 : 26 : 31
55 : 21 : 24
45 : 23 : 32
44 : 16 : 40
37 : 22 : 41
38 : 23 : 39
30 : 47 : 23
34 : 46 : 20
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
6.8 : 1 : 1.3
-CH3
318
318
318
318
298
1.0 – 1.2
2.57 ± 0.13
(3.94 ± 0.11) : 1 : (1.16 ± 0.03)
(3.82 ± 0.14) : 1 : (1.11 ± 0.06)
(3.89 ± 0.15) : 1 : (1.14 ± 0.06)
(3.42 ± 0.14) : 1 : (1.16 ± 0.05)
2.05 : 1 : 1.21
5.0 : 1.2 : 2.9
2
2
1
3.53 ± 0.34j
2.72 ± 0.28
6.9 : 1.8 : 4.0
5.0 : 1.5 : 3.4
0.85 – 0.90
-radk
Fentonh
photh
Electrol
photf
photf
1
water
water
water
none
4.1 : 1 : 2.1
1.7 : 1 : 1.7
1.47 : 1: 0.31
7.9 : 1 : 2.2
273
298
298
318
318
298
acetonitrile
benzene
acetonitrilei
water
6.3 : 1 : 1.7
-Cl
1.0 – 1.2
0.85 – 0.90
0.51 ± 0.04
0.67 ± 0.02
(1.66 ± 0.22) : 1 : (1.20 ± 0.02)
(2.56 ± 0.02) : 1 : (1.13 ± 0.01)
2.0 : 1 : 1.4
0.66 : 0.40 : 0.95
1.1 : 0.42 : 0.96
1
-radk
Fentonh
photh
photf
1
water
water
none
2.8 : 1 : 2.5
1.7 : 1 : 1.9
1.7 : 1 : 1.7
298
318
318
-CF3
benzene
1.2 – 1.4
0.85 – 1.10
0.19 ± 0.01
0.22 ± 0.01
(0.64 ± 0.06) : 1 : (0.49 ± 0.05)
(0.73 ± 0.06) : 1 : (0.44 ± 0.05)
0.17 : 0.27 : 0.26
0.22 : 0.30 : 0.26
acetonitrilei
1
b
aAdditional data for temperature ranges 318-348K in hydrocarbons, and 308-328K in acetonitrile may be found in the Supporting Information. Methods as described
in text unless otherwise indicated. cRange of mole ratio of substrate in benzene (mixture of solvents), concentration is cited for anisole, as it is diluted in benzene.
dProduct ratios determined by GC/MS unless otherwise indicated, and do not include reactivity such as ipso-substitution or hydrogen abstraction from side chains, see
text. Regioisomer ratios were determined relative to the meta-isomer. eCalculated relative to benzene: branching ratio = (% product distribution  product ratio
f
g
(substrate/benzene))  (6/n), where n is the number of each type of addition site available on the substrate. Photolysis of azohydroperoxide, ref. 51 Photolysis of
h
j
azohydroperoxide, ref. 52. Ref. 55, phot = photocatalytic dissociation of water over Pt/TiO2. iAcetonitrile/benzene co-solvents used. Calculated by Effective Carbon
Number, see text and SI. k-irradiation (60Co), ref. 53. Electrochemical generation (FeII/O2, ref. 54).
l
ACS Paragon Plus Environment

Page 9 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
Table 2. Observed Product Distributions for Hydroxyl Radical Attack on Substituted Arenes
7
8
9
Methoda
Product ratiosc
subs : benz
Product ratiosc
% Prod. dist.
Branching ratiosd
b
group
Temp.
(K)
co-
solvent
benz/subs
o-xylene
2,3- : 3,4-
(1.41 ± 0.06) : 1
(1.43 ± 0.03) : 1
(1.39 ± 0.04) : 1
(1.40 ± 0.03) : 1
2,4- : 3,5- : 2,6-
2,3- : 3,4-
59 : 41
59 : 41
58 : 42
58 : 42
2,3- : 3,4-
4.6 : 3.2
5.7 : 3.9
5.4 : 3.9
5.7 : 4.2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
348
338
328
318
benzene
benzene
benzene
benzene
1
1
1
1
1.25 – 1.35
1.25 – 1.35
1.25 – 1.35
1.25 – 1.35
2.6 ± 0.3
3.2 ± 0.6
3.1 ± 0.5
3.3 ± 0.4
m-xylene
p-xylene
2,4- : 3,5- : 2,6-
64 : 6 : 30
64 : 6 : 30
65 : 6 : 29
65 : 5 : 30
2,4- : 3,5- : 2,6-
8.4 : 1.6 : 7.9
8.4 : 1.6 : 7.9
8.6 : 1.6 : 7.7
8.0 : 1.2 : 7.4
348
338
328
318
benzene
benzene
benzene
benzene
1
1
1
1
1.25 – 1.35
1.25 – 1.35
1.25 – 1.35
1.25 – 1.35
4.4 ± 0.1
4.4 ± 0.1
4.4 ± 0.2
4.1 ± 0.2
(10.9 ± 0.4) : 1 : (5.2 ± 0.3)
(11.5 ± 0.1) : 1 : (5.4 ± 0.2)
(12.0 ± 1.2) : 1 : (5.4 ± 0.5)
(12.1 ± 0.2) : 1 : (5.5 ± 0.1)
348
338
328
318
benzene
benzene
benzene
benzene
1
1
1
1
1.29 – 1.37
1.29 – 1.37
1.29 – 1.37
1.29 – 1.37
3.3 ± 0.4
3.9 ± 1.5
3.9 ± 0.6
4.1 ± 0.3
5.0
5.9
5.9
6.2
aMethods as described in text unless otherwise indicated. bRange of mole ratio of substrate in benzene (mixture of solvents). Product ratios determined by GC/MS, and
do not include reactivity such as ipso-substitution or hydrogen abstraction from side chains, see text. eCalculated relative to benzene: branching ratio = (% product
distribution  product ratio (substrate/benzene))  (6/n), where n is the number of each type of addition site available on the substrate.
c
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 26
1
2
3
4
5
6
7
8
9
It is possible to determine relative rate coefficients for each of the substrates with respect to benzene
(ksubs/kbenzene) based on the product distributions and compare these to the relative rates obtained in other
media (Figure 1). Given the relatively small changes observed with temperature, the relative rates at 318
K are likely to be similar to those at 298 K.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3.00
acetonitrile
y = 0.819x + 0.011
R² = 0.932
hydrocarbon
2.00
-OCH
3
1.00
xylenes
-CH
3
0.00
-Cl
-CF3
-1.00
-1.00
0.00
1.00
2.00
3.00
log10(k/kbenzene gas
)
Figure 1. Correlation of observed relative rate coefficients for arenes in solution phase with gas phase rate coefficients
(Ref. 1). Data in acetonitrile (open circles) were determined by LFP for mono- and disubstituted benzenes, bicyclics
and heteroarenes at 298K (Ref. 15). Data in hydrocarbon at 318K (filled circles) are from this work.
Figure 1 demonstrates a strong linear correlation between relative kinetics observed in the gas phase
and in acetonitrile solution, without the “breaks” that might be associated with a mechanistic change, such
as electron transfer reactions between HO and electron-rich arenes such as anisole. In an even less polar
environment such as the hydrocarbon solvents used in this study, there is even more limited scope for
stabilization of electron transfer intermediates, and the correlation is very similar to that observed in
ACS Paragon Plus Environment

Page 11 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
acetonitrile. The data support the notion that the rate coefficients in organic phases are better estimated
from gas-phase data rather than aqueous data.15
7
8
9
The data available for the xylenes are less comprehensive, as we do not have a direct experimental
indication of the importance of abstraction in these systems: our product distribution studies report only
addition products, whereas the other studies report a total rate coefficient. There is a deviation from the
linear relationship in the xylenes that lends some support to the notion of a partial capture of the total rate
coefficient by our method. Nonetheless, we find the ratios ksubs/kbenzene of 3.3, 4.1 and 4.1 for o-, m- and p-
xylene respectively in hydrocarbon solvent at 318 K (partial k) to be comparable with (total k) values of
5.4, 6.6 and 5.5 for these species in acetonitrile at 298 K:14 both are somewhat smaller than the ratios of
9.0, 15.1 and 9.6 in the gas phase.1 In On the other hand, in aqueous solution, the relative rate coefficients
for o-, m- and p-xylene with respect to benzene are 0.85, 0.96 and 0.90 respectively.2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With respect to regioselectivity, the broad strokes in monosubstituted rings are similar to those
presented for SEAr reactions:56 electron-donating groups such as –OCH3 and –CH3 show a strong preference
for ortho- and para- over meta-substituted products; the latter becoming increasingly favored with weakly
donating (-Cl) and inductively electron withdrawing (-CF3) groups. In the case of the –CF3 group, the m-
product becomes the major, but not dominant, product. In principle, if radical stabilization effects were
dominant, we might expect greater parity in the product distribution since electron-withdrawing groups are
also radical stabilizing. Thus, the reactivity and overall regioselectivity data point to a situation where
electron transfer states are significant contributors to the transition state energy, and polar effects are also
important. Such a situation has precedent, since it is known that radical addition to olefins is controlled by
a combination of steric, polar, and thermochemical (radical stability) effects.32
Branching ratios, that correct for statistical biases due to differing numbers of sites of attack, are
included in Tables 1 and 2, and correspond to the reactivities of various sites on the monosubstituted ring
relative to the reactivity of benzene. For electron-donating groups, we observe a greater reactivity toward
the ortho-product over the para- product, which is reduced and ultimately reversed in systems bearing
electron-withdrawing groups. In general terms, it is difficult to predict o-/p- ratios a priori, but a case for
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 26
1
2
3
4
5
6
7
8
9
preference for para- attack in electrophilic aromatic substitution may be made on structural grounds.56
Alternatively, preference for ortho- attack has been observed for free radical substitutions on aromatic rings,
where spin density distribution and radical stabilization plays a role. The preference for o- attack over p-
attack observed in this study is consistent with earlier studies involving different radicals (Table 3).57-62
To determine whether any structure-reactivity relationships may be applied to questions of
regioselectivity, the observed relative rates in benzene at 318 K were plotted as a function of experimental
ionization potential (IP) of the arene (Figure 2). We assume that the observed chemistry exists under kinetic
control, with no significant reversibility of hydroxyl radical attack prior to quenching of the formed
cyclohexadienyl radicals. The current set of experimental data indicates that a linear free energy
relationship for selectivity may exist, which reflects the importance of both polar and radical stabilization
effects. Previous data tabulated for phenyl radical62 reactions do not exhibit the same magnitude in
substituent effects. As with the reactivity data,15 there is a clear trend in regioselectivity data (in the form
of relative reaction rates of hydroxyl radical) with respect to the Hammett parameter p, but the degree of
linearity is lower. The same may be said for the Swain-Lupton resonance parameter R, but not the field
parameter F.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The same directing effects are played out in the xylenes: in the case of o-xylene, addition to
ultimately yield 2,3-dimethylphenol (HO addition o- with respect to one methyl and m- to the other) is
favored over 3,4-dimethylphenol (HO addition p- with respect to one methyl and m- to the other). In the
case of m-xylene, the branching ratios for formation of 2,4- and 2,6-dimethylphenols (both with HO
installed o- and/or p- to pre-existing groups) are much the same, even though installation between the two
methyl groups should be sterically unfavorable. The 3,5-regioisomer is unfavored as HO attacks the
position m- to both groups.
ACS Paragon Plus Environment

Page 13 of 26
The Journal of Organic Chemistry
1
2
3
4
Table 3. Observed Selectivities for Radical Addition to Arenes
5
6
7
8
Substrate
o- : m- : p- ratios (Temp.,K)
a
b
c,d,e
CH3
CO2CH3
9.26f
C6H5
OH
13.01
1.83
Radical
Ionization potential (eV)
Electron Affinity (eV)
anisole
9.84
0.08
8.32
1.10
0.61g
9
69 : 18 : 13 (293)d
61 : 25: 14 (298)c
66 : 22 : 13 (293)d
42 : 34 : 24 (298)c
64: 21 : 15 (293)d
73 : 4 : 23 (318)
65 : 16 : 19 (318)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
toluene
45 : 18 : 37 (353) 56 : 27 : 17 (338)
62 : 28: 10 (408) 46 : 34 : 19 (338)
chlorobenzene
43 : 26 : 31 (318)
trifluorotoluene
29 : 41: 30 (353)e
30 : 47 : 23 (318)
aRef. 58, photolysis of methyl mercuric iodide in refluxing solvent. bRef. 61. Photolysis of iodobenzene, Ref. 60.
c
dRef. 59, decomposition of N-nitrosoacetanilide. Ref. 57. Vertical IP, estimated at CBS-QB3 level of theory,
adiabatic IP calculated as 7.41 eV. gVertical EA, estimated at CBS-QB3 level of theory, adiabatic IP could not be
calculated due to dissociation of anion.
e
f
The degree of uncertainty in the measurements of product ratios is too large to generate meaningful
Arrhenius curves, but the differences in the free energy of activation G‡ are modest: the product
distribution observed for anisole corresponds to G‡meta-G‡
of approximately 1.8 kcal/mol, and
ortho
G‡para-G‡
of approximately 0.3 kcal/mol. For trifluorotoluene we obtain G‡ortho-G‡
of
ortho
meta
approximately 0.3 kcal/mol and G‡ortho-G‡
of approximately 0.3 kcal/mol. The difference in
para
experimental rate coefficients observed for N,N-dimethylaniline and trifluorotoluene in acetonitrile at 298K
(a factor of approximately 400) corresponds to a difference in G‡ of approximately 3.6 kcal/mol. The
relative importance of entropic and enthalpic effects in the overall G‡ values is unclear, although we note
that the state correlation approach utilized previously14-15 is largely predicated on the notion that the nature
of the transition state is not significantly perturbed by substitution.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 26
1
2
3
4
5
6
7
8
9
1.40
1.20
1.00
0.80
0.60
0.40
0.20
0.00
-0.20
-0.40
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8.00
8.50
9.00
9.50
10.00
Ionization Potential (eV)
Figure 2. Plot of observed rate coefficients relative to that for meta-attack, as a function of experimental arene
ionization potential. Relative rate coefficients were measured in benzene at 318K.
Such data represent a significant challenge to computational determination of rate coefficients or
product distributions for these reactions: the working definition for “chemical accuracy” achievable by
high-level composite methods (such as CBS63 or Gn64-65 and their radical based modifications) is  1
kcal/mol. A preliminary computational study of the addition reactions at the CBS-QB3 level of theory66
was performed to determine whether the observed reactivity may be duplicated by theory. In addition, we
considered the reaction of tert-butylbenzene in order to probe the nature of any steric effects on reactivity.
The computed free energies of activation and reaction are summarized in Table 4, and calculated product
distributions at 298K in Table 5.
In general terms, the reactivity patterns predicted by CBS-QB3 calculations are consistent with
experimental results, bearing in mind that the calculations were performed in vacuo. Preferential solvation
to the extent of only fractions of a kcal/mol may cause a significant change in product ratios – previous
ACS Paragon Plus Environment

Page 15 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
studies indicate a degree of charge transfer character in the addition transition state that may be susceptible
to differing degrees of solvation. The general preference of ortho- over para- substitution for electron-
donating groups is reflected in the data, as is the increasing importance of meta-substitution with electron-
withdrawing groups. The greater sensitivity of rates of ortho-substitution (relative to para-substitution)
with respect to ring functionalization is also reflected in calculated data, and the calculated product
distributions observed for the xylenes are consistent with the experimental ones. Steric effects appear not
to play a significant role in these reactions: the reaction barrier for installation of -OH between the methyl
groups of m-xylene (2,6-) is similar to that for installation on one side (2,4-), consistent with the observed
experimental branching ratios; and the barrier for installation of -OH ortho- to a tert-butyl group is lower
than that computed for toluene.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Calculated Free Energies for Hydroxyl Radical Addition to Arenes (CBS-QB3)
G‡298 (kcal/mol, CBSQB3)a
Gr,298 (kcal/mol, CBSQB3)a
Substrate
ipso
7.1
8.2
7.4
8.9
ortho
meta
para
7.3
8.0
8.4
ipso
-12.2
-10.9
-11.6
-9.3
ortho
-10.7
-10.4
-9.4
meta
-10.5
-9.2
para
-10.7
-10.3
-9.9
anisole
toluene
tert-butylbenzene
benzene
6.0
8.1
7.9
8.5
7.2
8.3
-9.8
chlorobenzene
trifluorotoluene
o-xylene
12.0
10.7
ipso
6.6
ipso
9.6
9.1
10.5
2,3-
7.0
2,4-
8.9
9.5
9.6
3,4-
8.1
3,5-
9.8
8.9
9.5
-11.1
-9.9
ipso
-12.4
ipso
-9.2
ipso
-11.8
-10.4
-8.4
2,3-
-10.2
2,4-
-9.6
2,5-
-10.4
-7.4
-8.7
3,4-
-10.3
3,5-
-7.7
-10.3
-9.4
m-xylene
p-xylene
2,6-
8.7
2,6-
-9.6
ipso
7.3
2,5-
7.9
aCalculated in vacuo, relative to combined free energies of the separated reactants
One noteworthy feature of the calculated reaction energies in Table 4 is that in many cases, attack
of the hydroxyl radical at the ipso-position is a favorable process, particularly in the cases of o-and p-xylene,
where ipso-addition appears to be favored over other modes of addition on the ring. In both cases, ipso-
substitution yields a hydroxycyclohexadienyl radical that has significant spin density adjacent to a methyl
group, although the same could also be said for the intermediates arising from addition elsewhere on the
ring. The potential reversibility of formation and/or fate of ipso-substituted intermediates generated under
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 26
1
2
3
4
5
6
7
8
9
the reaction conditions utilized is not known. However, trapping of ipso- intermediates would lead to the
formation of 1,2- or 1,4-cyclohexadienes with labile groups that would be susceptible to rearomatization
and be difficult to isolate or detect using the current analytical method. As part of our computational study,
we considered the possibility of a 1,2-hydroxyl group migration, but no evidence of such a reaction could
be found.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Calculated Product Distributions for Hydroxyl Radical Addition to Arenes (CBS-QB3)
Substrate
% product distribution (298K, CBSQB3)a
ortho
meta
para
anisole
92
3
5
toluene
55
83
48
12
2,3-
85
21
12
23
57
3,4-
15
23
5
29
31
tert-butylbenzene
chlorobenzene
trifluorotoluene
o-xylene
m-xylene
2,4-
52
3,5-
6
2,6-
42
aCalculated in vacuo, relative to combined free energies of the separated reactants
Conclusions
The rates and regioselectivities of addition of radicals to alkene -bonds have long been described
as being dependent on a complex interplay of bond strength (radical stabilization), polar and steric effects.
The same may be said for the addition of radicals to arene rings, which tend to be considerably slower
reactions. Hydroxyl radical reactivity in organic solvents have been shown to be (a) slower, and (b) exhibit
a greater degree of sensitivity to ring functionalization than that in water. Interestingly, where comparative
homogenous data are available, the observed regioselectivities are similar – heterogeneous (e.g.
photocatalytic) data exhibit greater variability.
Hydroxyl radicals exhibit a regioselective preference for ortho-over para- substitution in ring
systems with donating groups, that is reduced in systems with electron-withdrawing substituents. This has
been observed for other cases of radical addition to arenes and has been described in terms of radical
stabilization effects. In general terms, the product distributions for HO are similar to those observed for
ACS Paragon Plus Environment

Page 17 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9

C6H5 , although the former has a greater selectivity of addition away from the meta-position than the latter.
Whether this is a function purely of radical stabilization effects, or a manifestation of a polar effect (in terms
of charge transfer character in the transition state and noting that the selectivity away from meta-substitution
is more marked for Lewis acid electrophiles) is not yet clear. Computational studies may be able to more
directly address some of these issues, and our preliminary gas phase calculations indicate that high level
composite methods such as CBS-QB3 can reproduce experimental selectivity data.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Alternative analytical studies aimed at elucidating the relative importance of side-chain abstraction
reactions, and the fate of ipso-adducts are required to complement this and other studies (which are blind
to one or both considerations). However, this study provides a readily implementable approach to
determining product distributions for hydroxyl radical reactions that are less susceptible to secondary
reactivity (oxidative or photochemical), and capable of generating relative kinetic (regioselectivity) data
for single elementary steps of complex oxidation reactions.
Experimental and Computational Methods
Materials: All starting materials were purchased from commercial sources; where available, HPLC
or spectroscopic grade solvents (acetonitrile, benzene, toluene and NMR solvents) were utilized.
Compounds were generally used as received - TEMPO was obtained by hydrogen peroxide/sodium
tungstate oxidation of commercially available 2,2,6,6-tetramethylpiperidine, and TMIO was prepared by
the procedure of Griffiths et al.67
NMR spectra were obtained on either a 300 or 400 MHz JEOL Multinuclear FT-NMR spectrometer
(chemical shifts determined relative to monoprotonated solvent peaks). UV-Visible spectra were obtained
with an Agilent 8453 UV-Visible spectrometer. GC-MS analysis of product mixtures was performed with
an Agilent Technologies 7890A gas chromatograph/5975C Mass Spectrometer system (acquisition
parameters are described in detail in the supplementary material).
Acetone tert-butyl hydrazone. The following is typical: A mixture of 16.5 mL of deionized H2O,
47 μL glacial acetic acid and 3.65 mL (50 mmol) of acetone was deoxygenated by a thin stream of bubbling
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 26
1
2
3
4
5
6
7
8
9
argon for 30 min, whereupon 3.43 g (86 mmol) of NaOH and 5.13 g (41 mmol) of tert-butylhydrazine
hydrochloride was added, and the reaction stirred for 2 hours at room temperature. The crude reaction
mixture was extracted with ethyl ether (3 × 50 mL) and the combined extracts were dried over anhydrous
MgSO4, and solvent removed in vacuo. Vacuum distillation yielded 2.83g of the target compound (54%
yield).68 1H NMR (CDCl3, 400 MHz)  = 4.19 (br. s, 1H); 1.91 (s, 3H); 1.70 (s, 3H); 1.16 (s, 9H) ppm;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(C6D12, 400 MHz)  = 3.7-4.0 (br. s, 1H); 1.84 (s, 3H); 1.60 (s, 3H); 1.13 (s, 9H) ppm.. 13C NMR (CDCl3,
100 MHz)  = 144.2, 53.1, 28.7, 25.5, 15.3 ppm; (C6D12, 100 MHz)  = 140.5, 52.5, 28.2, 24.5, 13.9 ppm.
Preparation of azohydroperoxide 1. acetone tert-butyl hydrazone was dissolved in spectroscopic
grade benzene to yield a concentration of approximately 0.05-0.10 M (70 mg of starting material in 10 mL
of benzene yields a solution of approximately 0.05M). The solution was transferred to a sealable quartz
cuvette, and a stream of bubbling oxygen is introduced through the septum via a fine (22G) needle. The
UV-visible absorbance of the solution was monitored at 368 nm - The peroxide exhibits a weak (probably
n→*) absorbance at 368 nm (See supplementary material). Oxygenation was halted after absorbance
reached a maximum (i.e., no significant change in A368 over a 10 minute interval), and the initiator was used
immediately without further purification. The autoxidation reaction was repeated in d12-cyclohexane for
1
analysis by NMR. H NMR (C6D12, 400 MHz)  = 8.5-9.5 (br. s, 1H); 1.33 (s, 6H); 1.20 (s, 9H) ppm. 13C
NMR (C6D12, 100 MHz)  = 101.9, 66.6, 26.1 ppm.
Product Studies. Method 1 (see Table 2): Aliquots of azohydroperoxide 1 solutions (0.05-0.08 M
prepared as above, target concentration in diluted solution 0.01M ) were injected into a stirred, thermally
pre-equilibrated solution of TEMPO (target concentration in diluted solution 0.025 M, 2.5 mol. equiv.) and
substrate in the appropriate solvent (benzene or acetonitrile, concentrations used depended on the substrate)
in a Reacti-Vial™. The reaction was heated in a constant temperature oil bath for the equivalent of 7 half-
lives of the initiator. The reaction was cooled to room temperature and the solvent removed under a stream
of argon. 300 μL of BSTFA was added to the reaction vial under a stream of argon, and the mixture heated
at 75 °C for 2 hours to ensure derivatization. The solution was diluted with benzene and analyzed using an
ACS Paragon Plus Environment

Page 19 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
Agilent Technologies 7890A/5975C gas chromatograph/mass spectrometer system (see Supporting
Information for further details).
7
8
9
Method 2 (see Table 2): Solutions of 1 were prepared as above and diluted into solutions of TMIO
(0.5M) in hydrocarbon (approximately 50% v/v benzene) to yield a final concentration of peroxide of
approximately 0.2 M. Solutions were degassed by freeze-pump-thaw techniques (4 cycles), sealed, and
heated at the desired temperature for a period corresponding to seven half-lives of the initiator. A 100 L
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aliquot of solution was added to 1.1 equivalents of BSTFA and heated at 65C for 2.5 hours. The obtained
mixture was analyzed using a Hewlett-Packard 5890A gas chromatograph with flame ionization detection
(FID, see Supporting Information for further details).
Preparation and confirmation of identity for trimethylsilyl ether standards. A typical example is
as follows: the phenol (1 equiv.) was dissolved in methylene chloride (dried over CaCl2) to make a 0.16M
solution. Triethylamine (3 equiv.) was added, the flask purged with argon, and the mixture stirred for 10
minutes. Chlorotrimethylsilane (2.4 equiv.) was added, and the reaction mixture was stirred overnight at
room temperature. The solvent was removed in vacuo, the residue was dissolved in diethyl ether and
filtered to remove solids. The filtrate was concentrated in vacuo, and the product purified by bulb-to-bulb
distillation in vacuo. Structures were confirmed by 1H NMR in CDCl3, based on prior literature data; EIMS
data were determined from GC/MS studies, and where available, matched the NIST database spectra for
these compounds.69
Trimethylsilyloxybenzene.70 1H NMR (CDCl3, 400 MHz)  = 7.24 (dd, J = 8.8, 6.6 Hz, 2H); 6.96 (t, J =
7.3 Hz, 1H); 6.84 (d, J = 6.6 Hz, 2H); 0.26 (s, 9H) ppm. EIMS m/z = 166 (29), 152 (14), 151 (100).
1-Methyl-2-trimethylsilyloxybenzene.71 1H NMR (CDCl3, 300 MHz)  = 7.15 (d, J = 7.1 Hz, 1H); 7.08
(t, J = 7.4, 6.0, Hz, 1H); 6.89 (t, J = 7.4, 7.1Hz, 1H); 6.79 (d, J = 8.5 Hz, 1H); 2.21 (s, 3H); 0.28 (s, 9H)
ppm. EIMS m/z = 181 (12), 180 (69), 166 (16), 165 (100), 149 (16), 135 (46), 91 (57).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 26
1
2
3
4
5
6
7
8
1-Methyl-3-trimethylsilyloxybenzene.71 1H NMR (CDCl3, 400 MHz)  = 7.15 (t, J = 7.7 Hz, 1H); 6.85
(d, J = 6.9 Hz, 1H); 6.65-6.71 (m, 2H); 2.34 (s, 3H); 0.31 (s, 9H) ppm. EIMS m/z = 180 (38), 166 (14), 165
(100), 91 (11).
9
1-Methyl-4-trimethylsilyloxybenzene.72 1H NMR (CDCl3, 400 MHz)  = 7.04 (d, J = 8.0 Hz, 2H); 6.76
(d, J = 8.4 Hz, 2H); 2.29 (s, 3H); 0.27 (s, 9H) ppm. EIMS m/z = 180 (41), 166 (15), 165 (100), 91 (12).
1-Methoxy-2-trimethylsilyloxybenzene.73 1H NMR (CDCl3, 400 MHz)  = 6.94 (ddd J = 7.7, 7.2, 1.8 Hz,
1H); 6.81-6.89 (m, 3H); 3.82 (s, 3H); 0.25 (s, 9H) ppm. EIMS m/z = 196 (22), 181 (27), 167 (15), 166
(100), 151 (22), 136 (12).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-Methoxy-3-trimethylsilyloxybenzene.73-74 1H NMR (CDCl3, 400 MHz) = 7.13 (dd, J = 8.4, 8.1 Hz,
1H); 6.53 (dd, J = 8.4, 2.2 Hz, 1H); 6.45 (dd, J = 8.1, 2.2 Hz, 1H); 6.41 (dd, J = 2.2, 2.2 Hz, 1H); 3.77 (s,
3H); 0.27 (s, 9H) ppm. EIMS m/z = 196 (47), 182 (18), 181 (100), 151 (10).
1-Methoxy-4-trimethylsilyloxybenzene.73-74 1H NMR (CDCl3, 400 MHz)  = 6.78 (apparent s, 4H) 3.76
(s, 3H); 0.25 (s, 9H) ppm. EIMS m/z = 197 (12), 196 (69), 182 (17), 181(100), 73 (25).
1-Chloro-2-trimethylsilyloxybenzene.71 1H NMR (CDCl3, 400 MHz)  = 7.35 (d, J = 7.7 Hz, 1H); 7.13
(ddd, J = 7.7, 8.0, 1.5 Hz, 1H); 6.89-6.93 (m, 2H), 0.30 (s, 9H) ppm. EIMS m/z = 202 (12), 200 (32), 187
(37), 186 (15), 185 (100), 150 (11), 149 (74), 95 (21), 93 (58), 91 (15), 73 (11), 63 (11).
1
1-Chloro-3-trimethylsilyloxybenzene. H NMR (CDCl3, 400 MHz)  = 7.16 (dd, J = 8.4, 8.1 Hz, 1H);
6.85 (ddd, J = 8.0, 2.2, 0.8 Hz, 1H); 6.86 (dd, J = 2.2, 2.2 Hz, 1H); 6.74 (ddd, J = 8.1, 2.2, 0.7 Hz, 1H);
0.28 (s, 9H) ppm. EIMS m/z = 202 (12), 200 (31), 187 (37), 186 (16), 185 (100), 93 (10), 73 (10).
1-Chloro-4-trimethylsilyloxybenzene.71 1H NMR (CDCl3, 400 MHz)  = 7.19 (d, J = 8.8 Hz, 2H); 6.77
(d, J = 8.8 Hz, 2H); 0.18 (s, 9H) ppm. EIMS m/z = 202 (14), 200 (38), 187 (36), 186 (15), 185 (100).
1-Trifluoromethyl-2-trimethylsilyloxybenzene. 1H NMR (CDCl3, 400 MHz)  = 7.54 (d, J = 7.7 Hz, 1H);
7.40 (dd, J = 7.7, 8.1 Hz, 1H); 7.01 (dd, J = 7.7 Hz, 8.0, 1H); 6.90 (d, J = 8.0 Hz, 1H); 0.31 (s, 9H) ppm.
EIMS m/z = 234 (23), 220 (14), 219 (100), 142 (12), 114 (10), 101 (12), 77 (20).
ACS Paragon Plus Environment

Page 21 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
1-Trifluoromethyl-3-trimethylsilyloxybenzene. 1H NMR (CDCl3, 300 MHz)  = 7.34 (t, J = 8.0 Hz, 1H);
7.22 (d, J = 7.7 Hz, 1H); 7.08 (s, 1H); 7.00 (d, J = 7.9 Hz, 1H); 0.29 (s, 9H) ppm. EIMS m/z = 234 (28),
220 (16), 219 (100).
9
1-Trifluoromethyl-4-trimethylsilyloxybenzene. 1H NMR (CDCl3, 300 MHz)  = 7.50 (d, J = 8.3 Hz, 2H);
6.91 (d, J = 8.2 Hz, 2H); 0.29 (s, 9H) ppm. EIMS m/z = 234 (20), 220 (16), 219 (100).
1,2-Dimethyl-3-trimethylsilyloxybenzene (TMS derivative of 2,3-dimethylphenol) 1H NMR (CDCl3, 300
MHz) = 6.95 (dd, J = 8.1, 7.7 Hz, 1H); 6.76 (d, J = 7.7 Hz, 1H); 6.65 (d, J = 8.0 Hz, 1H); 2.26 (s, 3H);
2.11 (s, 3H); 0.26 (s, 9H) ppm. EIMS m/z = 195 (15), 194 (80), 180 (16), 179 (100), 163 (17), 149 (34),
105 (70).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1,2-Dimethyl-4-trimethylsilyloxybenzene (TMS derivative of 3,4-dimethylphenol) 1H NMR (CDCl3, 300
MHz)  = 6.97 (d, J = 8.3 Hz, 1H); 6.65 (d, J = 2.5 Hz, 1H); 6.58 (dd, J = 8.0, 2.5 Hz, 1H); 2.22 (s, 3H);
2.20 (s, 3H); 0.25 (s, 9H) ppm. EIMS m/z = 195 (9), 194 (53), 180 (16), 179 (100), 163 (7), 149 (8), 105
(22).
1,3-Dimethyl-4-trimethylsilyloxybenzene (TMS derivative of 2,4-dimethylphenol)75 1H NMR (CDCl3,
400 MHz)  = 7.02 (s, 1H); 6.92 (d, J = 8.0 Hz, 1H); 6.74 (d, J = 8.0 Hz, 1H); 2.32 (s, 3H); 2.23 (s, 3H);
0.33 (s, 9H) ppm. EIMS m/z = 195 (18), 194 (94), 180 (17), 179 (100), 163 (15), 149 (28), 105 (62).
1,3-Dimethyl-5-trimethylsilyloxybenzene (TMS derivative of 3,5-dimethylphenol) 1H NMR (CDCl3, 400
MHz)  = 6.67 (s, 1H); 6.54 (s, 2H); 2.31 (s, 6H); 0.31 (s, 9H) ppm. EIMS m/z = 195 (6), 194 (44), 180
(14), 179 (100), 163 (7), 149 (6), 105 (19).
1,3-Dimethyl-2-trimethylsilyloxybenzene (TMS derivative of 2,6-dimethylphenol) 1H NMR (CDCl3, 400
MHz)  = 7.02 (d, J = 7.7 Hz, 2H); 6.85 (t, J = 7.3 Hz, 1H); 2.26 (s, 6H); 0.31 (s, 9H) ppm. EIMS m/z =
195 (14), 194 (75), 180 (16), 179 (100), 163 (17), 149 (35), 105 (65).
1,4-Dimethyl-2-trimethylsilyloxybenzene (TMS derivative of 2,5-dimethylphenol)76 1H NMR (CDCl3,
300 MHz)  = 7.00 (d, J = 7.4 Hz, 1H); 6.69 (d, J = 7.7 Hz, 1H); 6.59 (s, 1H); 2.27 (s, 3H); 2.14 (s, 3H);
0.27 (s, 9H) ppm. EIMS m/z = 195 (14), 194 (84), 180 (16), 179 (100), 163 (15), 149 (28), 105 (56).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 26
1
2
3
4
5
6
7
8
9
Computational Methods. All calculations were carried out using the Gaussian 09 program suite.77
Energies of chemical species were calculated using the complete basis set extrapolation (CBS-QB3)
composite method. The CBS-QB3 method includes geometry optimization and frequency calculations, and
all species were determined to be authentic minima (zero imaginary frequencies) – in some cases
conformational searches were undertaken to ensure the geometries corresponded to global minima.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Supporting Information
Additional information regarding analytical methods, product distributions measured at different
temperatures for monosubstituted rings, computational summaries and optimized geometries for CBS-
QB3 calculations.
Acknowledgements
The authors thank the American Chemical Society Petroleum Research Fund and the Indiana
Academy of Science for financial support (JSP). Calculations were performed on the BSU College of
Science and Humanities Beowulf cluster. Additionally, the authors thank the BSU Graduate School (LCM
& MDS) for financial support.
References
1.
2.
Atkinson, R., Kinetics and Mechanisms of the Gas Phase Reactions of the Hydroxyl Radical with
Organic Compounds. J. Phys. Chem. Ref. Data 1988, 1, 1-246.
Buxton, G. V.; Greenstock, C. L.; Helman, W. P.; Ross, A. B., Critical Review of Rate Constants
for Reactions of Hydrated Electrons, Hydrogen Atoms and Hydroxyl Radicals (ꞏOh/ꞏO-) in
Aqueous Solution. J. Phys. Chem. Ref. Data 1988, 17, 513-886.
3.
4.
5.
6.
7.
Cadet, J.; Douki, T.; Ravanat, J.-L., Oxidatively Generated Base Damage to Cellular DNA. Free
Radicals Biol. Med. 2010, 49, 9-21.
Weidinger, A.; Kozlov, A. V., Biological Activities of Reactive Oxygen and Nitrogen Species:
Oxidative Stress Versus Signal Transduction. Biomolecules 2015, 5, 472-484.
Cadet, J.; Davies, K. J. A.; Medeiros, M. H. G.; Di Mascio, P.; Wagner, J. R., Formation and Repair
of Oxidatively Generated Damage in Cellular DNA. Free Radicals Biol. Med. 2017, 107, 13-34.
Stone, D.; Whalley, L. K.; Heard, D. E., Tropospheric OH and HO2 Radicals: Field Measurements
and Model Comparisons. Chem. Soc. Rev. 2012, 41, 6348-6404.
Gligorovski, S.; Strekowski, R.; Barbati, S.; Vione, D., Environmental Implications of Hydroxyl
Radicals (OH). Chem. Rev. (Washington DC U.S.) 2015, 115, 13051-13092.
ACS Paragon Plus Environment

Page 23 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
8.
Moreira, F. C.; Boaventura, R. A. R.; Brillas, E.; Vilar, V. J. P., Electrochemical Advanced
Oxidation Processes: A Review on Their Application to Synthetic and Real Wastewaters. Appl.
Catal., B 2017, 202, 217-261.
Lelieveld, J.; Gromov, S.; Pozzer, A.; Taraborrelli, D., Global Tropospheric Hydroxyl Distribution,
Budget and Reactivity. Atmos. Chem. Phys. 2016, 16, 12477-12493.
Mostofa, K. M. G., et al., Phototransformation Induced by HO* Radicals. In Surface Water
Photochemistry, Calza, P.; Vione, D., Eds. Royal Scoeity of Chemistry: Cambridge, UK, 2016.
Atkinson, R., Kinetics and Mechanisms of the Gas-Phase Reactions of the Hydroxyl Radical with
Organic Compounds under Atmospheric Conditions. Chem. Rev. (Washington DC U.S.) 1985,
1985, 69-201.
Atkinson, R., A Structure-Activity Relationship for the Estimation of Rate Constants for the Gas
Phase Reactions of Oh Radicals with Organic Compounds. Int. J. Chem. Kinet. 1987, 19, 799-828.
Kwok, E. S. C.; Atkinson, R., Estimation of Hydroxyl Radical Reaction Rate Constants for Gas-
Phase Organic Compounds Using a Structure-Reactivity Relationship: An Update. Atmos. Environ.
1995, 29, 1685-1695.
Poole, J. S.; Shi, X.; Hadad, C. M.; Platz, M. S., Reaction of Hydroxyl Radical with Aromatic
Hydrocarbons in Nonaqueous Solutions: A Laser Flash Photolysis Study in Acetonitrile. J. Phys.
Chem. A 2005, 109, 2547-2551.
Johnson, E. M.; Waggoner, A. R.; Xia, S.; Luk, H. L.; Hadad, C. M.; Poole, J. S., Reactivity of
Hydroxyl Radical in Nonaqueous Phases: Addition Reactions. J. Phys. Chem. A 2018, 122, 8326-
8335.
DeMatteo, M. P.; Poole, J. S.; Shi, X.; Sachdeva, R.; Hatcher, P. G.; Hadad, C. M.; Platz, M. S.,
On the Electrophilicity of Hydroxyl Radical: A Laser Flash Photolysis and Computational Study.
J. Am. Chem. Soc. 2005, 127, 7094-7109.
Minakata, D.; Li, K.; Westerhoff, P.; Crittenden, J., Development of a Group Contirbution Method
to Predict Aqueous Phase Hydroxyl Radical (HO*) Reaction Rate Constants. Env. Sci. Technol.
2009, 43, 6220-6227.
Minakata, D.; Mezyk, S. P.; Jones, J. W.; Daws, B. R.; Crittenden, J. C., Development of Linear
Free Energy Relationships for Aqueous Phase Radical-Involved Chemical Reactions. Env. Sci.
Technol. 2014, 48, 13925-13932.
Wille, U., Radical Oxygenations with Inorganic Radicals: Can Hydroxyl Radicals (HO) Act as
Donors of Oxygen Atoms? Tetrahedron Lett. 2002, 43, 1239-1242.
Wille, U., Inorganic Radicals in Organic Synthesis. Chemistry – Eur. J. 2002, 8, 340-347.
Roeelova, M.; Vieceli, J.; Dang, L. X.; Garrett, B. C.; Tobias, D. J., Hydroxyl Radical at the Air-
Water Interface. J. Am. Chem. Soc. 2004, 126, 16308-16309.
Brusova, Z.; Stulik, K.; Marecek, V., The Potential Controlled Fenton Reaction at Liquid/Liquid
Interfaces as the Source of Hydroxyl Radicals. J. Electroanal. Chem. 2004, 563, 277-281.
Shenoy, R.; Bowman, C. N., Kinetics of Interfacial Radical Polymerization Initiated by a Glucose-
Oxidase Mediated Redox System. Biomaterials 2012, 33, 6909-6914.
Rudich, Y., Laboratory Perspectives on the Chemical Transformations of Organic Matter in
Atmospheric Particles. Chem. Rev. (Washington DC U.S.) 2003, 103, 5097-5124.
Donaldson, D. J.; Valsaraj, K. T., Adsorption and Reaction of Trace Gas-Phase Organic
Compounds on Atmospheric Water Film Surfaces: A Critical Review. Env. Sci. Technol 2010, 44,
865-873.
Georgiou, C. D., et al., Evidence for Photochemical Production of Reactive Oxygen Species in
Desert Soils. Nat. Comm. 2015, 6, 7100.
McKay, G.; Kleinman, J. L.; Johnston, K. M.; Dong, M. M.; Rosario-Ortiz, F.; Mezyk, S. P.,
Kinetics of the Reaction between the Hydroxyl Radical and Organic Matter Standards from the
International Humic Substance Society. J. Soils Sediments 2014, 14, 298-304.
9.
10.
11.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 26
1
2
3
4
5
6
7
8
9
28.
29.
Waggoner, D. C.; Chen, H.; Willoughby, A. S.; Hatcher, P. G., Formation of Black Carbon-Like
and Alicyclic Aliphatic Compounds by Hydroxyl Radical Initiated Degradation of Lignin. Org.
Geochem. 2015, 82, 69-75.
Jansen, T. G. T.; Meuldijk, J.; Lovell, P. A.; van Herk, A. M., On the Miniemulsion Polymerization
of Very Hydrophobic Monomers Initiated by a Completely Water-Insoluble Initiator:
Thermodynamics, Kinetics, and Mechanism. J. Polym. Sci. Part A-1: Polym. Chem. 2016, 54,
2731-2745.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
30.
31.
Tikekar, R. V.; Johnson, A.; Nitin, N., Fluorescence Imaging and Spectroscopy for Real-Time, in-
Situ Characterization of Interactions of Free Radicals with Oil-in-Water Emulsions. Food Res. Int.
2011, 44, 139-145.
Tony, M. A.; Purcell, P. J.; Zhao, Y. Q.; Tayeb, A. M.; El-Sherbiny, M. F., Photo-Catalytic
Degradation of an Oil-Water Emulsion Using the Photo-Fenton Treatment Process: Effects and
Statistical Optimization. J. Environ. Sci. Health Part A 2009, 44, 179-187.
Fischer, H.; Radom, L., Factors Controlling the Addition of Carbon-Centered Radicals to Alkenes
- an Experimental and Theoretical Perspective. Angew. Chem. Int. Ed. 2001, 40, 1340-1371.
Wojnarovits, L.; Takacs, E., Rate Coefficients of Hydroxyl Radical Reactions with Pesticide
Molecules and Related Compounds: A Review. Radiat. Phys. Chem. 2014, 96, 120-134.
von Sonntag, C.; Schuchmann, H.-P., Pulse Radiolysis. Methods Enzymol. 1994, 233, 3-20.
Mitroka, S.; Zimmeck, S.; Troya, D.; Tanko, J. M., How Solvent Modulates Hydroxyl Radical
Reactivity in Hydrogen Atom Abstractions. J. Am. Chem. Soc. 2010, 132, 2907-2913.
Gozzi, F.; Oliveira, S. C.; Dantas, R. F.; Silva, V. O.; Quina, F. H.; Machulek, A., Jr., Kinetic
Studies of the Reaction between Pesticides and Hydroxyl Radical Generated by Laser Flash
Photolysis. J. Sci. Food Agric. 2016, 96, 1580-1584.
Hansch, C.; Leo, A.; Taft, R. W., A Survey of Hammett Substituent Constants and Resonance and
Field Parameters. Chem. Rev. (Washington DC U.S.) 1991, 91, 165-195.
Fang, X.; Pan, X.; Rahmann, A.; Schuchmann, H.-P.; Von Sonntag, C., Reversibility in the
Reaction of Cyclohexadienyl Radicals with Oxygen in Aqueous Solution. Chem. – Eur. J. 1995, 1,
423-429.
Atkinson, R.; Arey, J., Mechanisms of the Gas-Phase Reactions of Aromatic Hydrocarbons and
PAHs with OH and NO3 Radicals; Taylor & Francis, 2007; Vol. 27, p 15-40.
Merga, G.; Schuchmann, H.-P.; Rao, B. S. M.; Von Sonntag, C., 'Oh Radical-Induced Oxidation
of Chlorobenzene in Aqueous Solution in the Absence and Presence of Oxygen. J. Chem. Soc.,
Perkin Trans. 2 1996, 1097-1103.
Grant, R. D.; Rizzardo, E.; Solomon, D. H., 2-(Tert-Butylazo)-2-Propyl Hydroperoxide: A
Convenient Source of Hydroxyl Radicals in Organic Media. J. Chem. Soc., Chem. Commun. 1984,
867-8.
Grant, R. D.; Rizzardo, E.; Solomon, D. H., Reactions of Hydroxyl Radical with Polymerizable
Olefins. J. Chem. Soc., Perkin Trans. 2 1985, 379-84.
Bagryanskaya, E. G.; Marque, S. R. A., Scavenging of Organic Ccentered Radicals by Nitroxides.
Chem. Rev. (Washington DC U.S.) 2014, 114, 5011-5056.
Samuni, A.; Goldstein, S.; Russo, A.; Mitchell, J. B.; Krishna, M. C.; Neta, P., Kinetics and
Mechanism of Hydroxyl Radical and Oh-Adduct Radical Reactions with Nitroxides and with Their
Hydroxylamines. J. Am. Chem. Soc. 2002, 124, 8719-8724.
Moad, G.; Rizzardo, E.; Solomon, D. H., The Reaction of Acyl Peroxides with 2,2,6,6-
Tetramethylpiperidinyl-1-Oxy. Tetrahedron Lett. 1981, 22, 1165-1168.
Cuthbertson, M. J.; Rizzardo, E.; Solomon, D. H., The Reactions of Tert-Butoxyl with Unsaturated
Hydrocarbons: Structure and Reactivity of Allylic Radicals. Aust. J. Chem. 1983, 36, 1957-73.
Ciriano, M. V.; Korth, H.-G.; van Scheppingen, W. B.; Mulder, P., Thermal Stability of 2,2,6,6-
Tetramethylpiperidine-1-Oxyl (Tempo) and Related N-Alkoxyamines. J. Am. Chem. Soc. 1999,
121, 6375-6381.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
ACS Paragon Plus Environment

Page 25 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
48.
49.
Moad, G.; Rizzardo, E.; Solomon, D. H., Selectivity of the Reaction of Free Radicals with Styrene.
Macromolecules 1982, 15, 909-14.
Ananchenko, G.; Fischer, H., Decomposition of Model Alkoxyamines in Simple and Polymerizing
Systems. I. 2,2,6,6-Tetramethylpiperidinyl-N-Oxyl-Based Compounds. J. Polym. Sci. Part A-1:
Polym. Chem. 2001, 39, 3604-3621.
Scanlon, J. T.; Willis, D. E., Calculation of Flame Ionization Detector Relative Response Factors
Using the Effective Carbon Number Concept. J. Chromatogr. Sci. 1985, 23, 333-40.
Tezuka, T.; Narita, N.; Ando, W.; Oae, S., Isomer Distribution Ratios of Phenols in Aromatic
Hydroxylation with the Hydroxyl Radical Generated from Α-Azohydroperoxide in Anhydrous
Organic Media. Comparison with Fenton's Reagent. J. Am. Chem. Soc. 1981, 103, 3045-9.
Tezuka, T.; Marusawa, H.; Ichikawa, K., Nonselective Disproportionation of Isomeric
Hydroxycyclohexadienyl Radicals to Phenols. Chem. Lett. 1984, 13, 2145-8.
Albarran, G.; Bentley, J.; Schuler, R. H., Substituent Effects in the Reaction of Oh Radicals with
Aromatics: Toluene. J. Phys. Chem. A 2003, 107, 7770-7774.
Matsue, T.; Fujihira, M.; Osa, T., Oxidation of Alkylbenzenes by Electrogenerated Hydroxyl
Radical. J. Electrochem. Soc. 1981, 128, 2565-2569.
Yuzawa, H.; Aoki, M.; Otake, K.; Hattori, T.; Itoh, H.; Yoshida, H., Reaction Mechanism of
Aromatic Ring Hydroxylation by Water over Platinum-Loaded Titanium Oxide Photocatalyst. J.
Phys.Chem. C 2012, 116, 25376-25387.
Smith, M. B.; March, J., March's Advanced Organic Chemistry, 5th ed.; Wiley Interscience, John
Wiley & Sons, NY, 2001.
Hey, D. H.; Orman, S.; Williams, G. H., Homolytic Aromatic Substitution. Part Xxiii. A
Redetermination of the Relative Rate of Phenylation of Nitrobenzene. J. Chem. Soc. 1961, 565-
569.
Hey, D. H.; Saunders, F. C.; Williams, G. H., Homolytic Aromatic Substitution. Part Xxi. The
Arylation of Benzotrihalides. J. Chem. Soc. 1961, 554-562.
Corbett, G. E.; Williams, G. H., Reactions of Alkyl Radicals. Part I. The Methylation of Benzene,
Fluorobenzene, Chlorobenzene, and Bromobenzene with Methyl Radicals Formed by the
Photolysis of Methylmercuric Iodide. J. Chem. Soc. 1964, 3437-3442.
Ito, R.; Migita, T.; Morikawa, N.; Simamura, O., Influence of Substituent Groups in the Arylation
of Substituted Benzenes by Aryl Radicals Derived from P-Substituted N-Nitrosoacetanilides.
Tetrahedron 1965, 21, 955-961.
Martelli, G.; Spagnolo, P.; Tiecco, M., Homolytic Aromatic Substitution by Phenylethynyl
Radicals. J. Chem. Soc. B 1970, 7, 1413-1418.
Fiorentino, M.; Testaferri, L.; Tiecco, M.; Troisi, L., Methoxycarbonylation of Substituted
Benzenes. Effect of the Electronic Configuration of Carbon Radicals in Homolytic Substitutions.
J. Org. Chem. 1976, 41, 173-175.
Ochterski, J. W.; Petersson, G. A.; Montgomery, J. A., A Complete Basis Set Model Chemistry. V.
Extensions to Six or More Heavy Atoms. J. Chem. Phys. 1996, 104, 2598-2619.
Curtiss, L. A.; Raghavachari, K.; Redfern, P. C.; Rassolov, V.; Pople, J. A., Gaussian-3 „G3…
Theory for Molecules Containing First and Second-Row Atoms. J. Chem. Phys. 1998, 109, 7764-
7776.
Curtiss, L. A.; Redfern, P. C.; Raghavachari, K.; Rassolov, V.; Pople, J. A., Gaussian-3 Theory
Using Reduced Moller-Plesset Order. J. Chem. Phys. 1999, 110, 4703-4709.
Montgomery, J. A.; Frisch, M. J.; Ochterski, J. W.; Petersson, G. A., A Complete Basis Set Model
Chemistry. Vi. Use of Density Functional Geometries and Frequencies. J. Chem. Phys. 1999, 110,
2822-2827.
Griffiths, P. G.; Moad, G.; Rizzardo, E.; Solomon, D. H., Synthesis of the Radical Scavenger
1,1,3,3-Tetramethylisoindolin-2-Yloxyl. Aust. J. Chem. 1983, 36, 397-401.
Wang, S. F.; Warkentin, J., Alkylation of Tert-Butyl Lithiohydrazones of Aldehydes and Ketones.
Can. J. Chem. 1988, 66, 2256-8.
50.
51.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 26
1
2
3
4
5
6
7
8
9
69.
70.
Lias, S. G.; Bartmess, J. E. Gas Phase Ion Thermochemistry. In NIST Chemistry Webbook;
Linstrom, P. J., Mallard, W. G., Eds. NIST Standard Reference Database Number 69; National
Institute of Standards and Technology: Gaithersburg, MD, http://webbook.nist.gov, (retrieved
August 20, 2018)
Garkani-Nejad, Z.; Poshteh-Shirani, M., Modeling of 13C Nmr Chemical Shifts of Benzene
Derivatives Using the Rc-Pc-Ann Method: A Comparative Study of Original Molecular
Descriptors and Multivariate Image Analysis Descriptors. Can. J. Chem. 2011, 89, 598-607.
Bhatt, S. S., Trimethylsilyl Aryloxides as Reagents in Polymer Reactions. Int. J. Theor. Appl. Sci.
2009, 1, 19-23.
Iida, A.; Horii, A.; Misaki, T.; Tanabe, Y., Anilinosilanes/Tbaf Catalyst: Mild and Powerful Agent
for the Silylation of Sterically Hindered Alcohols. Synthesis 2005, 16, 2677-2682.
Taddei, M.; Ricci, A., Electrophilic Hydroxylation with Bis(Trimethylsilyl)Peroxide. A Synthon
for Hydroxyl Cation. Synthesis 1986, 633-35.
Rajagopal, G.; Lee, H.; Sung, S., Nafion Sac-13: Heterogeneous and Reusable Catalyst for the
Activation of Hmds for Efficient and Selective O-Silylation Reactions under Solvent-Free
Condition. Tetrahedron 2009, 65, 4735-41.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
71.
72.
73.
74.
75.
76.
Tajik, H.; Niknam, K.; Karimian, S., Silylation of Alcohols and Phenols by Hmds in the Presence
of Ionic Liquid and Silica Supported Ionic Liquids. Iran. J. Catal. 2013, 3, 107-113.
Heaney, H.; Papageorgiou, G.; Wilkins, R. F., The Functionalization of Electron-Rich Aromatic
Compounds with 1,3-Oxazolidines and 1,3-Dimethylimidazolidine. Tetrahedron 1997, 53, 14381-
96.
77.
Frisch, M. J., Gaussian 09 2010, Revision C.01. For full reference, see the Supplementary
Information.
ACS Paragon Plus Environment