Synthetic Applications and Mechanistic Studies of the Hydroxide-Mediated Cleavage of Carbon-Carbon Bonds in Ketones

Article abstract of DOI:10.1021/acs.joc.7b00802

The hydroxide-mediated cleavage of ketones into alkanes and carboxylic acids has been reinvestigated and the substrate scope extended to benzyl carbonyl compounds. The transformation is performed with a 0.05 M ketone solution in refluxing xylene in the presence of 10 equiv of potassium hydroxide. The reaction constitutes a straightforward protocol for the synthesis of certain phenyl-substituted carboxylic acids from 2-phenylcycloalkanones. The mechanism was investigated by kinetic experiments which indicated a first order reaction in hydroxide and a full negative charge in the rate-determining step. The studies were complemented by a theoretical investigation where two possible pathways were characterized by DFT/M06-2X. The calculations showed that the scission takes place by nucleophilic attack of hydroxide on the ketone followed by fragmentation of the resulting oxyanion into the carboxylic acid and a benzyl anion.

Full text of DOI:10.1021/acs.joc.7b00802

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Article
Synthetic Applications and Mechanistic Studies of the Hydroxide-
Mediated Cleavage of Carbon-Carbon Bonds in Ketones
Andrea Mazziotta, Ilya S. Makarov, Peter Fristrup, and Robert Madsen
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 12 May 2017
Downloaded from http://pubs.acs.org on May 12, 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 26
The Journal of Organic Chemistry
1
2
3
4
5
6
Synthetic Applications and Mechanistic Studies of the Hydroxide-Mediated
Cleavage of Carbon-Carbon Bonds in Ketones
7
8
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
Andrea Mazziotta,† Ilya S. Makarov,‡ Peter Fristrup† and Robert Madsen*,†
†Department of Chemistry, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
‡Department of Chemistry, LudwigꢀMaximiliansꢀUniversität, Butenandtstr. 5ꢀ13, 81377 Munich, Germany
Eꢀmail: rm@kemi.dtu.dk
_____________________________________________________________________________
Abstract
The hydroxideꢀmediated cleavage of ketones into alkanes and carboxylic acids has been
reinvestigated and the substrate scope extended to benzyl carbonyl compounds. The
transformation is performed with a 0.05 M ketone solution in refluxing xylene in the presence of
10 equiv. of potassium hydroxide. The reaction constitutes a straightforward protocol for the
synthesis of certain phenylꢀsubstituted carboxylic acids from 2ꢀphenylcycloalkanones. The
mechanism was investigated by kinetic experiments which indicated a first order reaction in
hydroxide and a full negative charge in the rateꢀdetermining step. The studies were
complemented by a theoretical investigation where two possible pathways were characterized by
DFT/M06ꢀ2X. The calculations showed that the scission takes place by nucleophilic attack of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 26
1
2
3
4
hydroxide on the ketone followed by fragmentation of the resulting oxyanion into the carboxylic
5
6
7
acid and a benzyl anion.
8
_________________________________________________________________________________________________________________
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
INTRODUCTION
The cleavage of carbonꢀcarbon bonds in aldehydes and ketones by hydroxide has been
known for more than a century.1 The most prominent example is the haloform reaction where a
trihalomethyl anion is released from the carbonyl compound.2 In this case, the reaction occurs
readily due to the relatively low pKa of the corresponding acid (pKa for CHX3 = 18 – 21).3
However, the transformation is not limited to relatively acidic carbon moieties and a variety of
anions have been cleaved from aldehydes and ketones in hydroxide solution. This includes the
anions of methyl ketones,4 acetylenes,5 triphenylmethanes,6 2,6ꢀdihalobenzenes,7 cumenes8 and
benzenes9 where the pKa values of the acids varies between 20 and 43. The rate of the reactions
correlates very well with the stability of the released carbanions.1 The scissions are either
performed in aqueous hydroxide solution,4,5,7 with potassium hydroxide in an inert solvent6,9a or
with a special mixture of water (3 equiv.) and potassium tertꢀbutoxide (10 equiv.) in an ether
solvent.8,9b,c
The mechanism of the cleavage reaction has been investigated by kinetic measurements in
aqueous solution where two general pathways have been identified (Scheme 1).2,4,5,7 After
addition of hydroxide the resulting oxyanion 1 can either decompose to the products or undergo
a second reaction with hydroxide to form dioxyanion 2. The latter decomposes rapidly to the
products and this dioxyanion route has been determined as the main reaction pathway in water.
The direct decomposition of oxyanion 1 has only been detected experimentally when rather
ACS Paragon Plus Environment

Page 3 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
stable carbanions are released such as the anion of chloroform, methyl ketones and
phenylacetylene.2,4,5 It is, however, not a trivial task to distinguish between the two pathways
and the kinetic profile can in both cases be described as pseudo first order in hydroxide when the
base is used in excess.10 Except for the haloform reaction, the transformation has so far only
gained moderate attention in synthesis.11,12 This is mainly due to the narrow substrate scope and
the occurrence of competing reactions such as the Cannizzaro reaction for benzaldehydes and
the aldol reaction for enolizable carbonyl compounds. A variation of the reaction involves
formation of carboxamides by cleavage of ketones with alkali metal amides.11,13 This
transformation was originally termed the HallerꢀBauer reaction,14 but the name is today often
used to describe the splitting with both amide and hydroxide ions.
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. Two Mechanistic Pathways for Hydroxide-Mediated Cleavage
Toluene has a pKa of 41 and the anion should be able to serve as a departing group in the
cleavage reaction which would broaden the substrate scope of this very simple transformation.
In addition, it would be interesting to further investigate the mechanism by modern
computational methods which may provide a more clear distinction between the two reaction
pathways. Therefore, we herein describe the hydroxideꢀmediated cleavage of benzyl carbonyl
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 26
1
2
3
4
5
6
compounds and experimental investigations of the mechanism complemented by a density
functional theory study.
7
8
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
RESULTS AND DISCUSSION
The reaction was discovered during our work on the oxidation of primary alcohols into
carboxylic acids with the liberation of molecular hydrogen.15 This transformation is catalyzed by
the ruthenium complex [RuCl2IiPr(pꢀcymene)] (IiPr = 1,3ꢀdiisopropylimidazolꢀ2ꢀylidene) and
proceeds by dehydrogenation to the aldehyde followed by addition of hydroxide ion and
dehydrogenation to the acid. The optimized conditions employ 1% of [RuCl2IiPr(pꢀcymene)],
1% of PCy3·HBF4, and a slight excess of potassium hydroxide in refluxing toluene.15 In this
way, the potassium salt of phenylacetic acid was obtained by dehydrogenation of 2ꢀ
phenylethanol which after workup with hydrochloric acid gave the carboxylic acid (Scheme 2).15
However, it was never possible to isolate the acid in more than 75% yield. The byproduct
became evident when the solvent was replaced with refluxing xylene which now gave a 76% GC
yield of toluene. Apparently, the hydroxymethyl group is cleaved from the starting alcohol and
NMR analysis of the heterogeneous mixture revealed that potassium formate was also formed.
No fragmentation occurred when 2ꢀphenylethanol or 2ꢀphenylacetic acid were heated with KOH
in the absence of the ruthenium catalyst.
Scheme 2. Oxidation and Cleavage of 2-Phenylethanol
ACS Paragon Plus Environment

Page 5 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
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
These observations made us consider the reaction in Scheme 1 as a possible explanation for
the cleavage. Supposedly, the ruthenium catalyst dehydrogenates 2ꢀphenylethanol to the
aldehyde which is formed in amounts too low for an aldol condensation to occur. Instead, attack
of hydroxide takes place to furnish toluene and formate.16 This was confirmed by the addition of
2ꢀphenylacetaldehyde by syringe pump over 2 h to a refluxing mixture of KOH (10 equiv.) in
xylene which gave toluene in 89% yield as determined by GC (Table 1, entry 1). On the
contrary, only 11% of toluene was obtained when a 0.5 M solution of 2ꢀphenylacetaldehyde in
xylene was heated with KOH (entry 2). These results clearly illustrate the importance of a low
concentration of the aldehyde in order to achieve the carbonꢀcarbon cleavage product in good
yield. Notably, when the reaction was diluted 10ꢀfold and performed with a 0.05 M solution of
2ꢀphenylacetaldehyde, the yield of toluene increased to 85% (entry 3). This is almost the same
result as obtained by slow addition of the aldehyde, but using more convenient reaction
conditions. When the base was replaced by NaOH under the same conditions the yield dropped
to 20% (entry 4). The yield also decreased with lower amounts of KOH where the competing
aldol condensation occurred to a larger extend. No cleavage took place when lowering the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 26
1
2
3
4
5
6
7
8
9
temperature to 80 °C or by changing the solvent to refluxing water or DMSO which in all cases
led to poor conversion and several sideꢀproducts. Thus, the optimized conditions for the
fragmentation involve reflux of a 0.05 M solution of the carbonyl compound in xylene with 10
equiv. of KOH.
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 1. Cleavage of 2-Phenylacetaldehyde
_________________________________________________________
entry
[PhCH2CHO] (M)
yield (%)a
_________________________________________________________
1b
2
0.5
0.5
0.05
0.05
89
11
85
20
3
4c
__________________________________________________________
a GC yield. b PhCH2CHO added over 2 h. c NaOH used instead of KOH.
With these conditions in hand a number of carbonyl compounds with benzyl moieties were
subjected to the cleavage reaction in order to investigate the substrate scope and limitations
(Table 2). The scission proceeded smoothly with phenylacetone where toluene was obtained in
91% yield (entry 1). Diphenylacetaldehyde, on the other hand, gave diphenylmethane in only
21% yield together with several high molecular products which were not further identified (entry
2). The fragmentation was also amenable to cyclic ketones where useful procedures for
preparation of several carboxylic acids could be obtained. The cleavage of 2ꢀ
phenylcyclohexanone gave 6ꢀphenylhexanoic acid in 78% isolated yield (entry 3). A slightly
lower yield was achieved when an additional 2ꢀsubstituent was present in the cyclohexanone
ACS Paragon Plus Environment

Page 7 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
which is presumably due to the increased steric hindrance (entries 4ꢀ6). Essentially no cleavage
was observed with the parent cyclohexanone which illustrates the importance of the stabilization
from the 2ꢀphenyl substituent (result not shown). The fragmentation of βꢀtetralone was
completely regioselective although the product was only produced in a low yield (entry 7). Fiveꢀ
membered ketones could also undergo the cleavage as shown with 2ꢀphenylpentanone and 2ꢀ
indanone which afforded the carboxylic acids in 64 and 90% yield, respectively (entries 8 and
9). 2,2,5,5ꢀTetramethylcyclopentanone, on the contrary, did not react which confirms the
importance of the benzyl moiety for the scission to occur.
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 2. Hydroxide-Mediated Cleavage of Carbonyl Compoundsa
entry
1
substrate
product
yield (%)b
91c
2
21c
3
4
5
78
40
65
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 26
1
2
3
4
5
6
7
6
76
8
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
7
8
9
18
64
90
a Conditions: Carbonyl compound (2.5 mmol) and KOH (25 mmol) in refluxing xylene for 1 h. b
Isolated yield. c GC yield.
In addition to the synthetic utility we were also interested in a further clarification of the
reaction mechanism especially the differences and the analogies to the already established
pathways. We started with a kinetic analysis where phenylacetone was selected as the substrate
since it gave the highest yield in Table 2. As displayed in Scheme 1 two main pathways have
been identified for the cleavage of carbonyl compounds. When the oxyanion 1 is formed, the
nature of the leaving group R' determines the subsequent reaction where stabilized residues may
be expelled directly while strongly basic moieties require a larger activation energy giving rise to
the extremely reactive dioxyanion 2. The latter can only be formed with bases containing
extractable hydrogen such as the hydroxide and the amide anions. This was confirmed by
treating phenylacetone with stoichiometric amounts of sodium methoxide and potassium tertꢀ
butoxide which in both cases only led to poor conversion and small amounts of toluene (14%
and 5%, respectively). On the other hand, the addition of 3 equiv. of water to the reaction with
ACS Paragon Plus Environment

Page 9 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
potassium tertꢀbutoxide increased the yield to 77% which supports the fact that hydroxide ions
are responsible for the cleavage.
7
8
9
The reaction order with respect to the base was also determined for phenylacetone (Figure 1).
A linear dependence was observed, but only until a [OHꢁ] of around 0.4 M after which a minor
decrease in the rate of cleavage was detected. This may illustrate the point of saturation since the
base is not fully soluble under these conditions.17 The initial linear relationship suggests that the
reaction is first order in hydroxide.
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
Figure 1. Dependence between the rate of cleavage and the amount of the base
In an attempt to locate the rateꢀdetermining step, a Hammett study was carried out with
different paraꢀsubstituted aryl acetones. The reactions were conducted as competition
experiments in which the parent phenylacetone was allowed to compete with the other paraꢀ
substituted aryl acetones in the presence of potassium hydroxide (Scheme 3).18 The formation of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 26
1
2
3
4
5
6
the different toluene derivatives was quantified by GC as a function of the reaction time and the
results are displayed in Figure 2 and Table 3.19
7
8
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 3. Substrates for Hammett study
0
ꢀ0.1
ꢀ0.2
ꢀ0.3
ꢀ0.4
ꢀ0.5
ꢀ0.6
ꢀ0.7
H
Cl
F
OMe
Et
ꢀ0.3
ꢀ0.2
ꢀ0.1
0
σ –
0.1
0.2
0.3
Figure 2. Distribution of relative reactivities in Hammett experiment
ACS Paragon Plus Environment

Page 11 of 26
The Journal of Organic Chemistry
1
2
3
4
Table 3. Data from Hammett Experiment
5
6
7
8
9
log(krel) –
X
pKa*
σ‒
log(krel)
pKaX + pKaH
OMe 22.5 ꢀ0.26
ꢀ0.395
ꢀ0.646
0
ꢀ2.195
ꢀ1.446
0
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
Et
H
F
21.5 ꢀ0.19
20.7
0
20.7 ꢀ0.03
19.6 0.19
ꢀ0.382
ꢀ0.382
Cl
ꢀ0.266
0.834
*pKa in DMSO calculated: Jaguar, version 7.8. Schrodinger,
LLC, New York, NY, 2010
Clearly, no linear correlation was observed which is most likely due to the dual reactivity of
the ketones since the base can mediate both the cleavage reaction and a deprotonation. These
two factors can be isolated by determining the acid dissociation constant by DFT calculations for
the aryl acetones. The pKa values in DMSO for the structures minimized in xylene are also
displayed in Table 3. The dissociation constants for both the nonꢀsubstituted and the substituted
ketone are used to correct the relative reactivities from the competition experiments according to
eq. 1.20
log(krel) – pKa + pKa = σ‒ρ
(1)
X
H
The corrected values are also listed in Table 3 and from the new plot in Figure 3 a straight
line is now obtained with a slope of approximately 6.7 which shows that almost a full negative
charge is developed in the rateꢀdetermining step.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 26
1
2
3
4
5
6
7
8
9
1.5
1
y = 6.703x ꢀ 0.249
R² = 0.974
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
Cl
0.5
0
H
F
ꢀ0.5
ꢀ1
Et
ꢀ1.5
ꢀ2
OMe
ꢀ2.5
ꢀ0.3
ꢀ0.2
ꢀ0.1
0
σ –
0.1
0.2
0.3
Figure 3. Hammett plot modulated with the dissociation constants Ka
To increase our understanding of the reaction pathways the investigation was extended with a
computational study which has not been performed before for this cleavage reaction.21 2,6ꢀ
Dichlorobenzaldehyde 3 was selected as a reference substrate since the mechanism for the
cleavage of this compound has previously been studied in detail by kinetic measurements in
aqueous solution and all the necessary activation parameters were established (Scheme 4).7b
Moreover, molecule 3 is relatively small and does not have many conformational degrees of
freedom, which should facilitate the optimization and the search for the transition states. Finally,
3 as well as 2ꢀphenylacetaldehyde do not contain any heavy atoms and therefore the same basis
ACS Paragon Plus Environment

Page 13 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
sets can be used in both cases. It was shown experimentally that the cleavage occurs via the
dioxyanion 5 with the deformylation of this dioxyanion as the rateꢀdetermining step.7b The
following activation parameters were measured at 58.4 °C: ∆H≠ = 121.2 kJ·mol−1 and ∆S≠ =
37.6 J·mol−1·K−1 from which the activation Gibbs free energy can be calculated as ∆G≠ = ∆H≠ −
T∆S≠ = 108.8 kJ·mol−1.7b This value was used as a reference for selecting the proper
computational method.
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 4. Pathway for Cleavage of 2,6-Dichlorobenzaldehyde
The initial calculations were performed by using the B3LYPꢀD3 functional and the 6ꢀ31G*
basis set. However, it was quickly discovered that this level of theory was insufficient as
optimization of some of the charged molecules either in gas phase or in solution (without adding
explicit solvent molecules) did not converge. Even with a different functional (M06ꢀ2X) or
larger basis sets it was impossible to locate molecule 5 on the potential energy surface and all
attempts to optimize it led to the two separate species 6 and 7. As a possible solution it was
decided to add explicit water molecules around the oxygen atoms to better distribute the
negative charge and thus stabilize the intermediate 5. It has previously been shown that addition
of three water molecules around an oxygen anion could greatly improve the precision of the
calculated energy for the reactions involving this anion.22 The same approach was employed in
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 26
1
2
3
4
5
6
our recent work on the dehydrogenation of alcohols to carboxylic acids in the presence of
hydroxide.15
7
8
9
Indeed, adding explicit water molecules stabilized intermediate 5 when optimizing its structure
at the B3LYPꢀD3/6ꢀ31+G* level of theory. Three water molecules around each oxygen anion
formed a small hydrogenꢀbonded cluster with an average intermolecular O···H bond distance of
2.180 Å for the two clusters and an average O···H bond distance of 1.836 Å between the
negatively charged oxygen atoms of 5 and the hydrogen atoms of the water molecules. For
consistency three water molecules were similarly added to the other oxygen anions apart from
formate anion 7. Moreover, to take into account hydrogen bonding, a water molecule was also
optimized with three added water molecules. For all further calculations the water coordinated
species in Figure 4 were used instead of the structures in Scheme 4.
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
H
H O
H
Cl
OH
O
H
H
O
H
H
H
ꢀ
H
O
O
H
H
O
O
H
O
H
H O
H
Cl
H
ꢀ
H
O
H
O
O H
H
H
ꢀ
4—3H2O
(H2O)4
OH —3H2O
H
H
O
H
O
H
H
H
H
O
H
O
H
O
H
O
H
H
ꢀ
ꢀ
Cl
O
O
Cl
O
O
H
H
H
H
ꢀ
ꢀ
O
O
H O
H O
Cl
H
Cl
H
H
H
O
O
H
H
5—6H2O
TS1
—6H2O
Figure 4. Species with explicit water molecules used in the calculations
ACS Paragon Plus Environment

Page 15 of 26
The Journal of Organic Chemistry
1
2
3
4
According to the previous experimental studies the cleavage the C–C bond in
5
6
7
8
9
2,6ꢀdichlorobenzaldehyde proceeds through the formation of dianion 5 with its fragmentation as
the rateꢀdetermining step. For this reason, the finding of transition state TS1 is crucial for the
study. Unfortunately, all attempts to locate transition state TS1·6H2O at the B3LYPꢀD3/6ꢀ
31+G* level of theory were unsuccessful which made it impossible to use the calculated
energies for comparison with the experimental values. Larger basis sets were tried instead, and it
was found that only with the 6ꢀ31++G** basis set and the M06ꢀ2X functional was it possible to
locate all species. After a brief screening of the basis sets it was found that an acceptable
difference between the calculated and the measured Gibbs free energy of activation could be
obtained when optimizing the species with the 6ꢀ311++G** basis set in water (Table 4).
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. Gibbs Free Energy of Activation Calculated with Different Basis Setsa
ꢀGa, kJ·mol–1
150.0
139.3
113.7
ꢀꢀGa,b kJ·mol–1
41.2
30.5
4.9
Entry
1
Basis set
6ꢀ31++G**
6ꢀ311++G**
6ꢀ311++G**
ccꢀpVDZꢀPP
2
3c
4
140.1
31.3
a
Optimized using M06ꢀ2X functional and Gibbs free energy calculated
b
c
at 58 °C. Difference between the calculated and experimental values.
Geometry optimized in water
The complete energy profile for the cleavage of 2,6ꢀdichlorobenzaldehyde is shown in Figure
5. The overall transformation is exergonic by 178.9 kJ·mol–1. In the first step, aldehyde 3 is
attacked by a hydroxide ion (i.e. OH‒·3H2O) to give intermediate 4·3H2O which resulted in an
energy decrease of 15 kJ·mol–1. The deprotonation of this species leads to the formation of a key
intermediate – dioxyanion 5·6H2O which undergoes deformylation through the transition state
TS1·6H2O. The Gibbs free energy for this step is 113.7 kJ·mol–1 which is only 4.9 kJ·mol–1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 26
1
2
3
4
5
6
7
8
9
higher than the experimental value. The resulting dichlorophenyl anion 6 abstracts a proton from
a water molecule resulting in a further energy decrease of almost 90 kJ·mol–1. Thus, the selected
combination of the 6ꢀ311++G** basis set and the M06ꢀ2X functional made it possible to obtain
activation parameters for the cleavage of 2,6ꢀdichlorobenzaldehyde that are very close to the
experimental values.
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
Figure 5. Energy profile for the cleavage of 2,6ꢀdichlorobenzaldehyde
With this method available, the computational study could now be extended to 2ꢀ
phenylacetaldehyde in order to determine which of the two cleavage pathways are applicable in
this case. 2ꢀPhenylacetaldehyde was selected as the substrate for the calculations since the
ACS Paragon Plus Environment

Page 17 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
cleavage reaction was originally discovered with this molecule. Although, water is not explicitly
added to the reaction, solid KOH contains 0.35 – 0.55 equiv. of H2O per equiv. of hydroxide
depending on the quality of the base and KOH is used in excess in this transformation. The two
pathways are illustrated in Scheme 5 with the formation of the dioxyanion as pathway A and the
direct fragmentation of the monooxy anion as pathway B. The energy profiles for both pathways
are shown in Figure 6. It can be seen that pathway B is more favorable than pathway A by
almost 100 kJ·mol–1 starting from the common intermediate 10a·3H2O. Even though the barrier
for the fragmentation step is lower for pathway A (ꢀG≠ (A) = 40.5 kJ·mol–1, ꢀG≠ (B) = 117.1
kJ·mol–1), the preceding deprotonation step leads to a high lying dianion 10b·6H2O
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
(ꢀG(10b·6H2O) – ꢀG(10a·3H2O) = 173.3 kJ·mol–1) which renders pathway A less favorable
overall. With the monooxy anion pathway as the preferred route, the DFT calculations confirm
the results from the Hammett study where a full charge is revealed in the rateꢀdetermining step.
Scheme 5. Two Possible Pathways for Cleavage of 2-Phenylacetaldehyde
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 26
1
2
3
4
5
6
7
8
9
The solvent is most likely responsible for the monooxy anion pathway being favored in this
case. The previous kinetic studies on the cleavage of ketones and aldehydes have all been carried
out in water where the dianion pathway was shown to be the preferred cleavage route.2,4,7
However, xylene is poor at solvating oxygen anions (even with added water molecules) and as a
result the dioxyanion becomes more unfavorable in this case and leads to the fragmentation
through the monooxy anion.
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
ꢀ
ꢀ
(3H2O)O
O (3H2O)
227.9
ꢀ
ꢀ
(3H2O)O
O (3H2O)
187.4
TS10bc—6H2O
10b—6H2O
131.2
O
CH2
O
+
H
OH
86.8
10c
7a
ꢀ
HO
O (3H2O)
O
CH2
9
ꢀ
+
14.1
10.9
H
O
0.0
10c
7
ꢀ
TS10ac—3H2O
HO
O (3H2O)
CH3
11
10a—3H2O
ꢀ124.1
Figure 6. Energy profile for pathways A and B
In conclusion, the substrate scope of the potassium hydroxideꢀmediated carbonꢀcarbon
cleavage reaction was extended to benzyl carbonyl compounds and the mechanism for the
reaction was investigated with both experimental and theoretical methods. The reaction was
ACS Paragon Plus Environment

Page 19 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
found to proceed through a monooxy anion intermediate in xylene solution in contrast to what
has previously been reported in the literature for the scission of aldehydes and ketones in
aqueous media. The results show that DFT calculations can be employed to distinguish between
the two reaction pathways and the good agreement between experiment and theory opens up for
the possibility of in silico substrate screening.
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
EXPERIMENTAL SECTION
General Information. All solvents were of HPLC grade and were not further purified. Column
chromatography separations were performed on silica gel (220 – 440 mesh). NMR chemical
shifts were measured relative to the signals of residual CHCl3 (δH 7.26 ppm) and CDCl3 (δC
77.16 ppm). HRMS measurements were made using ESI with TOF detection. Phenylacetones,23
2ꢀphenylcyclopentanone24 and –cyclohexanone25 were prepared according to literature
procedures.
2-Methyl-2-phenylcyclohexanone (Table 2, entry 4):26 Following a literature procedure26 2ꢀ
phenylcyclohexanone (1.0 g, 5.74 mmol) in tertꢀbutanol (10 mL) was treated with potassium
tertꢀbutoxide (673 mg, 6.00 mmol) for 45 min followed by addition of methyl iodide (0.7 mL,
11.2 mmol). The mixture was stirred at room temperature for 2.5 h and worked up by addition of
water and extraction with EtOAc. Purification by flash chromatography (heptane/EtOAc 95/5)
gave 950 mg (88%) of the product as a colorless oil. 1H NMR (400 MHz, CDCl3)
7.6 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 7.20‒7.18 (m, 2H), 2.71‒2.68 (m, 1H), 2.45‒2.25 (m, 2H),
δ 7.35 (t, J =
1.76‒1.65 (m, 4H), 2.02‒1.92 (m, 1H), 1.27 (s, 3H). 13C NMR (100 MHz, CDCl3)
143.4, 129.1, 126.7, 126.2, 54.5, 40.1, 38.3, 28.6, 28.6, 22.0.
δ 214.3,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 26
1
2
3
4
2-Ethyl-2-phenylcyclohexanone (Table 2, entry 5):27 Prepared in 81% yield (940 mg) as a
5
6
7
colorless oil from 2ꢀphenylcyclohexanone and ethyl iodide as described above for 2ꢀmethylꢀ2ꢀ
8
9
phenylcyclohexanone. 1H NMR (400 MHz, CDCl3)
Hz, 1H), 7.15 (d, J = 7.3 Hz, 2H), 2.74‒2.70 (m, 1H), 2.40‒2.10 (m, 2H), 1.94 (ddd, J = 2.9, 5.9,
δ 7.34 (t, J = 7.6 Hz, 2H), 7.23 (t, J = 7.3
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
12.0 Hz, 1H), 1.88‒1.59 (m, 6H), 0.61 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ 214.1,
140.9, 128.8, 127.2, 126.7, 57.7, 40.4, 34.5, 32.6, 28.5, 21.8, 8.2.
2-Benzyl-2-phenylcyclohexanone (Table 2, entry 6):28 Prepared in 90% yield (1.4 g) as a white
solid from 2ꢀphenylcyclohexanone and benzyl bromide as described above for 2ꢀmethylꢀ2ꢀ
phenylcyclohexanone. 1H NMR (400 MHz, CDCl3)
δ 7.32‒7.21 (m, 3H), 7.13‒7.02 (m, 3H),
6.96‒6.94 (m, 2H), 6.57‒6.54 (m, 2H), 3.12 (d, J = 13.5 Hz, 1H), 2.98 (d, J = 13.5 Hz, 1H),
2.48‒2.46 (m, 1H), 2.36‒2.33 (m, 2H), 1.96‒1.92 (m, 1H), 1.74‒1.64 (m, 4H). 13C NMR (100
MHz, CDCl3)
δ 213.4, 140.0, 137.4, 130.9, 128.8, 127.5, 127.4, 126.9, 126.1, 58.1, 46.4, 40.3,
34.8, 28.4, 21.5.
General procedure for cleavage of ketones. A suspension of KOH (1.4 g, 25 mmol) in xylene
(50 mL) was heated to reflux followed by dropwise addition of a solution of the ketone (2.5
mmol) in xylene (1 mL) over 10 min (for reactions where the GC yield was determined 150 mg
of nonane was also added as an internal standard). The reaction was stirred at reflux for an
additional 1 h. The mixture was cooled to room temperature and extracted with water (3 × 50
mL). The combined aqueous phases were carefully acidified with 6 M hydrochloric acid to pH 2
and then extracted with ethyl acetate (3 × 60 mL). The combined organic layers were washed
with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash
column chromatography (pentane/ethyl acetate 95/5 → 80/20) to afford the carboxylic acid.
ACS Paragon Plus Environment

Page 21 of 26
The Journal of Organic Chemistry
1
2
3
4
6-Phenylhexanoic acid (Table 2, entry 3):29 Isolated as a colorless oil in 78% yield (374 mg). 1H
5
6
7
NMR (400 MHz, CDCl3)
δ 11.04 (bs, 1H), 7.26‒7.30 (m, 2H), 7.16‒7.20 (m, 3H), 2.62 (t, J =
8
9
7.7 Hz, 2H), 2.36 (t, J = 7.5 Hz, 2H), 1.61‒1.72 (m, 4H), 1.36‒1.44 (m, 2H). 13C NMR (100
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
MHz, CDCl3)
6-Phenylheptanoic acid (Table 2, entry 4):30 Isolated as a colorless oil in 40% yield (206 mg).
1H NMR (400 MHz, CDCl3)
2.79‒2.74 (m, 1H), 2.38 (t, J = 7.6 Hz, 2H), 1.75‒1.63 (m, 4H), 1.38‒1.19 (m, 5H). 13C NMR
δ 179.8, 142.6, 128.5, 128.4, 125.8, 35.8, 34.0, 31.2, 28.8, 24.7.
δ
11.57 (bs, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.27‒7.24 (m, 3H),
(100 MHz, CDCl3)
δ 180.5, 147.6, 128.5, 127.1, 126.0, 39.9, 38.1, 34.1, 27.3, 24.8, 22.5.
6-Phenyloctanoic acid (Table 2, entry 5): Isolated as a colorless oil in 65% yield (374 mg). 1H
NMR (400 MHz, CDCl3) δ 10.66 (bs, 1H), 7.27 (t, J = 7.6 Hz, 2H), 7.18 (t, J = 7.5 Hz, 1H),
7.13 (d, J = 7.5 Hz, 2H), 2.44‒2.36 (m, 1H), 2.30‒2.26 (m, 2H), 1.72‒1.42 (m, 6H), 1.29‒1.13
(m, 2H), 0.76 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ
180.2, 145.7, 128.4, 127.8,
126.0, 47.8, 36.2, 34.1, 29.9, 27.2, 24.9, 12.3. HRMS: m/z calcd for C14H20O2Na 243.1356 [M +
Na]+, found 243.1348.
6,7-Diphenylheptanoic acid (Table 2, entry 6): Isolated as a yellowish solid in 76% yield (534
mg). Mp: 77 – 80 °C (ethanol). 1H NMR (400 MHz, CDCl3)
δ 10.94 (bs, 1H), 7.28‒7.21 (m,
2H), 7.21‒7.12 (m, 4H), 7.10 (d, J = 6.9 Hz, 2H), 7.01 (d, J = 7.0 Hz, 2H), 2.89‒2.87 (m, 2H),
2.84‒2.77 (m, 1H), 2.26‒2.21 (m, 2H), 1.74‒1.46 (m, 4H), 1.22‒1.15 (m, 2H). 13C NMR (100
MHz, CDCl3) δ 180.3, 145.0, 140.7, 129.3, 128.4, 128.2, 127.8, 126.2, 125.9, 48.0, 44.0, 35.2,
33.9, 27.1, 24.8. HRMS: m/z calcd for C19H22O2Na 305.1512 [M + Na]+, found 305.1512.
3-(o-Tolyl)propanoic acid (Table 2, entry 7):31 Isolated as a colorless oil in 18% yield (74 mg).
1H NMR (400 MHz, CDCl3)
δ
7.18‒7.12 (m, 4H), 2.98‒2.94 (m, 2H), 2.67‒2.63 (m, 2H), 2.33
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 26
1
2
3
4
(s, 3H). 13C NMR (100 MHz, CDCl3)
δ 178.8, 138.3, 136.1, 130.5, 128.5, 126.6, 126.3, 34.4,
5
6
7
8
9
28.1, 19.4.
5-Phenylpentanoic acid (Table 2, entry 8):29 Isolated as a colorless oil in 64% yield (285 mg).
1H NMR (400 MHz, CDCl3)
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
δ
11.8 (bs, 1H), 7.30‒7.26 (m, 2H), 7.20‒7.17 (m, 3H), 2.66‒2.62
(m, 2H), 2.40‒2.36 (m, 2H), 1.70‒1.67 (m, 4H). 13C NMR (100 MHz, CDCl3)
128.5, 128.5, 126.0, 35.7, 33.9, 30.9, 24.4.
δ 179.5, 142.1,
2-(o-Tolyl)acetic acid (Table 2, entry 9):32 Isolated as a white solid in 90% yield (338 mg). 1H
7.21‒7.17 (m, 4H), 3.67 (s, 3H), 2.33 (s, 2H). 13C NMR (100 MHz,
NMR (400 MHz, CDCl3)
δ
CDCl3) δ 177.3, 137.0, 132.0, 130.4, 130.3, 127.7, 126.2, 38.8, 19.6.
Computational Details. All calculations were performed in Jaguar33 by using the Maestro
graphical interface.34 All the structures were optimized in the gas phase and the singleꢀpoint
solvation energy was calculated for the optimized structures by using a standard Poisson–
Boltzmann solver with suitable parameters for water or xylene as the solvent. Default dielectric
constant and probe radius were used for solvation with water while for xylene the following
parameters were employed: dielectric constant ε = 2.2, probe radius r = 2.9 Å. Gibbs free
energies were obtained from the vibrationalꢀfrequency calculations for the gasꢀphase geometries
at 298 K and 311 K (for structures from Figure 5) or 411 K (for structures from Figure 6). All
the transition states were characterized by the presence of one negative vibrational frequency.
Graphical representation of the calculated structures was made in CYLview.35
ACKNOWLEDGMENT
We thank the Danish Council for Independent Research ꢀ Technology and Production Sciences
for financial support (grant 09ꢀ066621).
ACS Paragon Plus Environment

Page 23 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Supporting Information. Copies of 1H and 13C NMR spectra for the prepared compounds,
kinetic data, derivation of equation 1 as well as energies and coordinates from the DFT
calculations. This material is available free of charge via the Internet at http://pubs.acs.org.
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
References
1)
2)
Artamkina, G. A.; Beletskaya, I. P. Russ. Chem. Rev. 1987, 56, 983‒1001.
(a) Guthrie, J. P.; Cossar, J. Can. J. Chem. 1990, 68, 1640‒1642. (b) Zucco, C.; Lima, C.
F.; Rezende, M. C.; Vianna, J. F.; Nome, F. J. Org. Chem. 1987, 52, 5356‒5359. (c)
Guthrie, J. P.; Cossar, J. Can. J. Chem. 1986, 64, 1250‒1266.
3)
4)
Symons, E. A.; Clermont, M. J. J. Am. Chem. Soc. 1981, 103, 3127‒3130.
(a) Rahil, J.; Pratt, R. F. J. Am. Chem. Soc. 1977, 99, 2661‒2665. (b) Fedor, L. R.; Murty,
B. S. R.; De, N. C. J. Am. Chem. Soc. 1975, 97, 4308‒4312. (c) Pearson, R. G.; Mayerle, E.
A. J. Am. Chem. Soc. 1951, 73, 926‒930.
5)
6)
Hine, J.; Koser, G. F. J. Org. Chem. 1971, 36, 1348‒1351.
(a) Stranberg, M.; Anselme, J.ꢀP. J. Chem. Educ. 1990, 67, 616. (b) Danilov, S. J. Russ.
Phys. Chem. Soc. 1917, 49, 282‒288.
7)
8)
(a) Forbes, E. J.; Gregory, M. J. J. Chem. Soc. B 1968, 205‒207. (b) Bunnett, J. F.; Miles,
J. H.; Nahabedian, K. V. J. Am. Chem. Soc. 1961, 83, 2512‒2516.
Calas, M.; Calas, B.; Giral, L. Bull. Soc. Chim. Fr. 1976, 857‒861.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 26
1
2
3
4
5
6
7
8
9
9)
(a) Artamkina, G. A.; Grinfel’d, A. A.; Beletskaya, I. P. Bull. Acad. Sci. USSR 1983, 32,
345‒352. (b) Hausigk, D. Chem. Ber. 1971, 104, 2637‒2639. (c) Davies, D. G.; Derenberg,
M.; Hodge, P. J. Chem. Soc. C 1971, 455‒460.
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
10) Pearson, R. G.; Dillon, R. L. J. Am. Chem. Soc. 1948, 70, 1933‒1936.
11) Mehta, G.; Venkateswaran, R. V. Tetrahedron 2000, 56, 1399‒1422.
12) For more recent examples, see: (a) CasasꢀSolvas, J. M.; Mooibroek, T. J.; Sandramurthy,
S.; Howgego, J. D.; Davis, A. P. Synlett 2014, 2591‒2594. (b) BenꢀHaida, A.; Hodge, P.
Org. Biomol. Chem. 2012, 10, 1754‒1763. (c) Wang, Q.; Chen, C. Org. Lett. 2008, 10,
1223‒1226. (d) Yamada, Y. M. A.; Uozumi, Y. Tetrahedron 2007, 63, 8492‒8498. (e)
Bello, A. M.; Kotra, L. P. Tetrahedron Lett. 2003, 44, 9271‒9274. (f) Mehta, G.; Reddy, D.
S. J. Chem. Soc., Perkin Trans. 1 2001, 1153‒1161. (g) Zabjek, A.; Petric, A. Tetrahedron
Lett. 1999, 40, 6077‒6078. (h) Maslak, P.; Varadarajan, S.; Burkey, J. D. J. Org. Chem.
1999, 64, 8201‒8209.
13) For recent examples, see: (a) Sarma, M. J.; Borah, A. J.; Rajbongshi, K. K.; Phukan, P.
Tetrahedron Lett. 2015, 56, 7008‒7011. (b) Braun, I.; Rudroff, F.; Mihovilovic, M. D.;
Bach, T. Synthesis 2007, 3896‒3906. (c) Ishihara, K.; Yano, T. Org. Lett. 2004, 6,
1983‒1986.
14) Li, J. J. Name Reactions: A Collection of Detailed Mechanisms and Synthetic
Applications; 5. Ed.; Springer, 2014, p. 299.
15) Santilli, C.; Makarov, I. S.; Fristrup, P.; Madsen, R. J. Org. Chem. 2016, 81, 9931‒9938.
16) The release of formate from aldehydes is also an unusual enzymatic reaction catalyzed by
cyanobacterial aldehydeꢀdeformylating oxygenase under aerobic conditions, see: Shokri, A.;
Que, L, Jr. J. Am. Chem. Soc. 2015, 137, 7686‒7691.
ACS Paragon Plus Environment

Page 25 of 26
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
17) The reason could also be the formation of hydrogen bonded species as observed in the
Mitsunobu esterification reaction where the addition of more nucleophile leads to slower
reactions, see: Hughes, D. L.; Reamer, R. A.; Bergan, J. J.; Grabowski, E. J. J. J. Am. Chem.
Soc. 1988, 110, 6487‒6491.
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
18) For other Hammett studies employing competition kinetics, see: (a) Fristrup, P.; Tursky,
M.; Madsen, R. Org. Biomol. Chem. 2012, 10, 2569‒2577. (b) Fristrup, P.; Kreis, M.;
Palmelund, A.; Norrby, P.ꢀO.; Madsen, R. J. Am. Chem. Soc. 2008, 130, 5206‒5215. (c)
Dam, J. H.; Fristrup, P.; Madsen, R. J. Org. Chem. 2008, 73, 3228‒3235. (d) Keinicke, L.;
Fristrup, P.; Norrby, P.ꢀO.; Madsen, R. J. Am. Chem. Soc. 2005, 127, 15757‒15761.
19) The GC yields of the paraꢀsubstituted toluenes (X = OMe, Et, Cl and F) varied between
42% and 65%.
20) See the Supporting Information for the derivation of the equation.
21) For our recent computational studies on other carbonyl addition reactions, see: (a)
reference 15. (b) Makarov, I. S.; Fristrup, P.; Madsen, R. Chem. Eur. J. 2012, 18,
15683‒15692.
22) Bryantsev, V. S.; Diallo, M. S.; van Duin, A. C. T.; Goddard, W. A., III J. Chem. Theory
Comput. 2009, 5, 1016‒1026.
23) He, C.; Guo, S.; Huang, L.; Lei, A. J. Am. Chem. Soc. 2010, 132, 8273‒8275.
24) Sifton, W.; Stothers, J. B.; Thomas, S. E. Can. J. Chem. 1992, 70, 1274‒1280.
25) Reichle, M. A.; Breit, B. Angew. Chem. Int. Ed. 2012, 51, 5730‒5734.
26) Haffemayer, B.; Gulias, M.; Gaunt, M. J. Chem. Sci. 2011, 2, 312‒315.
27) Nedenskov, P.; Taub, W.; Ginsburg, D. Acta Chem. Scand. 1958, 12, 1405‒1410.
28) Kano, T.; Hayashi, Y.; Maruoka, K. J. Am. Chem. Soc. 2013, 135, 7134‒7137.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 26
1
2
3
4
5
6
29) Owen, C. P.; Shahid, I.; Olusanjo, M. S.; Patel, C. H.; Dhanani, S.; Ahmed, S. J. Steroid
Biochem. Mol. Biol. 2008, 111, 117‒127.
7
8
9
30) Weix, D. J.; Dreher, S. D.; Katz, T. J. J. Am. Chem. Soc. 2000, 122, 10027‒10032.
31) Lim, M.; De Castro, K. A.; Oh, S.; Lee, K.; Chang, Y.ꢀW.; Kim, H.; Rhee, H. Appl.
Organomet. Chem. 2011, 25, 1‒8.
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
32) Hassner, A.; Ruse, M.; Gottlieb, H. E.; Cojocaru, M. J. Chem. Soc., Perkin Trans. 1 1988,
733‒737.
33) Jaguar, version 9.0, Schrodinger, Inc., New York, NY, 2015.
34) Bochevarov, A. D.; Harder, E.; Hughes, T. F.; Greenwood, J. R.; Braden, D. A.; Philipp,
D. M.; Rinaldo, D.; Halls, M. D.; Zhang, J.; R. Friesner, A. Int. J. Quantum Chem. 2013,
113, 2110‒2142.
35) Legault, C.Y. CYLview, version 1.0b, Université de Sherbrooke, 2009.
ACS Paragon Plus Environment