The Complete Mechanism of an Aldol Condensation

Article abstract of DOI:10.1021/acs.joc.6b00959

Although aldol condensation is one of the most important organic reactions, capable of forming new C-C bonds, its mechanism has never been fully established. We now conclude that the rate-limiting step in the base-catalyzed aldol condensation of benzaldehydes with acetophenones, to produce chalcones, is the final loss of hydroxide and formation of the C=C bond. This conclusion is based on a study of the partitioning ratios of the intermediate ketols and on the solvent kinetic isotope effects, whereby the condensations are faster in D₂O than in H₂O, regardless of substitution.

Full text of DOI:10.1021/acs.joc.6b00959

Subscriber access provided by the Henry Madden Library | California State University, Fresno
Article
The Complete Mechanism of an Aldol Condensation
Charles L Perrin, and Kuei-Lin Chang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00959 • Publication Date (Web): 09 Jun 2016
Downloaded from http://pubs.acs.org on June 12, 2016
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 16
The Journal of Organic Chemistry
1
2
3
4
5
6
The Complete Mechanism of an Aldol Condensation
7
8
9
Charles L. Perrin,* Kuei-Lin Chang
Dept. of Chemistry & Biochemistry, Univ. Calif. San Diego, La Jolla, CA 92093-0358
cperrin@ucsd.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
Table of Contents Graphic
‡
3 kcal/mol
–
ArCH(OH)CH COAr'
ArCH=CHCOAr'
CH =C(O )Ar'
2
2
–
–
CH COAr'
ArCH(OH)CH=C(O )Ar'
3
ArCH(O )CH COAr'
2
Abstract
Although aldol condensation is one of the most important organic reactions, capable of
forming new C-C bonds, its mechanism has never been fully established. It is now concluded
that the rate-limiting step in the base-catalyzed aldol condensation of benzaldehydes with
acetophenones, to produce chalcones, is the final loss of hydroxide and formation of the C-C
double bond. This conclusion is based on a study of the partitioning ratios of the intermediate
ketols and on the solvent kinetic isotope effects, whereby the condensations are faster in D O
2
than in H O, regardless of substitution.
2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 16
1
2
3
4
Introduction
5
6
7
8
The aldol reaction and the aldol condensation are among the most versatile of organic
reactions,1 with > 25000 entries in SciFinder. Each of these uses two carbonyl compounds, one
as electrophile and the other as nucleophile. Each succeeds in forming a new carbon-carbon
single bond, or else a carbon-carbon double bond, which distinguishes the aldol condensation.
There are many variants, including the Claisen, Dieckmann, Henry, and Darzens Condensations
and the Knoevenagel and Perkin Reactions. Because of their ability to construct larger molecules
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
2 6
7 9
from smaller ones, or to effect cyclization, often with control of stereochemistry,10 12 these
reactions are a mainstay of organic synthesis. They are also common in metabolism, where
aldolase, citrate synthase, and other enzymes catalyze aldol reactions and aldol condensations, or
-
-
-
their reverse,13 leading to the suggestion that they reflect primordial metabolism.14 15
-
We are interested in the particular aldol reaction of a benzaldehyde 1 and an
acetophenone 2 to form ketol (β-hydroxyketone) 3, which is then dehydrated to the chalcone
(benzylideneacetophenone) 4, as in Scheme 1. Chalcones have many medicinal and
pharmacological properties, with antimicrobial, anticancer, anti-inflammatory, antimalarial,
antibacterial, and antiproliferative activities.16 They are intermediates in the synthesis of various
natural products,17 18 as well as unusual polycyclic aromatics.19 The aromatic rings stabilize 4 and
-
increase the equilibrium constant for its formation, so that the reaction becomes more feasible for
study.
O
O
OH
O
O
+
Ar
H
Ar'
Ar
Ar'
Ar
Ar'
1
2
3
4
Scheme 1. Formation of Chalcone (4) from a Benzaldehyde (1) and an Acetophenone (2) via
Ketol 3.
The question we address is the mechanism of base-catalyzed chalcone formation, as a
representative of the aldol condensation. It may be thought that this mechanism is well
ACS Paragon Plus Environment

Page 3 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
understood, but, surprisingly, it has never been fully established. There are five steps, as shown
in Scheme 2, although the last two are sometimes merged into a single dehydration step, perhaps
merely for brevity.
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
-
O
2
-
O
O
O
O
-
OH
1
1
Ar
H
Ar'
Ar'
Ar
Ar'
2
-
3
OH
-
O
OH
O
-
OH
O
-
OH
4
- OH
5
Ar
Ar'
Ar
Ar'
Ar
Ar'
3
4
5
Scheme 2. Steps in Chalcone Formation: (1) First Enolization, (2) C-C Bond Formation, (3)
Proton Equilibration, (4) Second Enolization, (5) Hydroxide Elimination and C=C Bond
Formation.
According to an early kinetic study,20 the rate, for Ar = Ph = Ar', is given by eq 1, where k
is a third-order rate constant. Therefore Step 1 cannot be rate-limiting, because if it were, the rate
would be independent of [ArCHO]. For the aldol reaction, arrested at 3, Step 2 must be rate-
limiting, because the proton equilibration of Step 3 is fast (although there are examples where the
enolization of Step 1 is rate-limiting).21 23
-
–
v = d[chalcone]/dt = k[ArCHO][Ar'COCH ][OH ]
(1)
3
Which step is the rate-limiting step of the aldol condensation, as distinguished from the
aldol reaction? Noyce, Pryor, and Bottini studied the fate of the ketol intermediate,
independently synthesized.24 They found that 3 (Ar = Ph = Ar') is converted in base to a mixture
of 80% 1 + 2 and 20% 4. There has been disagreement about the mechanistic inference to be
drawn from this 4:1 ratio. Noyce, Pryor, and Bottini inferred that "in dilute solutions the C-C
bond forming step is rate-determining, with dehydration being rapid". This inference is echoed in
a recent advanced textbook: "Studies ... have shown that about 80% (sic) of [ketol] goes on to
product. These reactions are faster than the overall reaction, so the second step must be rate
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 16
1
2
3
4
5
6
7
8
9
controlling."25 An earlier monograph concluded, "observation that alkali transforms the
intermediate β-hydroxy ketone to benzaldehyde and acetophenone more rapidly than it
dehydrates it shows that the second step is not rate-controlling".26 It should be noted that these
two books draw exactly opposite conclusions about Step 2, and that the recent one misquoted the
experimental observation. We now resolve these contradictions.
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
According to one definition,27 the rate-limiting step of a multistep mechanism is the last
one whose rate constant remains in the kinetic equation. Because ketol 3 reverts to precursors
faster than it continues to chalcone, Steps 1, 2, and 3 of Scheme 2 are rapid and reversible and
cannot be rate-limiting. This holds even in dilute solution, where Step 2 is slower in the forward
direction but not retarded in the reverse direction.
Therefore dehydration must be rate-limiting. Although this can be represented as a single
–
step, it is possible to distinguish enolization (Step 4) from elimination of OH (Step 5). Which
one is rate-limiting, Step 4, Step 5, or their composite?
Kinetic isotope effects are often useful in elucidating reaction mechanisms and
distinguishing the rate-limiting step.28 29 Indeed, this question can be answered by measuring the
-
solvent deuterium kinetic isotope effect. Because Step 1 is rapid and reversible, Ar'COCH in
3
D O becomes Ar'COCD and 3 becomes ArCHODCD COAr'. The deuterated 3 may be
2
3
2
expected to form enolate 5 more slowly than undeuterated 3 does, as is generally seen in base-
catalyzed enolizations, owing to the lower zero-point energy of a C-D bond. A faster reaction in
D O would then be strong evidence against Step 4 as rate-limiting. We also choose to ascertain
2
whether the answer depends on substituents in the aryl rings and even the extent to which the
partition ratio of intermediate 3 might depend on substituents. We therefore have extended the
earlier studies to some substituted benzaldehydes 1 and acetophenones 2.
Although earlier studies were often performed in ethanol, a solvent isotope effect is more
readily interpreted in an aqueous medium. Then, to maintain solubility of substrates and of
chalcone product, it was found necessary to add acetonitrile as cosolvent to the H O or D O.
2
2
Fortunately, CH CN is sufficiently inert to base-catalyzed H/D exchange.30 We now report that
3
ACS Paragon Plus Environment

Page 5 of 16
The Journal of Organic Chemistry
1
2
3
4
–
the reaction is faster in D O than in H O, and we conclude that elimination of OH is the rate-
2
2
5
6
limiting step, regardless of substituents in the aromatic rings.
7
8
9
Results and Discussion
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
Partitioning of Ketol Intermediates. On treatment with dilute base, ketols 3 partition
between reversion to precursors 1 and 2 and progression to chalcone product 4. The partitioning
ratio was evaluated from the absorbances of the product mixture at both the λ
of chalcone 4,
max
near 312 nm, and the isosbestic wavelength of benzaldehyde 1 and acetophenone 2, near 250 nm.
Table 1 presents the ratio R, = [1]/[4] = [2]/[4]. Thus the dominant reaction is reversion to
24
precursors, as found for unsubstituted 3 by Noyce, Pryor, and Bottini. Moreover, this is general
for all ketols 3, regardless of aryl substitution. However, all ratios are slightly greater than the
4:1 originally reported. We attribute this to our more modern scanning spectrophotometer, rather
than to the difference in solvents, because a ratio of 7.4 was also found in ethanol.31
Table 1. Partitioning ratio R of ketol 3 to precursors 1 + 2, relative to product 4.
Ar
Ph
Ar'
Ph
R
6.4
5.4
5.8
6.9
6.9
6.9
pClPh
Ph
pO NPh
2
Ph
pMePh
Ph
Ph
pClPh
pO NPh
2
Ph
Solvent Kinetic Isotope Effect on Rates of Chalcone Formation. Third-order rate
constants for base-catalyzed conversion of benzaldehyde 1 plus acetophenone 2 to chalcone 4 in
both H O and D O at ambient temperature of 25.2 ºC are listed in Table 2, along with the ratios
2
2
k
/k
. Values of k are averages over all kinetic runs, and the error reported for each k and
D2O H2O
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 16
1
2
3
4
for each k
/k
is the standard error of the mean. In all cases the reaction is faster in D O.
D2O H2O 2
5
6
Although the errors are large enough that k
/k
does not always differ from unity at a high
D2O H2O
7
8
9
level of statistical significance, the fact that none is less than 1 excludes mechanistic alternatives
where this ratio would be much less than 1, as justified below.
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
-2 -1
Table 2. Rate constants (M s ) for base-catalyzed conversion of benzaldehyde 1 and
acetophenone 2 to chalcone 4 in H O or D O and ratio k
2
/k
D2O H2O
.
2
%CH CN
Ar
Ph
Ar'
Ph
Ph
Ph
k
k
k /k
D2O H2O
3
H2O
D2O
26
40
40
40
40
0.0111±0.0004 0.0127±0.0005 1.14±0.06
0.0412±0.0008 0.0506±0.0007 1.23±0.03
pClPh
pO NPh
0.440±0.019
0.512±0.013 1.16±0.06
2
Ph
Ph
pClPh 0.0298±0.0009 0.0334±0.0007 1.12±0.04
pO NPh 0.158±0.004 0.227±0.014 1.43±0.10
2
These results might have been anticipated. The elimination of methanol from 6 (R = H,
CH ) is faster in D O than in H O, by a factor of 1.15 (R=H) or 1.30 (R=CH ).32 Therefore it
3
2
2
3
was concluded that this mechanism is E1cb, as in Scheme 3, with the rate-limiting step being the
loss of methoxide from the enolate intermediate 8.
-
O
MeO
R
O
MeO
R
O
-
OH
R
6
8
7
Scheme 3. E1cb Elimination of Methoxide.
Because reaction is faster in D O, H (or D) removal (Step 4 of Scheme 2) cannot be rate-
2
limiting, because it would show k
<< k
. For example, enolizations of simple ketones
H2O
D2O
show a kinetic isotope effect k /k of 1/4 to 1/7.33 35 A mechanism more closely analogous to
-
D
H
ACS Paragon Plus Environment

Page 7 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Steps 4 and 5 of Scheme 2 is often operative for elimination of H and a good leaving group, such
as halide. Such a mechanism is, designated as E1cb(irrev), but it is less likely here for the poorer
leaving group hydroxide. Indeed, this mechanism would have shown a k /k of 1/7.36 Nor can a
D
H
9
concerted E2 elimination of H and OH be operative, for it would have shown a k /k of 1/3 to
D
H
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
1/7.37
Instead the rate-limiting step must be Step 5, the final loss of hydroxide from enolate
–
intermediate 5. The reaction is faster in D O because OD is a stronger base than OH , as judged
–
2
in D O.38
2
-14
-15
from the comparison between K = 1.01 x 10
w
in H O but 1.12 x 10
2
Consequently, there is a higher steady-state concentration of 5 in D O. This is consistent with the
2
observations that base-catalyzed epoxide formation from 2-haloethanols is faster in D O than in
2
H O.39 40 Thus the rate law for chalcone formation is
v
=
k [5]
5
=
-
2
–
k K K K K [Ar'COCH ][ArCHO][OH ], where K are equilibrium constants for Steps 1-4 in
5 4 3 2 1
3
1-4
Scheme 2 and k is the rate constant for Step 5. It should be noted that this solvent kinetic
5
isotope effect is not from the rate constant k but from the steady-state [5]. This is higher in D O
5
2
than in H O, owing to a larger K in D O.
2
4
2
It is necessary to justify the simplification to pseudo-first-order kinetics. In principle, the
–
stoichiometric OH concentration might partition itself among the anionic species of Scheme 2,
leading to a catalytic cycle with a more complicated rate expression. Thus Scheme 2 can
alternatively be drawn as a set of catalytic cycles, as in Scheme 4. Such a drawing places onto
the cycle not only the catalyst but also any species to which the catalyst is converted, while
reactants and products are shown as entering or leaving the cycle. A catalytic cycle is
advantageous for cases like Michaelis-Menten kinetics, where a high concentration of substrate S
can convert catalyst E to E-S. Such a complication does arise in proline-catalyzed aldol
reactions, where the enamine intermediate is present at levels that can be detected by NMR.41 In
contrast, the anionic species of Scheme 2, as well as ketol 3, are all high-energy intermediates
whose steady-state concentrations are too low to deplete hydroxide. For example, the pK of
a
42
PhCOCH (2) is 18.24, so that the ratio [2 ]/[OH ] at the typical [PhCOCH ] of 0.02 M is 10 ,
–
–
-6
3
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 16
1
2
3
4
5
6
7
8
9
which indeed represents negligible depletion. Nor does the concentration of ketol 3 accumulate,
because it too is unstable, as verified experimentally by evidence below. We therefore consider
Scheme 2 preferable to Scheme 4, because it focuses on the reactants, intermediates, and
products, rather than on the catalyst, whose constancy permits simplifying eq 1 to eq 2.
However, it should be noted that the transition state for conversion of 5 to 4 is still a rate-
determining state even when this terminology is applied to the catalytic cycles of Scheme 4.43
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
-
-
2
OH
OH
3
4
H2O
H2O
2-
3-
5
1
Scheme 4. Catalytic cycles for base-catalyzed chalcone formation from aldehyde 1 and
–
acetophenone 2, where 3 = ketol intermediate, 3 = alkoxide of 3, 5 = enolate of 3, and 4 =
chalcone.
Reaction Rates of Ketol Intermediates. For completeness, Table 3 lists rate constants
k for base-catalyzed disappearance of ketols 3. By using the partition ratios in Table 1, each of
3
them can be separated into rate constants for conversion to 4 and reversion to 1 + 2, as also listed
-1 -1
in Table 3. The value of 0.084 M s for Ar = Ph = Ar' in 80% aqueous CH CN is in
3
-1 -1
semiquantitative agreement with the values of 0.22 and 0.30 M s in the different solvents
31
water and 95% aqueous ethanol.
-1 -1
Table 3. Rate constants (M s ) for disappearance of ketols 3, for conversion to chalcones 4, and
for reversion to benzaldehydes 1 + acetophenones 2.
%CH CN
k
k
k
→1+2
Ar
Ph
Ar'
Ph
Ph
3
3
→4
80
26
0.084
0.41
0.011 0.073
0.065 0.35
pClPh
ACS Paragon Plus Environment

Page 9 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
pO NPh
2
Ph
Ph
60
70
70
60
0.40
0.20
0.32
0.60
0.059
0.025
0.041
0.077
0.34
0.17
0.28
0.53
pMePh
Ph
pClPh
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
pO NPh
Ph
2
–
In terms of Scheme 2 it is readily seen that k = (k K + k /K )[OH ], where k is the
3
5 4
-2
3
-2
rate constant for the reverse reaction of Step 2, which is rate-limiting for the reversion of 3 to 1 +
2. The individual terms of this rate constant correspond to the separate rate constants k and
→4
k
.
→1+2
Above it was claimed that the intermediate product 3 does not build up to any appreciable
extent under our reaction conditions, because it is not sufficiently stable. As evidence for this
claim, the second-order rate constants k for ketol disappearance in Table 3 are considerably
3
larger than the rate constants k
for chalcone formation in Table 2, converted to pseudo-
H2O
second-order rate constants k
[Ar'COCH ] at the typical [Ar'COCH ] of 0.02 M.
3 3
H2O
Summary and Conclusions
Our conclusion that Step 5 of Scheme 2 is rate-limiting was also reached, although
implicitly, by calculating rate and equilibrium constants by Marcus theory.44 In hindsight, we
should not be surprised at this conclusion. If Step 1 (enolization of CH COAr') is not rate-
3
limiting, then we might expect the similar Step 4 (enolization of ArCH(OH)CH COAr') not to be
2
rate-limiting. This conclusion is not inescapable though, because enolization of CH COAr' is
3
followed by a bimolecular reaction whereas enolization of ArCH(OH)CH COAr' is followed by
2
a unimolecular step, and because enolization is calculated to be rate-limiting in the similar
45
elimination of H and CH CO from CH YCOCH CH(OCOCH )CH (Y = O or S), where
+
–
3
2
3
2
3
3
acetate is admittedly a much better leaving group. Certainly though, the results here are
–
convincing experimental evidence for rate-limiting loss of OH .
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 16
1
2
3
4
5
6
7
8
Moreover, these results also provide evidence concerning the mechanism of the reverse
reaction, the hydration of chalcone 4 followed by the retro-aldol condensation reverting to 1 + 2.
According to the Principle of Microscopic Reversibility, the rate-limiting step for the reverse
9
–
reaction must be the initial Michael addition of OH to the C-C double bond.
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
Intermediate ketol 3 partitions predominantly (7:1) to precursors 1 + 2 regardless of
substitution. Therefore the first three steps in Scheme 2 are rapid and reversible. Because the
rates of chalcone formation are higher in D O than in H O, regardless of substitution, all of the
2
2
first four steps in Scheme 2 are rapid and reversible, and the rate-limiting step must be the loss of
–
OH (Step 5). This conclusion resolves the contradictions among Refs. 24-26.
All these results can be summarized in the energy diagram shown in Fig. 1, constructed
from these results (and others, as explained in Supporting Information). The highest-energy
–
transition state is for the final loss of OH , but it is not higher than the others by much. Another
transition state might have been the highest, and it is these experiments that support this
conclusion, not only for the parent chalcone but also for the substituted ones. Thus we now know
the complete free-energy profile for this simple aldol condensation.
‡
3 kcal/mol
–
CH =C(O )Ph
2
PhCH(OH)CH COPh
2
PhCH=CHCOPh
–
–
CH COPh
3
PhCH(OH)CH=C(O )Ph
PhCH(O )CH COPh
2
ACS Paragon Plus Environment

Page 11 of 16
The Journal of Organic Chemistry
1
2
3
4
Figure 1. (Free) energy diagram for aldol condensation of Scheme 2 (Ar = Ph = Ar').
5
6
7
8
Experimental Section
9
Materials. Acetonitrile was of a grade formulated for UHPLC-UV was purchased from
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
Fisher Scientific. Commercial benzaldehyde and acetophenone and their substituted derivatives
were purified by vacuum distillation or recrystallization and stored under N . Each was dissolved
2
in acetonitrile and diluted in oven-dried volumetric flasks to the concentrations needed.
Ketol intermediates were synthesized by aldol reaction of a benzaldehyde and an
acetophenone promoted by MgI + iPr NEt,46 but on a five-fold larger scale. The crude product
2
2
was purified by flash chromatography with hexane/ethyl acetate. Collected fractions were
spotted on TLC plate, developed with 6:1 hexane/ethyl acetate, and visualized under UV light.
Fractions containing ketol were combined, evaporated, and recrystallized from CH Cl -hexane.
2
2
1
Authenticity and purity were checked through melting points and H NMR spectra.
46
3-Hydroxy-1,3-diphenylpropane-1-one: m.p. 47.2-48.1 ºC, lit 44-46 ºC, H NMR δ
1
3.38 (d, 2H), 3.58 (br s, 1H), 5.35 (m, 1H), 7.32 (m, 1H), 7.39 (m, 2H), 7.46 (m, 4H), 7.59 (m,
46
1H), 7.96 (m, 2H); lit. 3.33 (m, 2 H); 3.68 (d, J = 3.0, OH); 5.32 (m, 1H); 7.31 (m, 1H); 7.39(
m, 2 H); 7.46 (m, 4 H); 7.59( m, 1H); 7.95 (m, 2 H).
3-Hydroxy-3-(4-chlorophenyl)-1-phenylpropan-1-one: m.p. 93.6-95.2 ºC, lit.47 96-96.5
1
ºC, H NMR δ 3.34 (m, 2H), 3.64 (br s, 1H), 5.32 (m, 1H), 7.37 (m, 4H), 7.48 (m, 3H), 7.60(m,
47
1H), 7.95 (m, 2H); lit. 3.295 (d, 1 H, J = 5.7 Hz), 3.299 (d, 1 H, J = 6.4 Hz), 3.81 (br s, 1 H),
5.28 (br t, 1 H), 7.10-7.65 (m, 7 H), 7.72-7.96 (m, 2 H
3-Hydroxy-3-(4-nitrophenyl)-1-phenylpropan-1-one: m.p. 111.3-112.7 ºC, lit.48 112.9
1
ºC, H NMR δ 3.37 (m, 2H), 3.82 (br s, 1H), 5.46 (m, 1H), 7.49 (m, 2H), 7.61 (m, 3H), 7.94 (m,
48
2H), 8.24 (m, 2H); lit. 3.29-3.46 (m, 2H), 3.93 (br s, 1H), 5.46 (dd, J = 4:1, 8.1 Hz, 1H), 7.45-
7.50 (m, 2H), 7.59-7.64 (m, 3H), 7.93-7.96 (m, 2H), 8.20-8.23 (m, 2H).
47
3-Hydroxy-3-(4-methylphenyl)-1-phenylpropan-1-one: m.p. 49.1-51.6 ºC, lit. 47-48
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 16
1
2
3
4
1
ºC, H NMR δ 2.35 (s, 3H), 3.37 (m, 2H), 3.51 (br s, 1H), 5.32 (t, 1H), 7.19 (d, 2H), 7.33 (d,
5
6
47
2H), 7.47 (m, 2H), 7.59 (m, 1H), 7.95 (m, 2H); lit. 2.32 (s, 3 H), 3.31 (d, 1 H, J = 5.3 Hz), 3.32
7
8
(d, 1 H, J = 6.8 Hz), 3.64 (br d, 1 H, J = 2.6 Hz), 5.08-5.36 (m, 1 H), 6.92-7.61 (m, 7 H), 7.68-
9
7.96 (m, 2 H);
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
3-Hydroxy-1-(4-chlorophenyl)-3-phenylpropan-1-one: m.p. 52.5-56.7 ºC, H NMR δ
3.37 (m, 3H), 5.34 (m, 1H), 7.25-7.45 (m, 7H), 7.90 (m, 2H); lit.49 7.89-7.86 (m, 2H), 7.44-7.25
(m, 7H), 5.31 (dd, J = 3.5, 8.4 Hz, 1H), 3.51 (br s, 1H), 3.41-3.25 (m, 2H).
50
3-Hydroxy-1-(4-nitrophenyl)-3-phenylpropan-1-one: m.p. 86.5-87.4 ºC, lit. 90 ºC, H
1
NMR δ 3.14 (br s, 1H), 3.41 (m, 2H), 5.38 (m, 1H), 7.23-7.63 (m, 5H), 8.11 (m, 2H), 8.29 (m,
50
2H); lit. 8.28 (d, J = 8.9, 1H), 8.08 (d, J = 8.9, 1H), 7.47-7.26 (m, 5H), 5.35 (dd, J = 9.0, 3.1,
1H), 3.48 (dd, J = 17.6, 9.0, 1H), 3.32 (dd, J = 17.6, 3.1, 1H), 3.05 (br s, 1H).
Rate measurements. Rates of base-catalyzed condensation of benzaldehyde 1 plus
acetophenone 2 to chalcone 4 were followed on a recording UV spectrophotometer by
monitoring the absorbance of 4 at its λ
near 312 nm.
max
Because NaOH is a catalyst and because 2 is in excess, neither of their concentrations
varies with time. Therefore pseudo-first-order conditions apply, and the third-order kinetics of eq
1 simplifies to eq 2. Although the solution to eq 2 is [ArCHO] = [ArCHO] exp(–k t), the
0 obs
spectrophotometer measures the absorbance A of product 4, as in eq 3, which was fit by
nonlinear least squares.
v = d[chalcone]/dt = –d[ArCHO]/dt = k [ArCHO]
obs
(2)
(3)
A = A – (A – A )exp(–k t)
∞
∞
0
obs
Extraction of Forward Rate Constant k. Because reaction does not go to completion, it
is necessary to extract the forward rate constant k of eq 1 from k of eq 2. These are related by
obs
eq 4, in which an average equilibrium constant K can be evaluated from the final concentrations
e
of benzaldehyde 1, acetophenone 2, and chalcone 4. Rate constants were averaged over 4 to 17
–
experiments at various initial concentrations of 1, 2, and OH or OD . Further details of
–
ACS Paragon Plus Environment

Page 13 of 16
The Journal of Organic Chemistry
1
2
3
4
procedure are described in the Supporting Information.
5
6
7
8
9
k
K
e
obs
-
k =
(4)
1+K [2]
e
[OH ]
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
Acknowledgments. This research was supported by NSF Grant CHE11-48992. We are
grateful to Prof. Robert Pomeroy for providing access to spectrophotometers and for helpful
advice. We thank Ms. Janet B. Willis for some preliminary experiments.
Supporting Information. details of procedure and construction of energy diagram.
representative time curves. reaction conditions, fitting parameters, and rate constants for
formation of chalcones.
References
(1) Smith, M. B. March's Organic Chemistry: Reactions, Mechanisms, and Structure, 7ed. John
Wiley, New York, 2013.
(2) Wender, P. A.; Schrier, A. J. J. Am. Chem. Soc. 2011, 133, 9228–9231.
(3) DeLorbe, J. E.; Jabri, S. Y.; Mennen, S. M.; Overman, L. E.; Zhang F.-L. J. Am. Chem. Soc.
2011, 133, 6549–6552.
(4) Laws, S. W.; Scheerer, J. R. J. Org. Chem. 2013, 78, 2422-2429.
(5) Egger, J.; Bretscher, P.; Freigang, S.; Kopf, M.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136,
17382-17385.
(6) Shvartsbart, A.; Smith, A. B. III J. Am. Chem. Soc. 2015, 137, 3510-3519.
(7) Nicolaou, K. C.; Ding, H.; Richard, J.-A.; Chen, D. Y.-K. J. Am. Chem. Soc. 2010, 132,
3815–3818.
(8) Snyder, S. A.; Wespe, D. A.; von Hof, J. M. J. Am. Chem. Soc. 2011, 133, 8850–8853.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 16
1
2
3
4
5
6
7
8
(9) Daub, M. E.; Prudhomme, J.; Le Roch, K.; Vanderwal, C. D. J. Am. Chem. Soc. 2015, 137,
4912-4915.
9
(10) Lam, Y.-h.; Houk, K. N. J. Am. Chem. Soc. 2015, 137, 2116-2127.
(11) List, B.; Lerner, R. A.; Barbas, C. F. III J. Am. Chem. Soc. 2000, 122, 2395-2396.
(12) Evans, D. A.; Nelson, J. V.; Taber, T. R. Topics in Stereochem. 1982, 13, 1-115.
(13) Silverman, R. B. The Organic Chemistry of Enzyme-Catalyzed Reactions. Academic Press,
San Diego (2000), pp. 453-478.
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
(14) Butch, C.; Cope, E. D.; Pollet, P.; Gelbaum, L.; Krishnamurthy, R.; Liotta, C. L. J. Am.
Chem. Soc. 2013, 135, 13440-13445.
(15) Sagi, V. N.; Punna, V.; Hu, F.; Meher, G.; Krishnamurthy, R. J. Am. Chem. Soc. 2012, 134,
3577-3589.
(16) Singh, P.; Anand, A.; Kumar, V. Eur. J. Med. Chem. 2014, 85, 758-777.
(17) Dialer, C.; Imbri, D.; Hansen, S. P.; Opatz, T. J. Org. Chem. 2015, 80, 11605-11610.
(18) Hong, K. K. C.; Ball, G. E.; Black, D. StC.; Kumar, N. J. Org. Chem. 2015, 80, 10668-
10674.
(19) Geng, X.; Mague, J. T.; Pascal, R. A., Jr. J. Org. Chem. 2015, 80, 4824-4827.
(20) Coombs, E.; Evans, D. P. J. Chem. Soc. 1940, 1295-1300.
(21) Bell, R. P. J. Chem. Soc. 1937, 1637-1640.
(22) Richard, J. P.; Nagorski, R. W. J. Am. Chem. Soc. 1999, 121, 4763-4770.
(23) Nozière, B.; Chabert, P. Intl. J. Chem. Kinet. 2010, 42, 676-686.
(24) Noyce, D. S.; Pryor, W. A.; Bottini, A. T. J. Am. Chem. Soc. 1955, 77, 1402-1405.
(25) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry 5ed 2007, Part A, p. 285.
(26) Hine, J. Physical Organic Chemistry 2ed 1962, p. 261.
(27) Rocek, J.; Westheimer, F. H.; Eschenmoser, A.; Moldoványi, L.; Schreiber, J. Helv. Chim.
Acta 1962, 42, 2554-2567.
(28) Pluth, M. D.; Bergman, R. G.; Raymond, K. N. J. Org. Chem. 2009, 74, 58-63.
ACS Paragon Plus Environment

Page 15 of 16
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
(29) Um, I.-H.; Kim, M.-Y.; Bae, A.-R.; Dust, J. M.; Buncel, E. J. Org. Chem. 2015, 80, 217-
222.
9
(30) Richard, J. P.; Williams, G.; Gao, J. J. Am. Chem. Soc. 1999, 121, 715-726.
(31) Guthrie, J. P.; Cossar, J.; Cullimore, P. A.; Kamkar, N. M.; Taylor, K. F. Canad. J. Chem.
1983, 61, 2621-2626.
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) Fedor, L. R. J. Am. Chem. Soc. 1969, 81, 908-913.
(33) Emmons, W. D.; Hawthorne, M. F. J. Am. Chem. Soc. 1956, 78, 5593-5596.
(34) Riley, T.; Long, F. A. J. Am. Chem. Soc. 1962, 84, 522-526.
(35) Green, A. J.; Kemp, T. J.; Littler, J. S.; Waters. W. A. J. Chem. Soc., 1964, 2722-2726.
(36) More O'Ferrall, R. A.; Slae, S. J. Chem. Soc. (B), 1970, 260-278.
(37) Saunders, W. H., Jr.; Edison, D. J. Am. Chem. Soc. 1960, 82, 138-142.
(38) CRC Handbook of Chemistry and Physics 96 ed, D. R. Lide Ed. (Internet Version 2016)
http://hbcpnetbase.com.
(39) Ballinger, P.; Long, F. A. J. Am. Chem. Soc. 1959, 81, 2347-2352.
(40) Swain, C. G.; Ketley, A. D.; Bader, R. F. W. J. Am. Chem. Soc. 1959, 81, 2353-2359.
(41) Haindl, M. M.; Hioe, J.; Gschwind, R. M. J. Am. Chem. Soc. 2015, 137, 12835-12842.
(42) Chiang, Y.; Kresge, A. J.; Wirz, J. J. Am. Chem. Soc. 1984, 106, 6392-6395.
(43) Kozuch, S.; Martin, J. M. L. ChemPhysChem 2011, 12, 1413-1418.
(44) Guthrie, J. P. J. Am. Chem. Soc. 1991, 113, 7249-7255.
(45) Kim, Y.; Mohrig, J. R.; Truhlar, D. G. J. Am. Chem. Soc. 2010, 132, 11071-11082.
(46) Wei, H.; Li, K.; Zhang, Q.; Jasoni, R. L.; Hu, J.; Pare, P. W. Helv. Chim. Acta. 2004, 87,
2354-2358.
(47) Hasegawa, E.; Ishiyama, K.; Horaguchi, T.; Shimizu, T. J. Org. Chem. 1991, 56, 1631-
1635.
(48) Nakagawa, T.; Fujisawa, H.; Nagata, Y.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2004, 77,
1555-1567.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 16
1
2
3
4
5
6
(49) Xie, K.; Cui, Y.; Liu, Y.-C.; Fu, Y. Chin. J. Chem. 2007, 25, 839-842.
7
8
(50) Olmos, A.; Alix, A.; Sommer, J.; Pale, P. Chem. Eur. J. 2009, 15, 11229-11234.
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
ACS Paragon Plus Environment