Solid state aldol reactions of solvated and unsolvated lithium pinacolone enolate aggregates

Article abstract of DOI:10.1016/j.tet.2019.130913

We reported the first systematic study of the solid-state aldol reactions of solvated and unsolvated lithium pinacolone enolate with a variety of solid aromatic aldehydes utilizing a mortar and pestle condition in comparison with the simple ball milling condition or tetrahydrofuran (THF) solution condition. In solution, the reactions are highly-selective with the aldol condensation product at room temperature. Under the condition of mortar and pestle, the reactions with unsolvated lithium pinacolone enolate showed the mixture of aldol condensation product and aldol addition product at room temperature. With the usage of solvated lithium pinacolone enolate, higher yields for most substrates were obtained. Furthermore, repeating the reactions under a simple ball billing condition with no other precautions at room temperature, we achieved high selectivity and yield of products for all substrates, indicating the powerful ability and the utility of solid-state, mechanochemical aldol reaction conditions.

Full text of DOI:10.1016/j.tet.2019.130913

Journal Pre-proof
Solid state aldol reactions of solvated and unsolvated lithium pinacolone enolate
aggregates
Huan Pang, Paul G. Williard
PII:
S0040-4020(19)31332-8
https://doi.org/10.1016/j.tet.2019.130913
TET 130913
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 July 2019
Revised Date: 19 December 2019
Accepted Date: 20 December 2019
Please cite this article as: Pang H, Williard PG, Solid state aldol reactions of solvated and
unsolvated lithium pinacolone enolate aggregates, Tetrahedron (2020), doi: https://doi.org/10.1016/
j.tet.2019.130913.
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Solid State Aldol Reactions of Solvated and Unsolvated Lithium Pinacolone
Enolate Aggregates
Huan Pang, Paul G. Williard
Department of Chemistry, Brown University
Providence, RI 02912 USA
Abstract: We reported the first systematic study of the solid-state aldol reactions of
solvated and unsolvated lithium pinacolone enolate with a variety of solid aromatic
aldehydes utilizing a mortar and pestle condition in comparison with the simple ball
milling condition or tetrahydrofuran (THF) solution condition. In solution, the
reactions are highly-selective with the aldol condensation product at room
temperature. Under the condition of mortar and pestle, the reactions with unsolvated
lithium pinacolone enolate showed the mixture of aldol condensation product and
aldol addition product at room temperature. With the usage of solvated lithium
pinacolone enolate, higher yields for most substrates were obtained. Furthermore,
repeating the reactions under a simple ball billing condition with no other precautions
at room temperature, we achieved high selectivity and yield of products for all
substrates, indicating the powerful ability and the utility of solid-state,
mechanochemical aldol reaction conditions.
Introduction
Aldol and related reactions are perhaps the most widely utilized carbon-carbon bond
forming reactions in organic chemistry. Despite the general utility of these reactions
only a few previous studies report that solvent free reaction conditions yield aldol
products, aldol condensation products or aldol-Tishchenko reaction products and
often mixtures thereof.1 In this study we focus on controlling parameters such as
1
(a) Sharma, D. K.; Singh, B.; Mukherjee, D. Aldol reaction of kojic acid using alumina supported base
catalyst and enzymatic resolution of the aldol adduct by CALB. Tet. Let. 2014, 55, 5846-5850. (b)
Banon-Caballero, A.; Guillena, G.; Najera, C., Solvent-free enantioselective organocatalyzed aldol
reactions. Mini-Reviews in Organic Chemistry 2014, 11, 118-128. (c) Niu, F.; Zhang, L.; Luo, S.-Z.; Song,
W.-G. Room temperature aldol reactions using magnetic Fe3O4@Fe(OH)3 composite microspheres in
hydrogen bond catalysis. Chem. Commun. (Cambridge, United Kingdom) 2010, 46, 1109-1111. (d)
Rodriguez, B.; Bruckmann, A.; Rantanen, T.; Bolm, C., Solvent-free carbon-carbon bond formations in
1

stoichiometry, time, reagent composition and reaction protocol to assess their
influence on the yield and selectivity of formation of aldol reaction products of the
lithium enolate of pinacolone utilizing a simple mechanochemical protocol.
Specifically, this study correlates the solvation state and the aggregation state of the
lithium enolate of t-butyl methyl ketone by starting with a solid enolate of rigorously
known composition and solvation to access the selectivity for formation of the
aforementioned products upon reaction with some aromatic aldehydes.
Preparative mechanochemical reactions typically imply milling, e.g. ball, vibration,
attritor or planetary, although alternatives such as screw extrusion and shearing are
known.2 The advantages and drawbacks of preparative mechanochemistry as well as
the scope of different reaction types are concisely elucidated in a 2013 issue of
Chemical Reviews devoted exclusively to this topic and more recently in a 2017
ball mills. Adv. Synthesis & Catalysis 2007, 349, 2213-2233. (e) Rodriguez, B.; Bruckmann, A.; Bolm, C.,
A highly efficient asymmetric organocatalytic aldol reaction in a ball mill. Chem. - A European Journal
2007, 13, 4710-4722. (f) Kaupp, G., Stereoselective thermal solid state reactions. Topics in
Stereochemistry 2006, 25, 303-354. (g) Raston, C. L.; Scott, J. L. Chemoselective, solvent-free aldol
condensation reaction. Green Chem. 2000, 2, (2), 49-52. (h) Tanaka, K.; Toda, F., Solvent-free organic
synthesis. Chem. Rev. (Washington, D. C.) 2000, 100, 1025-1074. (i) Toda, F.; Tanaka, K.; Hamai, K.,
Aldol condensations in the absence of solvent: acceleration of the reaction and enhancement of the
stereoselectivity. J. Chem. Soc, Perkin 1 1990, 3207-3209.
2
(a) Quaresma, S.; Andre, V.; Fernandes, A.; Duarte, M. T. Mechanochemistry - A green synthetic
methodology leading to metallodrugs, metallopharmaceuticals and bio-inspired metal-organic
frameworks. Inorg. Chim. Acta 2017, 455, (Part_2), 309-318. (b) Hernandez, J. G.; Bolm, C. Altering
product selectivity by mechanochemistry. J. Org. Chem. 2017, 82, (8), 4007-4019. (c) Do, J.-L.; Friscic, T.
Chemistry 2.0: Developing
a New, Solvent-free system of chemical synthesis based on
mechanochemistry. Synlett 2017, 28, (16), 2066-2092. (d) Tan, D.; Loots, L.; Friscic, T. Towards
medicinal mechanochemistry: evolution of milling from pharmaceutical solid form screening to the
synthesis of active pharmaceutical ingredients (APIs). Chem. Commun. (Cambridge, U. K.) 2016, 52,
(50), 7760-7781. (e) Hernandez, J. G.; Friscic, T. Metal-catalyzed organic reactions using
mechanochemistry. Tetrahedron Lett. 2015, 56, (29), 4253-4265. (f) Takacs, L. The historical
development of mechanochemistry. Chem. Soc. Rev. 2013, 42, (18), 7649-7659. (g) Craig, S. L.
Mechanochemistry: A tour of force Nature (London, U. K.) 2012, 487, (7406), 176-177. (h) Kaupp, G.
Stereoselective thermal solid-state reactions. Top. Stereochem. 2006, 25, 303-350.
2

Journal of Organic Chemistry perspective.3 In this manuscript, we emphasize the
influence of solvation of the pinacolone enolate in small scale reactions that are
routinely performed without any special milling equipment.
The major potential advantages of solvent-free and solid-state reactions are that they
are significantly less sensitive to moisture, are routinely performed at room
temperature and usually do not require an inert, dry atmosphere or rigorously purified,
dry solvents. Thus, performing aldol reactions under mechanochemical conditions
eliminates the use of bulk solvents but also mitigates significant safety concerns in
handling bulk solutions of very reactive alkali metal organic compounds under inert
and frequently sub-ambient temperature. Atmospheric moisture seems to have little
effect on solvent-free and/or mechanochemical aldol-type reactions mainly because
ambient water is at the ppm level.4
RESULTS AND DISCUSSION
This study of aldol reactions utilizes the lithium enolate of pinacolone as the
nucleophile because we can precisely control its aggregation and solvation state.
Hence unsolvated lithium pinacolone enolate 1 (unsolvated) was prepared as a white
solid by treating pinacolone with freshly made LDA in pentane at 0° C per an
established protocol.5 Our previous x-ray crystallographic study revealed that the
3
(a) James, S. L.; Friscic, T. Mechanochemistry. Chem. Soc. Rev. 2013, 42, (18), 7494-7496. (b)
Boldyreva, E. Mechanochemistry of inorganic and organic systems: what is similar, what is different?
Chem. Soc. Rev. 2013, 42, (18), 7719-7738. (c) Hopgood, H.; Mack, J. "An increased understanding of
enolate additions under mechanochemical conditions". Molecules 2017, 22, (5), 6961-6967.
4
Waddell, D. C.; Clark, T. D.; Mack, J. Conducting moisture sensitive reactions under
mechanochemical conditions. Tetrahedron Lett. 2012, 53, (34), 4510-4513.
5
Williard, P. G.; Carpenter, G. B., X-ray crystal structure of an unsolvated lithium enolate anion. J. Am.
Chem. Soc. 1985, 107, 3345-3346.
3

enolate 1 (unsolvated) exists as a hexameric aggregate having a Li6O6 core structure
illustrated in Figure 1a. Six lithium and six oxygen atoms of the enolate hexamer
occupy alternatively the twelve corners of a hexagonal prism. Each lithium atom is
surrounded by three enolate oxygens.
(a)
(b)
Figure 1. Lithium enolate aggregates derived from pinacolone
Alternatively, crystallization from THF and pentane solution yields a THF-solvated
lithium pinacolone enolate as a tetrameric aggregate depicted in Figure 1b as 1
(solvated).6 The tetrameric aggregate of 1 (solvated) is an almost perfect cube with
vertices consisting of four lithium and four oxygen atoms. The lithium atoms are each
surrounded by one THF oxygen and three enolate oxygens so that a distorted
tetrahedral coordination sphere results. Hence utilizing these different aggregates of
unsolvated and THF-solvated pinacolone enolate, entirely different reactants initiate
solid state reactions described below.
Initially we investigated solid-state, mechanochemical aldol reactions utilizing the
hexameric enolate 1 (unsolvated) using an agate mortar and pestle and manual
grinding. With a goal to optimize the yield of the products of the reaction of this
unsolvated enolate with either p-Cl-benzaldehyde or p-Br-benzaldehyde, we report
6
Amstutz, R.; Schweizer, W. B.; Seebach, D.; Dunitz, J. D., Tetrameric cubic structures of two solvated
lithium enolates. Helvetica Chimica Acta 1981, 64, 2617-2621.
4

the results of changing the ratio of enolate to the aldehyde electrophiles shown in
Table 1. All of reactions were carried out as described above using ratios of
unsolvated pinacolone enolate 1 to 4-halobenzaldehydes 2a or 2b, ranging from 1.2:1
to 2:1 (Table 1). These results clearly show that there is a specific ratio of enolate to
electrophile required to optimize the yield of products, i.e. 1.2:1.
Table 1. Effect of the ratio of reactants on the solid state aldol reaction between
pinacolone enolate 1 (unsolvated) and p-halo-benzaldeydes (2a and 2b)
Entry Aldehyde 1 (unsolvated)/2 Conversion (%) Yield(%) 3
Yield (%) 4
Total Yield (%)
1
2
3
4
5
6
1.2:1.0
1.6:1.0
2.0:1.0
1.2:1.0
1.6:1.0
2.0:1.0
98
41
34
35
20
20
12
45
29
26
25
14
15
86
63
61
45
34
27
2a
2a
2a
2b
2b
2b
>99
>99
97
>99
>99
Reactions were conducted on a 2.0 mmol scale for 0.5h at room temperature using mortar and
pestle. Isolated yields of products after column chromatography are reported.
The first noteworthy observation is that the solid-state aldol reaction using mortar and
pestle resulted in complete conversion of the aldehyde 2a into products. When 2 full
equivalents of pinacolone enolate were used, the aldol condensation product 3a and
the aldol addition product 4a were obtained in 35% and 26% isolated yield
respectively (Table 1, entry 3). It is also noteworthy that the isolated yields of both
3a and 4a differ slightly as the stoichiometry of enolate decreased from 2.0 to 1.6
equivalents (entry 2). The optimum combined yield of 86% of aldol and
condensation products was achieved by using 1.2 equivalents of unsolvated
5

pinacolone enolate (entry 1).
Similar results were obtained when
4-bromobenzaldehyde 2b was employed (entry 4). With aldehyde 2b, we observed
that the best combined yield (45%) was also obtained using 1.2 equivalents of
pinacolone enolate. Use of more than 1.6 equivalents of enolate led to a dramatic
decrease in the combined yield of aldol condensation product and aldol addition
product. We found that yields of aldol and condensation products 3 and 4 were
lowered due to the Michael addition reaction of excess enolate to the aldol
condensation product as seen in the crude NMR spectra of the reaction mixtures
although these Michael addition products were not purified and isolated. Thus, with a
higher ratio of enolate to aldehyde, the conversion of the aldehyde (2a and 2b) can be
increased but at the same time, Michael addition of excess enolate to 3b is more
favorable. Based on the results in Table 1, subsequent experiments were limited to an
enolate to aldehyde ratio of 1.2:1.
Figure 2. Structures of substituted aldehydes in aldol reaction
O
O
H
H
Br
Cl
2a
2b
2e
2h
2c
2f
2i
O
O
H
H
O2N
NO2
2d
2g
6

O
H
2j
2k
2n
2l
2m
The aldol derived product yields are significantly influenced by the electronic nature
of the substitution in the aldehyde 2 (Figure 2 and Table 2). Electron withdrawing
groups on the para or ortho position of the benzene ring (Table 2, entries 1-6, 9-10)
leads to reactions being completed in shorter time, while the electron-donating groups,
such as benzyloxy (entries 19-20), phenyl (entries 21-22), and dimethylamino (entries
23-24) lead to reactions being completed in longer time utilizing either unsolvated
enolate or THF solvated enolate. This observations mirror expected reactivity
differences among the differing electrophiles. It is also noteworthy that yields of
products with electrophiles depicted in entries 17-28 of Table 2 are improved by
lengthening the reaction times to 1h instead of 0.5h. The longer reaction times also
result in a higher ratio of aldol condensation product to aldol addition product.
Table 2. Scope of the aldol reaction of the lithium pinacolone enolate (1) to
aldehydes (2) in the solid state using mortar and pestle
Entry
Enolate
Aldehyde
Time (h)
Yield 3 (%) Yield 4 (%) Total Yield (%)
7

1a
2a
1 (solvated)
1 (solvated)
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
45
32
7
43
28
18
51
10
16
3
88
60
25
60
20
22
8
2a
2b
2c
2c
2d
2d
2e
2e
2f
3b
1 (unsolvated)
1 (solvated)
4b
9
5b
1 (unsolvated)
1 (solvated)
10
6
6b
7b
1 (unsolvated)
1 (solvated)
5
8b
5
4
9
9
1 (unsolvated)
1 (solvated)
4
20
24
25
28
19
27
8
24
33
33
40
39
50
25
33
50
10
11
12
13
14
15a
16a
17
9
2f
1 (unsolvated)
1 (solvated)
2g
2g
2h
2h
2i
8
12
20
23
17
22
42
1 (unsolvated)
1 (solvated)
1 (unsolvated)
1 (solvated)
1
11
8
2i
1 (unsolvated)
2j
1
8

18
19a
20a
21
1 (solvated)
1 (unsolvated)
1 (solvated)
1
1
1
1
1
1
1
1
1
54
32
34
38
50
42
50
41
40
10
8
64
40
58
47
61
44
60
44
50
2j
2k
2k
2l
24
9
1 (unsolvated)
1 (solvated)
22
11
2
2l
23
1 (unsolvated)
1 (solvated)
2m
2m
2n
2n
24
10
3
25a
26a
1 (unsolvated)
1 (solvated)
10
Reactions were conducted on a 2.0 mmol scale for 0.5h-1h at room temperature using mortar and
a
pestle. Isolated yields of products after column chromatography are reported. Aldol-Tishchenko
reaction was detected (vide infra). bThe major reaction pathway is the Cannizzaro reaction.
From Table 1, entries 1 and 4, we note that reaction of unsolvated lithium enolate 1
with aldehydes with a chloro or bromo substituent at the para position yield aldol
condensation products 3 and aldol addition products 4 in moderate yields. The
methoxy group at the ortho position of the benzene ring resulted in a combination of
aldol condensation product and aldol addition product in 39% yield (Table 2, entry
13). With two methoxy groups at the meta and para position of the benzene ring, a
similar total yield of 44% was observed (entry 25). Regardless of the electronic
character, a substituent at meta position of the benzene ring had little impact on the
total yield of the reaction. However, a longer reaction time always yielded more
aldol condensation than aldol addition product. The para benzyloxy group on the
benzaldehyde produced a higher yield than the meta benzyloxy group (entries 15 and
17). Products with a p-phenyl- and p-dimethylamino- substituted rings were
9

obtained in similar yields (entries 19 and 21). Moreover, 9-anthraldehyde was also
compatible with the reaction conditions and lead to moderate yield (entry 23). Quite
surprisingly, the strongly electron-withdrawing nitro group resulted in a low reaction
yield regardless of its position on the ring (entries 3, 5, 7, 9 and 11). With this
strongly electron withdrawing substituent, we observed that Cannizzaro reaction
product predominated relative to the aldol reaction products shown in Table 3.
Table 3. Cannizzaro reaction between the lithium pinacolone enolate (1) and
some aldehydes (2) in the solid state using mortar and pestle
Entry
Enolate
Aldehyde
Time (h)
0.5
Yield 5 (%)
Yield 6 (%)
1
2
3
4
5
6
1 (unsolvated)
1 (solvated)
1 (unsolvated)
1 (solvated)
1 (unsolvated)
1 (solvated)
55
18
66
58
73
70
51
15
61
54
69
67
2c
2c
2d
2d
2e
2e
0.5
0.5
0.5
0.5
0.5
Reactions were conducted on a 2.0 mmol scale for 0.5h at room temperature using mortar and
pestle. The ratio of alcohol and carboxylic acid should be identical. The yields reported above
are calculated by assuming that the starting aldehyde theoretically yields half an equivalent of
each product and are reported after column chromatography.
We suspected that atmospheric moisture was a factor decreasing the yields of addition
10

and condensation products. The presence of even trace quantities of water can lead to
observation of Cannizzaro reaction products by offering a source of hydroxide
generated from the reaction of lithium enolate especially since no special precautions
were taken to conduct these reactions in an inert atmosphere. It is also noteworthy
that an aldol-Tishchenko reaction7 was also detected for some substrates (Table 4). In
this process, the lithiated aldolate adduct reacts with one additional equivalent of
aldehyde to effect Tishchenko reaction ultimately forming products 7 and 8.8
Table 4. Aldol-Tishchenko reaction between the lithium pinacolone enolate (1)
and some aldehydes (2) in the solid state using mortar and pestle
Entry
Enolate
Aldehyde
Time (h) Yield 7 (%) Yield 8 (%) Total Yield (%)
1
2
3
1 (unsolvated)
1 (solvated)
1 (unsolvated)
0.5
0.5
0.5
3
3
5
10
8
13
11
28
2a
2a
2b
23
7
(a) Nishiura, M.; Kameoka, M.; Imamoto, T., Michael and tandem Aldol-Tischenko reactions
catalyzed by samarium(III) aryloxide complexes. Kidorui 2000, 36, 294-295. (b) Bodnar, P. M.; Shaw, J.
T.; Woerpel, K. A., Tandem Aldol-Tishchenko Reactions of Lithium Enolates: A Highly Stereoselective
Method for Diol and Triol Synthesis. J. Org. Chem. 1997, 62, 5674-5675.
8
Evans, D. A.; Hoveyda, A. H., Samarium-catalyzed intramolecular Tishchenko reduction of b-hydroxy
ketones. A stereoselective approach to the synthesis of differentiated anti 1,3-diol monoesters. J. Am.
Chem. Soc. 1990, 112, 6447-6449.
11

4
5
1 (solvated)
1 (unsolvated)
1 (solvated)
0.5
1
5
-
20
15
10
21
14
12
10
25
15
10
25
20
12
10
2b
2i
6
1
-
2i
7
1 (unsolvated)
1 (solvated)
1
4
6
-
2k
2k
2n
2n
8
1
9
1 (unsolvated)
1 (solvated)
1
10
1
-
Reactions were conducted on a 2.0 mmol scale for 0.5 h-1h at room temperature using mortar and
pestle. Isolated yields of products after column chromatography are reported.
Our next comparison focuses on the solvated lithium pinacolone enolate also shown
in Table 2. Based upon analogy with solution phase enolate reactions in THF solution,
we anticipated that smaller aggregates may react faster than larger aggregates.9
Hence solvated enolate 1 (solvated) appears to react more rapidly and proceed with
improved yields with the same high conversion. Aldehydes with a chloro- or bromo-
group at the para position of the benzene ring lead to improved yields (Table 2,
entries 1 and 2). The ortho methoxy- and meta, para dimethoxy- substitued rings
were similarly observed to produce higher total yields (entries 13, 14, 25 and 26).
Importantly, for those aldehydes with low reactivity, the use of highly-reactive
solvated enolate 1 (solvated) improves the total yields by about 10-20% (entries
17-24). To our surprise, for the aldehyde with a nitro group on ortho position, a large
improvement in yield (35%) was obtained (entries 3 and 4). However, for other
benzaldehydes with a nitro substituent, THF-solvated enolate has little impact on the
9
Kolonko, K. J.; Wherritt, D. J.; Reich, H. J., Mechanistic studies of the lithium enolate of
4-fluoroacetophenone: Rapid-injection NMR study of enolate formation, dynamics, and aldol
reactivity. J. Am. Chem. Soc. 2011, 133, 16774-16777.
12

total yield of aldol and condensation products because the Cannizzaro reaction
dominates the product mixture - see Table 2 entries 6 and 8 and Table 3 entries 4 and
6. The low yields for most aldehydes with a nitro group prompted us to seek
optimize reaction conditions for reactants with strong electron drawing substituents.
We now turned our attention to the reaction protocol itself. Ball milling is a
mechanochemical technique, which can be applied as an alternative method of manual
grinding in a mortar and pestle. The most trivial ball milling procedure we utilized
involves milling of the solid reactants with inert glass balls in a rotating vial secured
to the rotating shaft of a rotatory evaporator although there are many more
sophisticated variations available. 10 Previous studies have shown that enolate
chemistry using a mortar and pestle in open atmosphere gives lower yields of
products than utilizing sealed ball milling conditions presumably because of the
presence of atmospheric moisture.11 Since our ball mill analog reactions in a vial on a
rotary evaporator are not open, contact with atmospheric moisture is limited and the
level of the water is constant at the ppm level. Although no special precaution was
taken to rigorously exclude moisture and the enolates were generated in situ in all of
the previous studies, the conjugate acid of the base utilized to generate the enolate
was always present in these reactions reported previously. This feature distinguishes
our results reported from all previously reported mechanochemical aldol reactions
since we initiate all of our reactions utilizing pure precipitated or crystallized enolates.
Hence to assess the effect of conducting reactions in the open atmosphere relative to
10
(a) Rodriguez, B.; Bruckmann, A.; Rantanen, T.; Bolm, C., Solvent-free carbon-carbon bond
formations in ball mills. Advanced Synthesis & Catalysis 2007, 349, 2213-2233. (b) Rodriguez, B.;
Bruckmann, A.; Bolm, C., A highly efficient asymmetric organocatalytic aldol reaction in a ball mill.
Chemistry - A European Journal 2007, 13, 4710-4722. (c) Rodriguez, B.; Rantanen, T.; Bolm, C.,
Solvent-free asymmetric organocatalysis in a ball mill. Angew. Chem., Int.l Ed. 2006, 45, 6924-6926.
11
(a) Toda, F.; Kiyoshige, K.; Yagi, M., Solid-state reduction of ketones with sodium borohydride.
Angewandte Chemie 1989, 101, 329-330. (b) Waddell, D. C.; Clark, T. D.; Mack, J., Conducting moisture
sensitive reactions under mechanochemical conditions. Tetrahedron Letters 2012, 53, 4510-4513.
13

conducting the reactions in a controlled atmosphere, we repeated all the reactions with
unsolvated lithium enolate 1 (unsolvated) and aldehydes 2 in a pre-dried sealed vial
using the crude ball milling like conditions described above (Table 5). To our
gratification, we observed an increased yield of aldol adducts with higher selectivity
for the aldol addition product relative to aldol condensation product for all substrates.
Thus, aldehydes with chloro group at the para position of the benzene ring provided
the desired aldol addition product in 74% with high selectivity versus the aldol
condensation product (91:9) (entry 1). A similar result was obtained with the use of
para bromo substrate (entry 2). The highest yield and selectivity are seen utilizing
the aldehyde with benzyloxy group at the meta position (84%, 95:5) (entry 9).
Importantly, for those aldehydes with lower reactivity, the selectivity becomes slightly
lower, compared with those aldehydes with high reactivity (entries 11-14).
Regardless of the position of the nitro group on the benzene ring, nitro- substituted
aldehydes resulted in good yields for aldol addition product with high selectivity
(entries 3-7). This observation confirmed that the low yields of products from
aldehydes with a nitro substituent could be dramatically improved when moisture is
minimized. Thus, under ball milling conditions, even without taking precautions to
remove moisture, the unsolvated, hexameric lithium pinacolone enolate preferentially
reacts with substituted benzaldehydes to yield aldol products. The most likely
explanation for this is that quenching of the enolate by the moisture in the atmosphere
is minimized. This also explains why there is a decrease in the relative portion of
Cannizzaro reaction product since less hydroxide is present to catalyze the Cannizzaro
reaction.
Table 5. Scope of aldol reaction of unsolvated lithium pinacolone enolate 1 to
aldehydes 2 in a sealed vial under ball milling conditions
14

Entry
1
Aldehyde
Time (h)
4
Yield 3 (%)
Yield 4 (%)
Selectivity 4:3
7
74
91:9
2a
2
3
4
5
4
73
78
69
74
46
52
70
84
57
53
74
69
61
94:6
95:5
2b
2c
2d
2e
2f
6
4
8
9
88:12
95:5
5
6
4
6
12
12
4
3
94:6
7
5
91:9
2g
2h
2i
8
12
4
85:15
95:5
9
12
12
12
12
12
12
10
11
12
13
14
6
90:10
74:26
83:17
76:24
88:12
2g
2k
2l
19
15
22
8
2m
2n
Reactions were conducted on a 2.0 mmol scale for 4h-12h at room temperature in a sealed vial
under ball milling conditions. Isolated yields of products after column chromatography are
reported.
For comparison, we contrast the corresponding aldol reactions in solution with
15

solid-state reactions. As seen in the Table 6, the aldol reaction in solution can
generate solely aldol condensation product in a decent yield with high conversions at
the room temperature utilizing a pinacolone enolate in THF solution. This solution
phase reaction has been studied in detail by others.12 Although solution phase
reactions are typically conducted at -78° C, for our comparative studies we conducted
both the solution phase and solid-state reactions at room temperature. Furthermore,
our solution phase reactions are complicated by the uncertainty of both the
aggregation state and the solvation state of reactive enolate in THF at room
temperature.13 In the solution phase reactions, aldol reaction product was not
observed and only aldol condensation product was found.
For most aromatic aldehydes in this study, the total yield of all products under ball
milling conditions described above is comparable with the yields in solution although
the selectivity of products differs. In many cases, yields under ball milling conditions
are higher than yields in solution. The single most significant and important
advantage of the mechanochemical reaction conditions is that these reactions can be
carried at room temperature on a preparative scale with increased selectivity relative
to the ubiquitous solution phase reactions at -78° C. These results indicated the
powerful ability and the utility of solid-state, mechanochemical aldol reaction
conditions.
12
(a) Reich, H. J., Role of organolithium aggregates and mixed aggregates in organolithium
mechanisms. Chemical Reviews (Washington, DC, United States) 2013, 113, 7130-7178. (b)
Rothenberg, G.; Downie, A. P.; Raston, C. L.; Scott, J. L. Understanding solid/solid organic reactions. J.
Am. Chem. Soc. 2001, 123, (36), 8701-8708.
13
(a) Liou, L. R.; McNeil, A. J.; Ramirez, A.; Toombes, G. E. S.; Gruver, J. M.; Collum, D. B., Lithium
enolates of simple ketones: Structure determination using the method of continuous variation. J. Am.
Chem. Soc. 2008, 130, 4859-4868. (b) Gruver, J. M.; Liou, L. R.; McNeil, A. J.; Ramirez, A.; Collum, D. B.,
Solution structures of lithium enolates, phenolates, carboxylates, and alkoxides in the presence of
N,N,N',N'-tetramethylethylenediamine: A prevalence of cyclic dimers. J. Org. Chem. 2008, 73,
7743-7747.
16

Table 6. Scope of aldol reaction of the lithium pinacolone enolate 1 (unsolvated)
to aldehydes (2) in THF solution
O
O
OLi
THF
rt
H
+
R
R
2(a-n)
3(a-n)
1(unsolvated)
Entry
Aldehyde
Time (h)
Conversion 2 (%) Yield 3 (%)
1
2
2
2
2
2
2
2
2
3
5
5
2
2
3
>99
>99
>99
>99
>99
97
61
55
81
55
66
22
40
63
62
70
83
58
59
2a
2b
2c
2d
2e
2f
3
4
5
6
7
98
2g
2h
2i
8
>99
>99
>99
97
9
10
11
12
13
2j
2k
2l
97
98
2m
17

14
2
98
50
2n
Reactions were conducted on a 2.0 mmol scale for 2h-5h at room temperature in THF solution.
Isolated yields of products after column chromatography are reported.
CONCLUSIONS
We disclose systematic studies of aldol reaction of differently solvated lithium enolate
of pinacolone with a variety of aromatic aldehydes using different reaction methods
and conditions. In THF solution, aldol reaction of unsolvated lithium pinacolone
enolate afforded aldol condensation product in a decent yield along with Michael
adduct. However, the same aldol reaction conducted without solvent with a mortar
and pestle resulted in a combination of aldol addition product and aldol condensation
product. Low yields are seen when utilizing aldehydes with powerful electron
withdrawing groups such as a nitro group. The presence of moisture in the
mechanochemical reactions resulted in observation of increased selectivity for
Cannizzaro reaction product. To obtain optimal yields in the mechanochemical
reactions, a THF-solvated pinacolone enolate is preferred leading to improved yield
for all substrates other than aldehydes with the strongly electron withdrawing nitro
substituent. Furthermore, by using a sealed vial under ball milling conditions without
any precautions to remove water, the aldol reactions are all remarkably clean and
yield mostly aldol addition product. This is not the major product observed in solution
phase reactions or by using a mortar and pestle. Gratifyingly, under the simple ball
milling conditions utilizing a sealed vial, glass beads and a rotary evaporator protocol,
the aldehydes containing a nitro group resulted in a high yield of aldol addition
product as well. Hence the observation of good yields with high selectivity for all
substrates under relatively unsophisticated ball milling conditions demonstrates the
strong potential for carrying out solid-state enolate reactions such as the aldol reaction.
Additionally, it is not necessary to rigorously remove the moisture when utilizing
moisture-sensitive, crystalline enolates as reactants in mechanochemical reactions. We
anticipate that these reaction conditions are easily scalable. Results reported in this
article provide useful initial guidelines for conducting enolate reactions in addition to
18

the aldol related family of reactions under solid state conditions.
EXPERIMENTAL SECTION
General Methods. Solid state reactions were carried out in either a mortar and
pestle or a sealed vial without any special precautions to remove the oxygen and
moisture. Reactions in a sealed vial were conducted using the motor unit of the rotary
evaporator in horizontal position with a 20 mL glass vial sealed with rubber septum.
This instrument rotated at a speed of approximately 200 rpm. The grinding media is
20 balls (5 mm diameter) made of glass. Grinding cycles are repeated during the
reaction time. Solution-based reactions were carried out in glassware without
nitrogen-protection. Liquid and solutions were transferred via syringe. 1H NMR and
13C NMR spectra were recorded at 600 MHz and 150 MHz, respectively. Chemical
shifts are recorded in parts per million (ppm, δ) downfield using the residual solvent
1
signal of CDCl3 (7.26 ppm for H NMR, 77.16 ppm for 13C NMR) or DMSO (2.50
ppm for 1H NMR, 39.51 ppm for 13C NMR). Reactions in solution were monitored by
thin-layer chromatography on silica gel 60 using UV light (254 nm) as a visualizing
agent and hexane/ethyl acetate as developing agent. Purification of products was
accomplished by flash chromatography (silica gel 60, particle size 0.04-0.063 mm).
Yields were determined after column chromatography.
All reagents were purchased from commercial suppliers. Pentane, diisopropylamine
(DIPA) were dried by stirring with calcium hydride (CaH2) under an Ar atmosphere
overnight and then distilled. p-Chlorobenzadehyde and p-bromobenzaldehyde were
purified by crystallizing from EtOH/H2O(3:1). o-Nitrobenzaldehyde was distilled
under reduced pressure before use. m-Nitrobenzaldehyde and p-nitrobenzaldehyde
were purified by crystallizing from water. Other purchased aldehydes were dried
before use. All aldehydes are in solid phase for the reaction.
Solid phase enolates 1 (unsolvated) and 1 (solvated) were prepared according to
described procedures.5
General Procedures for Aldol Reaction of Lithium Pinacolone Enolates 1
19

(unsolvated) or 1 (solvated) to Aldehydes (2) Using Mortar and Pestle.
A
mixture of excess 1 (unsolvated) or 1 (solvated) (2.4 mmol, 1.2 equiv) and aldehydes
2 (2.0 mmol, 1.0 equiv) was ground with an agate mortar and pestle by hand. After
grinding at room temperature for 0.5h (or other time spans as specified) in open air,
the reaction mixture was quenched by adding 5.0 mL of saturated NH4Cl aqueous
solution, followed by 15 mL of methylene chloride. The organic layer was separated
in a separatory funnel and saved. The aqueous layer was further extracted with
methylene chloride (2x10 mL). The combined organic extract was dried over
anhydrous Na2SO4. Upon removal of the solvent at room temperature under reduced
pressure, the crude mixture of products was obtained, and purified by column
chromatography (hexane/ethyl acetate).
General Procedures for Aldol Reaction of Unsolvated Lithium Pinacolone
Enolate 1 (unsolvated) to Aldehydes (2) under Ball Milling Conditions.
A
standard vial of approximately 20 mL volume was charged with enolate 1 (unsolvated)
(2.4 mmol, 1.2 equiv), aldehydes 2 (2.0 mmol, 1.0 equiv) and 20 glass balls of
approximately 0.5 mm diameter. Grinding was started using the ball mill with a
rotation speed of 200 rpm. An identical work-up procedure was utilized as for the
reactions described above.
General Procedures for Aldol Reaction of Unsolvated Lithium Pinacolone
Enolate 1 (unsolvated) to Aldehydes (2) in THF Solution. A solution of enolate 1
(unsolvated) was prepared by dissolving (2.4 mmol, 1.2 equiv) 1 (unsolvated) to 10
mL of THF at room temperature. Aldehydes 2 (2.0 mmol, 1.0 equiv) were added
into this 10 mL of THF solution all at once. The reactions were stirred at room
temperature and monitored by TLC. After completion of the reaction (2-5h), the
mixture was quenched by adding 5.0 mL of saturated NH4Cl aqueous solution and the
identical work-up procedure followed.
(E)-1-(4-chlorophenyl)-4,4-dimethylpent-1-en-3-one (3a): 1H NMR (600 MHz,
CDCl3) δ (ppm) 7.62 (d, J = 15.6 Hz, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.4
20

Hz, 2H), 7.09 (d, J = 15.6 Hz, 1H), 1.23 (s, 9H). 13C NMR (150 MHz, CDCl3) δ (ppm)
204.16, 141.62, 136.18, 133.58, 129.59, 129.27, 121.30, 43.43, 26.42. HRMS (ESI+)
m/z calcd for C13H15OCl + H+ 223.0884, found 223.0880.
(E)-1-(4-bromophenyl)-4,4-dimethylpent-1-en-3-one (3b): 1H NMR (600 MHz,
CDCl3) δ (ppm) 7.60 (d, J = 15.6 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.4
Hz, 2H), 7.10 (d, J = 15.6 Hz, 1H), 1.23 (s, 9H). 13C NMR (150 MHz, CDCl3) δ (ppm)
204.15, 141.68, 134.03, 132.24, 129.81, 124.52, 121.41, 43.44, 26.42. HRMS (ESI+)
m/z calcd for C13H15OBr + H+ 267.0379, found 267.0380.
(E)-4,4-dimethyl-1-(2-nitrophenyl)pent-1-en-3-one (3c): 1H NMR (600 MHz,
CDCl3) δ (ppm) 8.06 (d, J = 15.5 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.69 – 7.61 (m,
2H), 7.58 – 7.49 (m, 1H), 7.00 (d, J = 15.5 Hz, 1H), 1.24 (s, 9H). 13C NMR (150 MHz,
CDCl3) δ (ppm) 203.31, 148.78, 138.19, 133.47, 131.39, 130.22, 129.26, 125.63,
124.95, 43.44, 26.20. HRMS (ESI+) m/z calcd for C13H15O3N + H+ 234.1124, found
234.1117.
(E)-4,4-dimethyl-1-(3-nitrophenyl)pent-1-en-3-one (3d): 1H NMR (600 MHz,
CDCl3) δ (ppm) 8.43 (s, 1H), 8.23 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.69
(d, J = 15.6 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.23 (d, J = 15.6 Hz, 1H), 1.25 (s, 9H).
13C NMR (150 MHz, CDCl3) δ (ppm) 203.75, 148.78, 140.14, 136.83, 134.46, 130.06,
124.52, 123.54, 122.25, 43.54, 26.26. HRMS (ESI+) m/z calcd for C13H15O3N + H+
234.1124, found 234.1117.
(E)-4,4-dimethyl-1-(4-nitrophenyl)pent-1-en-3-one (3e): 1H NMR (600 MHz,
CDCl3) δ (ppm) 8.25 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 15.7
Hz, 1H), 7.22 (d, J = 15.6 Hz, 1H), 1.25 (s, 9H). 13C NMR (150 MHz, CDCl3) δ (ppm)
203.70, 148.51, 141.28, 140.06, 128.94, 124.63, 124.25, 43.57, 26.24. HRMS (ESI+)
m/z calcd for C13H15O3N + H+ 234.1124, found 234.1121.
(E)-4,4-dimethyl-1-(5-nitrofuran-2-yl)pent-1-en-3-one (3f): 1H NMR (600 MHz,
CDCl3) δ (ppm) 7.21 (d, J = 15.5 Hz, 1H), 7.17 (d, J = 3.6 Hz, 1H), 7.10 (d, J = 15.1
Hz, 1H), 6.59 (d, J = 3.6 Hz, 1H), 1.05 (s, 9H). 13C NMR (150 MHz, CDCl3) δ (ppm)
203.37, 153.31, 152.20, 126.99, 124.51, 116.22, 113.32, 43.60, 26.11. HRMS (ESI+)
m/z calcd for C11H13O4N + H+ 224.0917, found 224.0918.
(E)-4,4-dimethyl-1-(5-nitrothiophen-2-yl)pent-1-en-3-one (3g): 1H NMR (600
MHz, CDCl3) δ (ppm) 7.85 (d, J = 4.2 Hz, 1H), 7.64 (d, J = 15.4 Hz, 1H), 7.20 (d, J =
4.2 Hz, 1H), 7.05 (d, J = 15.4 Hz, 1H), 1.22 (s, 9H). 13C NMR (150 MHz, CDCl3) δ
(ppm) 203.12, 151.86, 146.57, 133.59, 129.46, 129.20, 124.13, 43.51, 26.17. HRMS
(ESI+) m/z calcd for C11H13O3NS + H+ 240.0689, found 240.0697.
(E)-1-(2-methoxyphenyl)-4,4-dimethylpent-1-en-3-one (3h): 1H NMR (600 MHz,
CDCl3) δ (ppm) 8.00 (d, J = 15.8 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 7.8 Hz,
21

1H), 7.21 (d, J = 15.8 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 3.88
(s, 3H), 1.22 (s, 9H). 13C NMR (150 MHz, CDCl3) δ (ppm) 204.79, 158.78, 138.36,
131.45, 129.04, 124.12, 121.61, 120.73, 111.27, 55.60, 43.29, 26.52. HRMS (ESI+)
m/z calcd for C14H18O2 + H+ 219.1379, found 219.1378.
(E)-1-(3-(benzyloxy)phenyl)-4,4-dimethylpent-1-en-3-one (3i): 1H NMR (600 MHz,
CDCl3) δ (ppm) 7.64 (d, J = 15.5 Hz, 1H), 7.45 (d, J = 7.0 Hz, 2H), 7.40 (t, J = 7.1 Hz,
2H), 7.37 – 7.28 (m, 2H), 7.21-7.15 (m, 2H), 7.09 (d, J = 15.5 Hz, 1H), 7.01 (d, J =
7.7 Hz, 1H), 5.10 (s, 2H), 1.23 (s, 9H). 13C NMR (150 MHz, CDCl3) δ (ppm) 204.32,
159.20, 142.83, 136.81, 136.53, 130.02, 128.80, 128.26, 127.67, 121.38, 121.22,
116.70, 114.61, 70.29, 43.40, 26.43. HRMS (ESI+) m/z calcd for C20H22O2 + H+
295.1693, found 295.1705.
(E)-1-(4-(benzyloxy)phenyl)-4,4-dimethylpent-1-en-3-one (3j): 1H NMR (600 MHz,
CDCl3) δ (ppm) 7.65 (d, J = 15.5 Hz, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 7.2
Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.01 (d, J = 15.6 Hz, 1H),
6.98 (d, J = 8.7 Hz, 2H), 5.10 (s, 2H), 1.22 (s, 9H). 13C NMR (150 MHz, CDCl3) δ
(ppm) 204.38, 160.67, 142.71, 136.65, 130.12, 128.81, 128.29, 128.09, 127.60,
118.77, 115.36, 70.25, 43.29, 26.58. HRMS (ESI+) m/z calcd for C20H22O2 + H+
295.1693, found 295.1691.
(E)-1-([1,1'-biphenyl]-4-yl)-4,4-dimethylpent-1-en-3-one (3k): 1H NMR (600 MHz,
CDCl3) δ (ppm) 7.73 (d, J = 15.6 Hz, 1H), 7.68 – 7.60 (m, 6H), 7.46 (t, J = 7.6 Hz,
2H), 7.38 (t, J = 7.3 Hz, 1H), 7.17 (d, J = 15.6 Hz, 1H), 1.25 (s, 9H). 13C NMR (150
MHz, CDCl3) δ (ppm) 204.37, 143.11, 142.58, 140.35, 134.05, 129.04, 128.93,
127.96, 127.65, 127.18, 120.73, 43.42, 26.50. HRMS (ESI+) m/z calcd for C19H20O +
H+ 265.1587, found 265.1571.
(E)-1-(4-(dimethylamino)phenyl)-4,4-dimethylpent-1-en-3-one (3l): 1H NMR (600
MHz, CDCl3) δ (ppm) 7.65 (d, J = 15.4 Hz, 1H), 7.48 (d, J = 8.7 Hz, 2H), 6.93 (d, J =
15.4 Hz, 1H), 6.67 (d, J = 8.7 Hz, 2H), 3.02 (s, 6H), 1.22 (s, 9H). 13C NMR (150 MHz,
CDCl3) δ (ppm) 204.57, 151.91, 143.72, 130.19, 122.88, 115.85, 111.95, 43.15, 40.30,
26.79. HRMS (ESI+) m/z calcd for C15H21NO + H+ 232.1696, found 232.1704.
(E)-1-(anthracen-9-yl)-4,4-dimethylpent-1-en-3-one (3m): 1H NMR (600 MHz,
CDCl3) δ (ppm) 8.64 (d, J = 15.9 Hz, 1H), 8.45 (s, 1H), 8.22 (d, J = 8.2 Hz, 2H), 8.02
(d, J = 9.0 Hz, 2H), 7.55 – 7.43 (m, 4H), 7.11 (d, J = 15.9 Hz, 1H), 1.30 (s, 9H). 13C
NMR (150 MHz, CDCl3) δ (ppm) 203.90, 140.01, 131.43, 130.61, 130.35, 129.71,
129.01, 128.17, 126.38, 125.50, 125.43, 43.45, 26.28. HRMS (ESI+) m/z calcd for
C21H20O + H+ 289.1587, found 289.1588.
(E)-1-(3,4-dimethoxyphenyl)-4,4-dimethylpent-1-en-3-one (3n): 1H NMR (600
MHz, CDCl3) δ (ppm) 7.63 (d, J = 15.5 Hz, 1H), 7.17 (dd, J = 8.3, 1.5 Hz, 1H), 7.07
(d, J = 1.4 Hz, 1H), 6.99 (d, J = 15.5 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 3.94 (s, 3H),
22

3.92 (s, 3H), 1.23 (s, 9H). 13C NMR (150 MHz, CDCl3) δ (ppm) 204.31, 151.24,
149.30, 143.11, 128.06, 122.83, 118.75, 111.23, 110.32, 56.13, 56.12, 43.31, 26.60.
HRMS (ESI+) m/z calcd for C15H20O3 + H+ 249.1485, found 249.1482.
1-(4-chlorophenyl)-1-hydroxy-4,4-dimethylpentan-3-one (4a): 1H NMR (600 MHz,
CDCl3) δ (ppm) 7.35-7.27 (m, J = 8.6 Hz, 4H), 5.10 (dt, J = 7.9, 3.2 Hz, 1H), 3.64 (d,
J = 2.8 Hz, 1H), 2.89 – 2.76 (m, 2H), 1.13 (s, 9H). 13C NMR (150 MHz, CDCl3) δ
(ppm) 216.92, 141.65, 133.37, 128.76, 127.20, 69.62, 45.45, 44.55, 26.28. HRMS
(ESI+) m/z calcd for C13H17O2Cl + Na+ 263.0809, found 263.0810.
1-(4-bromophenyl)-1-hydroxy-4,4-dimethylpentan-3-one (4b): 1H NMR (600
MHz, CDCl3) δ (ppm) 7.47 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 5.09 (dt, J =
8.1, 3.2 Hz, 1H), 3.63 (d, J = 2.9 Hz, 1H), 2.89 – 2.79 (m, 2H), 1.13 (s, 9H). 13C NMR
(150 MHz, CDCl3) δ (ppm) 216.88, 142.19, 131.72, 127.55, 121.47, 69.67, 45.42,
44.55, 26.29. HRMS (ESI+) m/z calcd for C13H17O2Br + Na+ 307.0304, found
307.0308.
1-hydroxy-4,4-dimethyl-1-(2-nitrophenyl)pentan-3-one (4c): 1H NMR (600 MHz,
CDCl3) δ (ppm) 7.96 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.67 (t, J = 7.6 Hz,
1H), 7.43 (t, J = 7.7 Hz, 1H), 5.59 (d, J = 9.2 Hz, 1H), 4.13 (s, 1H), 3.25 (d, J = 17.8
Hz, 1H), 2.66 (dd, J = 17.8, 9.3 Hz, 1H), 1.16 (s, 9H). 13C NMR (150 MHz, CDCl3) δ
(ppm) 217.22, 147.27, 138.82, 133.91, 128.39, 128.32, 124.54, 66.27, 44.71, 44.67,
26.21. HRMS (ESI+) m/z calcd for C13H17O4N + H+ 252.1230, found 252.1228.
1-hydroxy-4,4-dimethyl-1-(3-nitrophenyl)pentan-3-one (4d): 1H NMR (600 MHz,
CDCl3) δ (ppm) 8.22 (s, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.51
(t, J = 7.9 Hz, 1H), 5.25 – 5.16 (m, 1H), 3.85 (d, J = 2.3 Hz, 1H), 2.94 – 2.82 (m, 2H),
1.13 (s, 9H). 13C NMR (150 MHz, CDCl3) δ (ppm) 216.48, 148.44, 145.35, 131.99,
129.54, 122.57, 120.84, 69.23, 45.22, 44.54, 26.23. HRMS (ESI+) m/z calcd for
C13H17O4N + Na+ 274.1050, found 274.1054.
1-hydroxy-4,4-dimethyl-1-(4-nitrophenyl)pentan-3-one (4e): 1H NMR (600 MHz,
CDCl3) δ (ppm) 8.22 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 5.23 (dt, J = 8.8,
2.9 Hz 1H), 3.76 (d, J = 3.2 Hz, 1H), 2.94-2.80 (m, 2H), 1.15 (s, 9H). 13C NMR (150
MHz, CDCl3) δ (ppm) 216.54, 150.44, 147.47, 126.60, 123.91, 69.47, 45.24, 44.63,
26.30. HRMS (ESI+) m/z calcd for C13H17O4N + Na+ 274.1050, found 274.1053.
1-hydroxy-4,4-dimethyl-1-(5-nitrofuran-2-yl)pentan-3-one (4f): 1H NMR (600
MHz, CDCl3) δ (ppm) 7.29 (d, J = 3.6 Hz, 1H), 6.58 (d, J = 3.5 Hz, 1H), 5.21-5.14 (m,
1H), 3.82 (d, J = 5.5 Hz, 1H), 3.16 – 3.03 (m, 2H), 1.17 (s, 9H). 13C NMR (150 MHz,
CDCl3) δ (ppm) 216.25, 159.31, 151.72, 112.78, 109.81, 64.75, 44.70, 41.26, 26.26.
+
HRMS (ESI+) m/z calcd for C11H15O5N + NH4 259.1288, found 259.1293.
23

1-hydroxy-4,4-dimethyl-1-(5-nitrothiophen-2-yl)pentan-3-one (4g): 1H NMR (600
MHz, CDCl3) δ (ppm) 7.81 (d, J = 4.1 Hz, 1H), 6.88 (d, J = 4.1 Hz, 1H), 5.37-5.31 (m,
1H), 3.91 (d, J = 4.1 Hz, 1H), 3.05-2.95 (m, 2H), 1.17 (s, 9H). 13C NMR (150 MHz,
CDCl3) δ (ppm) 215.95, 156.10, 128.64, 122.20, 110.13, 66.88, 44.84, 44.64, 26.31.
HRMS (ESI+) m/z calcd for C11H15O4NS + H+ 258.0795, found 258.0794.
1-hydroxy-1-(2-methoxyphenyl)-4,4-dimethylpentan-3-one (4h): 1H NMR (600
MHz, CDCl3) δ (ppm) 7.49 (d, J = 7.4 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 6.99 (t, J =
7.5 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 5.38 (d, J = 9.0 Hz, 1H), 3.84 (s, 3H), 3.79 (d, J
= 3.7 Hz, 1H), 3.03 (dd, J = 17.4, 2.6 Hz, 1H), 2.76 (dd, J = 17.4, 9.0 Hz, 1H), 1.12 (s,
9H). 13C NMR (150 MHz, CDCl3) δ (ppm) 217.55, 155.72, 131.32, 128.29, 126.47,
120.90, 110.20, 65.71, 55.32, 44.50, 43.60, 26.12. HRMS (ESI+) m/z calcd for
C14H20O3 + Na+ 259.1305, found 259.1309.
1-(3-(benzyloxy)phenyl)-1-hydroxy-4,4-dimethylpentan-3-one (4i): 1H NMR (600
MHz, CDCl3) δ (ppm) 7.44 (d, J = 7.1 Hz, 2H), 7.39 (t, J = 7.2 Hz, 2H), 7.33 (t, J =
7.1 Hz, 1H), 7.30-7.22 (m, 1H), 7.03 (s, 1H), 6.95 (d, J = 7.4 Hz, 1H), 6.89 (dd, J =
7.9, 1.6 Hz, 1H), 5.15-5.03 (m, 1H), 5.09 (s, 2H), 3.56 (d, J = 2.8 Hz, 1H), 2.93 – 2.76
(m, 2H), 1.13 (s, 9H). 13C NMR (150 MHz, CDCl3) δ (ppm) 217.05, 159.17, 144.92,
137.13, 129.72, 128.73, 128.11, 127.66, 118.36, 114.08, 112.37, 70.15, 70.13, 45.60,
44.55, 26.31. HRMS (ESI+) m/z calcd for C20H24O3 + Na+ 335.1618, found 335.1631.
1-(4-(benzyloxy)phenyl)-1-hydroxy-4,4-dimethylpentan-3-one (4j): 1H NMR (600
MHz, CDCl3) δ (ppm) 7.43 (d, J = 7.4 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.32 (t, J =
7.3 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 5.10 – 5.07 (m, 1H),
5.07 (s, 2H), 3.51 (d, J = 2.8 Hz, 1H), 2.86 (d, J = 5.8 Hz, 2H), 1.13 (s, 9H). 13C NMR
(150 MHz, CDCl3) δ (ppm) 217.12, 158.41, 137.12, 135.64, 128.72, 128.09, 127.58,
127.10, 114.99, 70.18, 69.88, 45.55, 44.54, 26.31. HRMS (ESI+) m/z calcd for
C20H24O3 + Na+ 335.1618, found 335.1627.
1-([1,1'-biphenyl]-4-yl)-1-hydroxy-4,4-dimethylpentan-3-one (4k): 1H NMR (600
MHz, CDCl3) δ (ppm) 7.64-7.52 (m, 4H), 7.50-7.39 (m, 4H), 7.35 (t, J = 7.2 Hz, 1H),
5.22-5.13 (m, 1H), 3.60 (d, J = 2.8 Hz, 1H), 2.97 – 2.85 (m, 2H), 1.16 (s, 9H). 13C
NMR (150 MHz, CDCl3) δ (ppm) 217.08, 142.20, 140.97, 140.72, 128.92, 127.44,
127.41, 127.24, 126.26, 70.03, 45.57, 44.58, 26.34. HRMS (ESI+) m/z calcd for
C19H22O2 + Na+ 305.1512, found 305.1520.
1-(4-(dimethylamino)phenyl)-1-hydroxy-4,4-dimethylpentan-3-one (4l): 1H NMR
(600 MHz, CDCl3) δ (ppm) 7.27 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 8.5 Hz, 2H), 5.07 (d,
J = 8.7 Hz, 1H), 3.46 (d, J = 2.2 Hz, 1H), 2.97 (s, 6H), 2.94 – 2.83 (m, 2H), 1.16 (s,
9H). 13C NMR (150 MHz, CDCl3) δ (ppm) 217.05, 150.33, 131.08, 126.74, 112.65,
69.96, 45.50, 44.45, 40.76, 26.27. HRMS (ESI+) m/z calcd for C15H23NO2 + H+
250.1802, found 250.1800.
24

1-(anthracen-9-yl)-1-hydroxy-4,4-dimethylpentan-3-one (4m): 1H NMR (600 MHz,
CDCl3) δ (ppm) 8.66 (br, 2H), 8.43 (s, 1H), 8.02 (d, J = 7.7 Hz, 2H), 7.55-7.43 (m,
4H), 6.79 (d, J = 9.2 Hz, 1H), 3.76 (dd, J = 17.8, 10.4 Hz, 1H), 3.57 (s, 1H), 2.93 (d, J
= 18.1 Hz, 1H), 1.19 (s, 9H). 13C NMR (150 MHz, CDCl3) δ (ppm) 216.93, 134.26,
133.11, 131.86, 129.52, 128.41, 127.38, 125.98, 124.95, 67.03, 44.67, 43.89, 26.37.
HRMS (ESI+) m/z calcd for C21H22O2 + Na+ 329.1512, found 329.1533.
1-(3,4-dimethoxyphenyl)-1-hydroxy-4,4-dimethylpentan-3-one (4n): 1H NMR
(600 MHz, CDCl3) δ (ppm) 6.94 (s, 1H), 6.86 (d, J = 7.4 Hz, 1H), 6.83 (d, J = 7.8 Hz,
1H), 5.07 (s, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.57 (d, J = 2.1 Hz, 1H), 2.86 (d, J = 5.5
Hz, 2H), 1.13 (s, 9H). 13C NMR (150 MHz, CDCl3) δ (ppm) 217.04, 149.21, 148.56,
135.91, 117.95, 111.17, 109.06, 70.08, 56.07, 56.02, 45.64, 44.52, 26.29. HRMS
(ESI+) m/z calcd for C15H22O4 + Na+ 289.1410, found 289.1413.
2-nitrobenzyl alcohol (5c): 1H NMR (600 MHz, CDCl3) δ (ppm) 8.10 (d, J = 8.2 Hz,
1H), 7.74 (d, J = 7.6 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 4.97
(d, J = 6.5 Hz, 2H), 2.57 (t, J = 6.6 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ (ppm)
147.83, 136.91, 134.28, 130.14, 128.66, 125.17, 62.71. HRMS (ESI+) m/z calcd for
C7H7NO3 + H+ 154.0499, found 154.0496.
3-nitrobenzyl alcohol (5d): 1H NMR (600 MHz, CDCl3) δ (ppm) 8.20 (s, 1H), 8.10
(d, J = 8.1 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.9 Hz, 1H), 4.79 (d, J = 5.0
Hz, 2H), 2.48 – 2.38 (m, 1H). 13C NMR (150 MHz, CDCl3) δ (ppm) 148.47, 143.02,
132.76, 129.54, 122.55, 121.57, 64.01. HRMS (ESI+) m/z calcd for C7H7NO3 + H+
154.0499, found 154.0494.
4-nitrobenzyl alcohol (5e): 1H NMR (600 MHz, CDCl3) δ (ppm) 8.20 (d, J = 8.7 Hz,
2H), 7.53 (d, J = 8.7 Hz, 2H), 4.83 (s, 2H), 2.06 (s, 1H). 13C NMR (150 MHz, CDCl3)
δ (ppm) 148.29, 147.44, 127.13, 123.86, 64.14. HRMS (ESI+) m/z calcd for C7H7NO3
+ H+ 154.0499, found 154.0494.
2-nitrobenzoic acid (6c): 1H NMR (600 MHz, DMSO) δ (ppm) 13.87 (s, 1H), 7.98
(dd, J = 7.7, 1.1 Hz, 1H), 7.86 (dd, J = 7.4, 1.5 Hz, 1H), 7.83 – 7.75 (m, 2H). 13C
NMR (150 MHz, DMSO) δ (ppm) 165.86, 148.37, 133.08, 132.39, 129.86, 127.24,
123.68. HRMS (ESI+) m/z calcd for C7H5NO4 + H+ 168.0291, found 168.0289.
3-nitrobenzoic acid (6d): 1H NMR (600 MHz, DMSO) δ (ppm) 13.77 (br, 1H), 8.60
(s, 1H), 8.45 (d, J = 7.8 Hz, 1H), 8.33 (d, J = 7.6 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H). 13C
NMR (150 MHz, DMSO) δ (ppm) 165.50, 147.86, 135.32, 132.59, 130.47, 127.23,
123.64. HRMS (ESI+) m/z calcd for C7H5NO4 - H+ 166.0146, found 166.0141.
4-nitrobenzoic acid (6e): 1H NMR (600 MHz, DMSO) δ (ppm) 13.73 (br, 1H), 8.30
(d, J = 8.3 Hz, 2H), 8.15 (d, J = 8.3 Hz, 2H). 13C NMR (150 MHz, DMSO) δ (ppm)
25

165.80, 149.99, 136.51, 130.66, 123.67. HRMS (ESI+) m/z calcd for C7H5NO4 - H+
166.0146, found 166.0139.
1-(4-chlorophenyl)-1-hydroxy-4,4-dimethylpentan-3-yl 4-chlorobenzoate (7a): 1H
NMR (600 MHz, CDCl3) δ (ppm) 8.02 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H),
7.30-7.24 (m, 4H), 5.19 (d, J = 10.9 Hz, 1H), 4.51 (d, J = 10.1 Hz, 1H), 3.49 (d, J =
3.1 Hz, 1H), 1.99-1.82 (m, 2H), 1.01 (s, 9H). 13C NMR (150 MHz, CDCl3) δ (ppm)
167.15, 142.54, 140.10, 133.10, 131.35, 129.07, 128.63, 128.26, 127.16, 79.55, 69.39,
40.14, 34.81, 26.24. HRMS (ESI+) m/z calcd for C20H22O3Cl2 + Na+ 403.0838, found
403.0831.
1-(4-bromophenyl)-1-hydroxy-4,4-dimethylpentan-3-yl 4-bromobenzoate (7b):
1H NMR (600 MHz, CDCl3) δ (ppm) 7.94 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz,
2H), 7.42 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 5.18 (dd, J = 11.1, 2.0 Hz, 1H),
4.49 (dt, J = 10.3, 3.1 Hz, 1H), 3.46 (d, J = 3.7 Hz, 1H), 1.98 – 1.84 (m, 2H), 1.01 (s,
9H). 13C NMR (150 MHz, CDCl3) δ (ppm) 167.29, 143.04, 132.09, 131.59, 131.47,
128.80, 128.71, 127.53, 121.21, 79.57, 69.46, 40.10, 34.81, 26.24. HRMS (ESI+) m/z
calcd for C20H22O3Br2 + Na+ 490.9828, found 490.9800.
1-([1,1'-biphenyl]-4-yl)-1-hydroxy-4,4-dimethylpentan-3-yl [1,1'-biphenyl]-4-
carboxylate (7k): 1H NMR (600 MHz, CDCl3) δ (ppm) 8.18 (d, J = 8.1 Hz, 2H), 7.71
(d, J = 8.1 Hz, 2H), 7.63 (d, J = 7.4 Hz, 2H), 7.58-7.52 (m, 4H), 7.49 (t, J = 7.5 Hz,
2H), 7.47 – 7.38 (m, 5H), 7.33 (t, J = 7.2 Hz, 1H), 5.28 (d, J = 11.0 Hz, 1H), 4.64 (d,
J = 10.2 Hz, 1H), 3.56 (d, J = 3.0 Hz, 1H), 2.11 – 1.96 (m, 2H), 1.06 (s, 9H). 13C
NMR (150 MHz, CDCl3) δ (ppm) 167.93, 146.30, 143.19, 141.05, 140.40, 140.09,
130.55, 129.13, 128.86, 128.64, 128.41, 127.47, 127.38, 127.32, 127.29, 127.22,
126.26, 79.27, 69.84, 40.20, 34.89, 26.34. HRMS (ESI+) m/z calcd for C32H32O3 +
Na+ 487.2244, found 487.2264.
1-(4-chlorophenyl)-3-hydroxy-4,4-dimethylpentyl 4-chlorobenzoate (8a): 1H
NMR (600 MHz, CDCl3) δ (ppm) 8.00 (d, J = 7.8 Hz, 2H), 7.44 (d, J = 7.8 Hz, 2H),
7.38 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 6.25 (d, J = 10.8 Hz, 1H), 3.36 (dd,
J = 10.2, 2.7 Hz, 1H), 2.31 (d, J = 3.9 Hz, 1H), 2.17 (t, J = 13.0 Hz, 1H), 1.77 (t, J =
12.7 Hz, 1H), 0.92 (s, 9H). 13C NMR (150 MHz, CDCl3) δ (ppm) 165.66, 139.95,
139.65, 133.96, 131.22, 129.02, 128.99, 128.50, 127.75, 75.37, 74.05, 39.64, 34.77,
25.82. HRMS (ESI+) m/z calcd for C20H22O3Cl2 + Na+ 403.0838, found 403.0874.
1-(4-bromophenyl)-3-hydroxy-4,4-dimethylpentyl 4-bromobenzoate (8b): 1H
NMR (600 MHz, CDCl3) δ (ppm) 7.92 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H),
7.49 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 6.28 – 6.14 (m, 1H), 3.35 (dd, J =
10.5, 4.1 Hz, 1H), 2.26 (d, J = 4.7 Hz, 1H), 2.19 – 2.11 (m, 1H), 1.80 – 1.71 (m, 1H),
0.91 (s, 9H). 13C NMR (150 MHz, CDCl3) δ (ppm) 165.79, 140.15, 132.04, 131.95,
131.35, 128.94, 128.65, 128.07, 122.09, 75.37, 74.11, 39.60, 34.77, 25.82. HRMS
(ESI+) m/z calcd for C20H22O3Br2 + Na+ 490.9828, found 490.9801.
26

1-(3-(benzyloxy)phenyl)-3-hydroxy-4,4-dimethylpentyl 3-(benzyloxy)benzoate
(8i): 1H NMR (600 MHz, CDCl3) δ (ppm) 7.69 (br, 2H), 7.55 – 7.26 (m, 12H), 7.20
(d, J = 7.1 Hz, 1H), 7.11 – 7.02 (m, 2H), 6.92 (d, J = 7.1 Hz, 1H), 6.26 (d, J = 9.7 Hz,
1H), 5.12 (s, 2H), 5.07 (s, 2H), 3.35 (dd, J = 9.5, 3.4 Hz, 1H), 2.39 (d, J = 4.2 Hz, 1H),
2.22 – 2.09 (m, 1H), 1.86-1.74 (m, 1H), 0.92 (s, 9H). 13C NMR (150 MHz, CDCl3) δ
(ppm) 166.47, 159.15, 158.93, 142.96, 136.99, 136.64, 131.57, 129.87, 129.70,
128.82, 128.74, 128.30, 128.15, 127.73, 127.70, 122.53, 120.44, 118.89, 115.67,
114.16, 113.08, 75.30, 74.36, 70.38, 70.23, 39.95, 34.75, 25.90. HRMS (ESI+) m/z
calcd for C34H36O5 + Na+ 547.2455, found 547.2457.
1-(3,4-dimethoxyphenyl)-3-hydroxy-4,4-dimethylpentyl 3,4-dimethoxybenzoate
(8k): 1H NMR (600 MHz, CDCl3) δ (ppm) 7.73 (dd, J = 8.4, 1.8 Hz, 1H), 7.58 (d, J =
1.7 Hz, 1H), 7.03 (dd, J = 8.3, 1.7 Hz, 1H), 6.96 (d, J = 1.6 Hz, 1H), 6.91 (d, J = 8.5
Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.22 (dd, J = 10.8, 2.1 Hz, 1H), 3.95 (s, 3H), 3.93 (s,
3H), 3.90 (s, 3H), 3.87 (s, 3H), 3.36 (dd, J = 10.3, 3.9 Hz, 1H), 2.54 (d, J = 4.6 Hz,
1H), 2.22 – 2.15 (m, 1H), 1.83 – 1.76 (m, 1H), 0.90 (s, 9H). 13C NMR (150 MHz,
CDCl3) δ (ppm) 166.66, 153.38, 149.13, 148.86, 133.99, 123.80, 122.73, 118.57,
112.38, 111.33, 110.42, 110.13, 109.90, 75.36, 74.24, 56.22, 56.14, 56.12, 56.08,
39.88, 34.74, 25.95. HRMS (ESI+) m/z calcd for C24H32O7 + Na+ 455.2040, found
455.2057.
1-([1,1'-biphenyl]-4-yl)-3-hydroxy-4,4-dimethylpentyl [1,1'-biphenyl]-4-
carboxylate (8n): 1H NMR (600 MHz, CDCl3) δ (ppm) 8.19 (d, J = 8.0 Hz, 2H), 7.70
(d, J = 8.0 Hz, 2H), 7.66-7.54 (m, 8H), 7.51-7.39 (m, 5H), 7.35 (t, J = 7.2 Hz, 1H),
6.39 (d, J = 10.6 Hz, 1H), 3.44 (dd, J = 10.5, 3.8 Hz, 1H), 2.51 (d, J = 4.4 Hz, 1H),
2.25 (t, J = 12.7 Hz, 1H), 1.87 (t, J = 12.7 Hz, 1H), 0.96 (s, 9H). 13C NMR (150 MHz,
CDCl3) δ (ppm) 166.65, 146.17, 141.09, 140.87, 140.34, 140.10, 130.46, 129.12,
128.92, 128.38, 127.56, 127.51, 127.44, 127.34, 127.28, 126.79, 126.26, 75.35, 74.24,
39.97, 34.78, 25.94. HRMS (ESI+) m/z calcd for C32H32O3 + Na+ 487.2244, found
487.2259.
ACKNOWLEDGMENTS
This work was supported by NSF grant 1464538 to PGW.
Appendix A. Supplementary Data
Supplementary data to this can be found online at:
https://
27

We report a systematic study and comparison of the solid-state aldol reactions of solvated and
unsolvated lithium pinacolone enolate with a variety of solid aromatic aldehydes. In solution, the
reactions are highly-selective for the aldol condensation product at room temperature. Using a
mortar and pestle, the reactions with unsolvated lithium pinacolone enolate yielded a mixture of
aldol condensation product and aldol addition product at room temperature.