Controlling the Conformational Energy of a Phenyl Group by Tuning the Strength of a Nonclassical CH···O Hydrogen Bond: The Case of 5-Phenyl-1,3-dioxane

Article abstract of DOI:10.1021/acs.joc.6b02428

Anancomeric 5-phenyl-1,3-dioxanes provide a unique opportunity to study factors that control conformation. Whereas one might expect an axial phenyl group at C(5) of 1,3-dioxane to adopt a conformation similar to that in axial phenylcyclohexane, a series of studies including X-ray crystallography, NOE measurements, and DFT calculations demonstrate that the phenyl prefers to lie over the dioxane ring in order to position an ortho-hydrogen to participate in a stabilizing, nonclassical CH···O hydrogen bond with a ring oxygen of the dioxane. Acid-catalyzed equilibration of a series of anancomeric 2-tert-butyl-5-aryl-1,3-dioxane isomers demonstrates that remote substituents on the phenyl ring affect the conformational energy of a 5-aryl-1,3-dioxane: electron-withdrawing substituents decrease the conformational energy of the aryl group, while electron-donating substituents increase the conformational energy of the group. This effect is correlated in a very linear way to Hammett substituent parameters. In short, the strength of the CH···O hydrogen bond may be tuned in a predictable way in response to the electron-withdrawing or electron-donating ability of substituents positioned remotely on the aryl ring. This effect may be profound: a 3,5-bis-CF₃ phenyl group at C(5) in 1,3-dioxane displays a pronounced preference for the axial orientation. The results are relevant to broader conformational issues involving heterocyclic systems bearing aryl substituents.

Full text of DOI:10.1021/acs.joc.6b02428

Subscriber access provided by UNIV OF WEST FLORIDA
Featured Article
Controlling the Conformational Energy of a Phenyl
Group by Tuning the Strength of a Non-Classical CH…
O Hydrogen Bond: The Case of 5-Phenyl-1,3-dioxane
William F Bailey, Kyle M Lambert, Zachary D. Stempel, Kenneth B Wiberg, and Brandon Q. Mercado
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02428 • Publication Date (Web): 16 Nov 2016
Downloaded from http://pubs.acs.org on November 21, 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 49
The Journal of Organic Chemistry
1
2
3
4
Controlling the Conformational Energy of a Phenyl Group by Tuning
5
6
7
…
the Strength of a Non-Classical CH O Hydrogen Bond: The Case of 5-
8
9
Phenyl-1,3-dioxane
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
William F. Bailey,* † Kyle M. Lambert,† Zachary D. Stempel,† Kenneth B. Wiberg,* ‡
Brandon Q. Mercado‡
†Department of Chemistry, University of Connecticut, Storrs, CT, 06269-3060, United
States
‡Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United
States
William.Bailey@uconn.edu; Kenneth.Wiberg@yale.edu
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 49
1
2
3
4
5
6
7
8
9
ABSTRACT: Anancomeric 5-phenyl-1,3-dioxanes provide a unique opportunity to study
factors that control conformation. Whereas one might expect an axial phenyl group at
C(5) of 1,3-dioxane to adopt a conformation similar to that in axial-phenylcyclohexane, a
series of studies including X-ray crystallography, NOE measurements and DFT
calculations demonstrate that the phenyl prefers to lie over the dioxane ring in order to
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
…
position an ortho-hydrogen to participate in a stabilizing, non-classical CH O hydrogen
bond with a ring oxygen of the dioxane. Acid-catalyzed equilibration of a series of
anancomeric 2-t-butyl-5-aryl-1,3-dioxane isomers demonstrates that remote substituents
on the phenyl ring affect the conformational energy of a 5-aryl-1,3-dioxane: electron-
withdrawing substituents decrease the conformational energy of the aryl group while
electron-donating substituents increase the conformational energy of the group. This
effect is correlated in a very linear way to Hammett substituent parameters. In short, the
…
strength of the CH O hydrogen bond may be tuned in a predictable way in response to
the electron-withdrawing or electron-donating ability of substituents positioned remotely
on the aryl ring. This effect may be profound: a 3,5-bis-CF3 phenyl group at C(5) in 1,3-
dioxane displays a pronounced preference for the axial orientation. The results are
relevant to broader conformational issues involving heterocyclic systems bearing aryl
substituents.
2
ACS Paragon Plus Environment

Page 3 of 49
The Journal of Organic Chemistry
1
2
3
4
5
6
INTRODUCTION
7
8
9
Seminal, fundamental investigations by Eliel’s group in the 1960’s and 70’s of
conformational equilibria in substituted 1,3-dioxanes have contributed significantly to
current understanding of the nature of steric and electronic effects in saturated
heterocyclic systems.1 The 1,3-dioxane system has three distinct sites of substitution,
each of which displays a unique steric and stereoelectronic environment. Perhaps most
importantly, facile acid-catalyzed equilibration of configurationally isomeric 1,3-dioxanes
allows for accurate and precise determination of conformational energies.2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The conformational energy of a phenyl group at the C(5) position of 1,3-dioxane
was determined in diethyl ether solvent at room temperature, as illustrated in Scheme 1,
by Eliel and Knoeber in 1968 by BF3 - catalyzed equilibration of cis- and trans-2-t-butyl-5-
phenyl-1,3-dioxane.3 Significantly, the energy difference, 1.03 ± 0.02 kcal / mol, is
substantially lower than the 2.8 kcal/mol conformational energy (A-value) of
phenylcyclohexane.4 The considerably lower conformational energy of 5-phenyl-1,3-
dioxane vis-à-vis phenylcyclohexane was attributed at the time to, “a diminution of the
[syn-] axial interactions because, where in cyclohexane there are axial hydrogens in
positions 1 and 3, in 1,3-dioxane there are, instead, electron pairs on oxygen”.5 In
retrospect, given the results of more recent investigations of the conformational behavior
of phenylcyclohexane, this explanation must be reassessed.
Scheme 1. Conformational Energy of 5-Phenyl-1,3-dioxane.
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 49
1
2
3
4
5
6
7
8
H
BF3
O
O
H
O
O
Et2O
9
H
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
K = 5.71 ± 0.23
!G° = –1.03 ± 0.02 kcal / mol
The dominant interactions responsible for the sizeable conformational energy of
phenylcyclohexane, in which the plane of the axial phenyl ring is perpendicular to the
benzylic C–H bond, are now known to be steric repulsion between the equatorial
hydrogens at the C(2) and C(6) positions of the cyclohexane ring and the ortho-
hydrogens of the axial phenyl group.6 In short, syn-axial interactions contribute modestly,
at best, to the conformational energy of phenylcyclohexane. Clearly, the same repulsive
steric interactions present in phenylcyclohexane should beset an axial 5-phenyl group in
the 1,3-dioxane system were it also to adopt a rotameric conformation having the plane of
the ring perpendicular to the C(5) benzylic hydrogen. Given this background, the question
remains: why is the conformational energy of a phenyl group in 5-phenyl-1,3-dioxane only
a third as large as that of phenylcyclohexane?
An answer to the question is provided by an unanticipated result of our recent
computational investigation of the rotameric conformations of a phenyl ring in a series of
axially and equatorially substituted 1,3-dioxanes and tetrahydropyrans.7 As shown below
(Figure 1), the computed minimum energy rotamer of axial 5-phenyl-1,3-dioxane is one in
which the plane of the phenyl ring bisects the 1,3-dioxane ring and is parallel to the
benzylic C(5)–H bond. This arrangement positions an ortho hydrogen proximate to the
4
ACS Paragon Plus Environment

Page 5 of 49
The Journal of Organic Chemistry
1
2
3
4
…
two ring oxygens, leading to attractive CH O Coulombic interactions.
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
Figure 1. Calculated minimum energy rotamer of axial 5-phenyl-1,3-dioxane.
To the extent that the computational results comport with reality, we reasoned that
8
…
the strength of the non-classical CH O hydrogen bond between an ortho hydrogen and
a ring oxygen in axial 5-phenyl-1,3-dioxane should respond to substituents placed
remotely on the phenyl ring: electron-withdrawing groups should strengthen the attractive
…
CH O interaction, electron-donating groups should attenuate the interaction. As
demonstrated by the results presented below, this is indeed the case.
RESULTS and DISCUSSION
Equilibration Studies. At the outset of the study, cis - (1) and trans-2-isopropyl-5-
phenyl-1,3-dioxane (2) were prepared in order to demonstrate, once again,3 that the
nature of the 2-alkyl holding group has no effect on the conformational energy of a C(5)
substituent determined by direct equilibration of the 1,3-dioxane isomers. A representative
series of anancomeric 2-t-butyl-5-aryl-1,3-dioxanes (3 - 14), depicted in Chart 1, were
also prepared as illustrated in Scheme 2 by acid catalyzed condensation of pivaldehyde
with 2-aryl-1,3-propane diols. The diastereoisomeric pairs of 5-aryl-1,3-dioxanes were,
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 49
1
2
3
4
5
6
7
8
9
with some difficulty, separated chromatographically and fully characterized. The
configuration of the individual dioxane isomers follows from the method of preparation of
each pair: in each case but one (discussed below) the thermodynamically more stable
trans-isomer (even numbered compounds in Chart 1) was the major product of the
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
condensation reactions. Nonetheless, the configurations were further confirmed by H
NOESY analysis as detailed in the Supporting Information.
Chart 1. Anancomeric 5-Aryl-1,3-dioxanes.
6
ACS Paragon Plus Environment

Page 7 of 49
The Journal of Organic Chemistry
1
2
3
4
Cl
5
6
7
8
9
H
H
O
O
O
O
H
H
H
O
H
O
O
O
H
H
H
H
Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2
3
4
CF3
Br
H
H
O
O
O
O
O
H
O
O
O
H
H
CF3
H
H
Br
5
6
7
8
OCH3
F3C
O
CF3
H
H
O
CF3
O
O
O
H
O
O
O
H
H
H
H
OCH3
CF3
9
10
11
12
TMS
H
O
O
O
H
O
H
H
TMS
14
13
Scheme 2. Preparation of 2-t-Butyl-5-aryl-1,3-dioxanes.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 49
1
2
3
4
5
6
7
8
9
O
O
O
O
HO
OH
G
1. NaH
2.
OH
OEt
EtO
OEt
O
1. LiAlH4
Et2O, RT, 18h
acetyl chloride
EtOH
EtO
OEt
reflux, 1.5 – 4h
84 – 97%
THF, reflux, 4h
40 – 90%
2. H2O, NaOH
20 – 63%
G
G
G
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
G = p-Cl
p- Br
1. 2.2 equiv. t-BuLi
Et2O, 45 min
–78°C to RT
2. TMSCl, RT, 45 min
97%
t-Bu-CHO
p–TsOH
H
p-CF3
3,5-bis-CF3
p-OCH3
p-TMS
G
+
O
O
O
H
O
benzene
reflux, 12h
42–96%
H
H
(mixture)
An X-ray crystallographic analysis of cis-2-t-butyl-5-p-chlorophenyl-1,3-dioxane (3),
portrayed in Figure 2, corroborates the computational result noted in above. There are
two chemically identical, but crystallographically distinct molecules in the asymmetric unit.
The axial phenyl ring in both cases adopts a rotameric arrangement in which an otho
…
hydrogen is in close proximity to one of the dioxane oxygen atoms. The CH O distances
in each of the molecules in the unit cell (Table 7, Supporting Information) are virtually
identical: 2.41(2) Å and 2.44(2) Å.
8
ACS Paragon Plus Environment

Page 9 of 49
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
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 49
1
2
3
4
5
6
7
8
9
Figure 2. Crystal structure of cis-2-t-butyl-5-p-chlorophenyl-1,3-dioxane (3). All thermal
ellipsoids are shown at a 50% probability level, and hydrogen atoms are shown as
arbitrary spheres. The top view is from the side; the lower view, from above, shows the
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
…
CH O interaction.
Each of the 5-aryl-1,3-dioxane pairs (1-14) were equilibrated at room temperature
(~ 23 °C) in sealed ampoules under nitrogen as solutions in either cyclohexane or diethyl
ether over dry Amberlyst-15 resin. Equilibrium was approached independently from
samples of the cis-isomer and the trans-isomer and, after the solutions were neutralized
by shaking with anhydrous K2CO3, the area ratio of the isomeric mixture was determined
by capillary GC analysis providing baseline separation. It was deemed that equilibrium
had been reached when the same area ratios were obtained from initially pure samples of
each isomer. Area ratios for each equilibration, which reflect the equilibrium constant for
the process, were taken as the average of 5−14 independent determinations from each
side, and the free energy difference for the equilibrium was calculated in the normal way:
ΔG° = −RT ln K. The results of these studies are summarized in Table 1.
10
ACS Paragon Plus Environment

Page 11 of 49
The Journal of Organic Chemistry
1
2
3
4
Table 1. Equilibria in 5-Phenyl-1,3-dioxanes.a
5
6
7
8
entry
dioxanes
solvent
K
ΔG°, kcal/mol
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
1
2
H
C6H12
5.71 ± 0.05
6.09 ± 0.07
–1.03 ± 0.01
–1.06 ± 0.01
O
O
O
H
H
H
O
Et2O
H
H
1
2
Cl
3
4
C6H12
Et2O
3.19 ± 0.07
3.25 ± 0.07
–0.68 ± 0.01
–0.69 ± 0.01
H
O
O
O
O
H
Cl
H
4
3
Br
5
6
C6H12
Et2O
3.06 ± 0.01
3.19 ± 0.01
–0.66 ± 0.01
–0.68 ± 0.01
H
O
O
O
O
H
Br
H
6
5
CF3
7
8
C6H12
Et2O
2.31 ± 0.02
3.10 ± 0.01
–0.49 ± 0.01
–0.67 ± 0.01
H
O
O
O
H
O
H
CF3
H
8
7
CF3
CF3
H
9
C6H12
0.63 ± 0.01
0.68 ± 0.01
+0.27 ± 0.01
+0.22 ± 0.01
O
CF3
O
O
H
O
CH3CNb
H
10
H
CF3
9
10
OCH3
11
12
C6H12
Et2O
6.35 ± 0.02
5.73 ± 0.04
–1.09 ± 0.01
–1.03 ± 0.01
H
O
O
O
H
O
H
OCH3
H
12
11
TMS
13
14
C6H12
Et2O
7.17 ± 0.12
6.70 ± 0.14
–1.16 ± 0.02
–1.12 ± 0.01
H
O
O
O
H
O
H
TMS
H
14
13
aDetermined at room temperature: errors in K are propagated standard deviations; the
errors in ΔG° are estimated errors that are larger than the propagated standard deviation
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 49
1
2
3
4
5
6
7
8
9
b
to account for an assumed GC response ratio of 1.0 for a given pair of isomers. During
the slow equilibration of 9 and 10 in Et2O partial decomposition of the dioxanes to
unidentified products was observed and, for this reason, the data for this experiment is
not reported.
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
As expected, the conformational energy of 5-phenyl-1,3-dioxane in diethyl ether
solvent determined by equilibration of compounds 1 and 2 having a 2-isopropyl holding
group (–1.06 kcal/mol; Table 1, entry 2) is identical, within combined experimental error,
to that reported by Eliel and Knoeber from equilibration of 2-t-butyl-5-phenyl-1,3-dioxane
(–1.03 kcal/mol).3 The effect of solvent on the conformational energies of the 5-aryl
groups are, on the whole, rather minimal: for a given pair of isomers, the difference in ΔG°
is on the order of 0.01 - 0.17 kcal/mol. The more significant conclusion to be drawn from
the results is that substituents on the phenyl ring, as remote as the para position, affect
the conformational energy of a phenyl group.
Cursory inspection of the data presented in Table 1 demonstrates that electron-
withdrawing substituents (p-Cl, p-Br, p-CF3, and 3,5-bis-CF3) stabilize the cis-isomer
while electron-donating groups (p-OMe and p-TMS) have a destabilizing effect.
Remarkably and unexpectedly, a 3,5-bis-CF3 phenyl group actually displays a
pronounced preference for the axial orientation in both cyclohexane and acetonitrile
(Table 1, entries 9 and 10). To our knowledge, this is an unprecedented result.
…
The etiology of the effect of substituents on the strength of the CH O hydrogen
bond and, hence, the conformational energy of a 5-phenyl-1,3-dioxane is very likely
electrostatic. A Hammett plot of the experimental ΔG° values in cyclohexane solution from
Table 1 versus σm constants,9 derived from the pKa’s of substituted benzoic acids, is
12
ACS Paragon Plus Environment

Page 13 of 49
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
shown in Figure 3. There is a good linear correlation (r = 0.98) having a slope (ρ) of +1.5.
In this connection, it might be noted that para-substituents are meta with respect to the
ortho hydrogen of the phenyl ring that interacts with a ring oxygen. The linear correlation
strongly suggests that the effect of substituents on the conformational energy of a 5-
phenyl-1,3-dioxane has the same origin as the effect of those substituents on the acidity
of benzoic acid: an inductive, electrostatic phenomenon. The picture that emerges is one
in which electron-withdrawing substituents render the ortho hydrogens of the axial C(5)
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
…
phenyl group more positive thus increasing the attractive CH O hydrogen bond of that
hydrogen with an oxygen of the 1,3-dioxane.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 49
1
2
3
4
5
6
7
8
9
Figure 3. Hammett plot of experimental ΔG° values (Table 1) determined in cyclohexane
solution vs σm values. The σ for the 3,5-di-CF3 case was calculated from the pKa of 3,5-
bis-CF3 benzoic acid.
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
This conclusion is further reinforced by the behavior of cis-2-t-butyl-5-(2-pyridyl)-
1,3-dioxane (15) and trans-2-t-butyl-5-(2-pyridyl)-1,3-dioxane (16) as well as that of their
corresponding pyridinium bromide salts, 17 and 18. As illustrated in Scheme 3, acid-
catalyzed condensation of 2-(2-pyridyl)-1,3-propanediol with pivaldehyde gave a mixture
of the salts of 15 and 16 containing a preponderance of the salt of the cis-isomer (15).
Neutralization of the reaction mixture and separation of the free amines afforded pure,
crystalline cis-2-t-butyl-5-(2-pyridyl)-1,3-dioxane (15): the X-ray structure of this material is
shown in Figure 4. The molecule adopts a rotameric conformation in which the pyridyl ring
very nearly eclipses the C(4)–C(5) bond of the dioxane. The torsion angle made by the
pyridyl ring and C(4)–C(5) bond is 7.51(12)o, and positions the nitrogen atom away from
the ring oxygens.
Each of the free amines was converted to a pyridinium bromide in high yield under
neutral conditions by reaction with t-BuBr in chloroform solution (Scheme 3).10 The cis-
salt (17) is quite stable both as a solid and in chloroform solution; the trans-
diastereoisomer, 18, rapidly isomerizes to 17 particularly in solution. Apparently, the
acidic hydrobromide catalyzes equilibration of 17 to 18. At what we assume to be
1
equilibrium, there is less 18 present than can be detected by H NMR and we estimate
that the ΔG° (17
18) exceeds 4.0 kcal/mol. Clearly, the classical hydrogen bond that
presumably stabilizes the axial salt (17) is an extreme manifestation of the equivalent
14
ACS Paragon Plus Environment

Page 15 of 49
The Journal of Organic Chemistry
1
2
3
4
…
electrostatic CH O interaction responsible for the effect of remote substituents on the
5
6
7
conformational energy of 5-phenyl-1,3-dioxanes.
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. Preparation of 2-t-Butyl-5-(2-pyridyl)-1,3-dioxanes (15 and 16) and their
HBr Salts (17 and 18) .
O
H
N
O
HO
OH
N
1.
p-TsOH
cyclohexane
reflux 12 h
O
separate
2. K2CO3, 1.5 h
cis/ trans ~ 5
N
Br
H
N
5 equiv.
t-BuBr
O
H
O
O
O
H
N
reflux, 12 h
CHCl3
H
H
15
17
98%
Br
H
N
H
5 equiv.
t-BuBr
H
O
O
O
O
fast
O
H
O
N
reflux, 12 h
CHCl3
H
H
H
H
16
18
17
93%
Br
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 49
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
16
ACS Paragon Plus Environment

Page 17 of 49
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
Figure 4. Crystal structure of cis-2-t-butyl-5-(2-pyridyl)-1,3-dioxane (15). All thermal
ellipsoids are shown at a 50% probability level, and hydrogen atoms are shown as
arbitrary spheres. The top view is from the side; the lower view is from above.
Before consideration of the results of DFT calculations, described below, that
support this conclusion, it is important to note that the entropy contribution to the ΔG° in
these systems is negligible. The results of a study of the effect of temperature on the
acid-catalyzed equilibrium of between cis-2-isopropyl-1,3-dioxane (1) and its trans-isomer
(2) in cyclohexane solution are summarized in Table 2. A van’t Hoff plot, ln K vs T–1, of
the equilibrium data, having a correlation coefficient of r = 0.99, is shown in Figure 5. The
slope of the plot is ΔH°/ R, where ΔH° is the conformational enthalpy difference between
the isomers and the intercept is ΔS°/ R, where ΔS° is the conformational entropy
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 49
1
2
3
4
5
6
7
8
9
difference. The slope of the plot leads to ΔH° = –1.06 ± 0.06 kcal/mol and the intercept
gives ΔS° = +0.03 ± 0.09 eu. The results demonstrate that the entropy contribution to ΔG°
is insignificant.
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. Effect of Temperature on the Acid-Catalyzed Equilibrium of cis- (1) and
trans-2-Isopropyl-5-phenyl-1,3-dioxane (2) in Cyclohexane Solution.
entry
temp, °C
K
ΔG°, kcal/mol
1
2
3
4
39.8
56.1
66.0
77.1
5.58 ± 0.04
5.14 ± 0.04
4.81 ± 0.04
4.69 ± 0.04
–1.07 ± 0.01
–1.07 ± 0.01
–1.06 ± 0.01
–1.08 ± 0.01
18
ACS Paragon Plus Environment

Page 19 of 49
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
Figure 5. van’t Hoff plot of the equilibrium data summarized in Table 2.
Computational Studies. In an effort to achieve further insight into the origin of the
effect of aryl substituents on the conformational energy of 5-aryl-1,3-dioxanes (Table 1),
the 2-t-butyl-5-aryl-1,3-dioxanes were explored using density functional theory
calculations at the B3LYP/6-311+G* level11 using tight convergence criteria (opt =
verytight, int = ultrafine) for both the optimizations and for calculation of thermal
corrections; all of the following data are for 298 K. Details of the calculations may be
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 49
1
2
3
4
5
6
7
8
9
found in the Supporting Information. The 2-t-butyl-5-aryl-1,3-dioxanes have many
relatively uncertain low frequencies and the correction from 0 K, as in the DFT
calculations, to 298 K is more reliable for ΔH° than for ΔG°; the former is used in the
following discussion. In any event, as demonstrated above, the entropy contribution to
ΔG° is essentially zero.
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 3 summarizes the computed substituent effects on the conformational
enthalpies (ΔΔH°), corrected for differences in zero-point energies and thermal
corrections to 25 °C, with the experimental substituent effects (ΔΔG° from Table 1).
Overall, there is a good correspondence between the experimental and calculated values.
Since we are interested primarily on the effect aryl substituents may have on the strength
of the interaction between the proximate ortho-hydrogen of an axial phenyl ring with an
oxygen of the 1,3-dioxane, it was of interest to explore the charges on the atoms involved
in this electrostatic interaction. The calculation of charge distribution within a molecule is
fraught with difficulty; such quantities are not well defined. We have chosen to use
Hirshfeld charges derived from the electron density distributions.12 The effect of
substituents on the charges at both the ortho-hydrogen of the phenyl ring and the dioxane
oxygen with which it interacts are summarized in Table 3. Not surprisingly, the positive
charge on the ortho-hydrogen increases as the substituent become more electron-
withdrawing and decreases in the case of an electron-donating TMS substituent.
Qualitatively, the Coulombic energy associated with these intramolecular electrostatic
…
CH O interactions accounts nicely for the effect of remote aryl substituents on the
conformational energy of 5-phenyl-1,3-dioxane. Beyond that, as we have noted
previously,13 it would not be prudent to attempt to quantitate the effect by summation of
20
ACS Paragon Plus Environment

Page 21 of 49
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Coulombic energies (E = q1q2/r12) between the non-bonded atoms because, as
demonstrated by Kirkwood and Westheimer, simple two-center calculated Coulombic
energies in molecules are attenuated by electric fields associated with the bonds in a
molecule.14
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 3. Comparison of Experimental and Calculated Substituent Effects on the
Conformational Equilibria of 2-t-Butyl-5-aryl-1,3-dioxanes.
G
H
G
O
O
O
H
O
H
H
G
q (H)b, e q (O)c, e
ΔΔG°, from Table 1a calc ΔΔH°
relative to G=H relative to G=H
H
p-Cl
0.00
0.35
0.37
0.54
1.30
–0.06
0.13
0.00
0.36
0.43
0.65
1.26
–0.09
0.06
0.0432 –0.1800
0.0472 –0.1760
0.0476 –0.1636
0.0471 –0.1633
0.0509 –0.1648
0.0452 –0.1639
0.0428 –0.1636
p-Br
p-CF3
3,5-bisCF3
p-OMe
p-TMS
a In cyclohexane solution. bHirshfeld charge on ortho-hydrogen proximate to ring oxygen. c
Hirshfeld charge of ring oxygen closest to ortho -hydrogen.
CONCLUSIONS
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 49
1
2
3
4
5
6
7
8
9
In agreement with the results of a recent computational study,7 the minimum
energy rotameric conformation of an axial 5-phenyl-1,3-dioxane has been demonstrated
to one that positions the aryl ring such that an ortho-hydrogen is in close proximity to one
of the dioxane ring oxygens (Figure 1). The results described above demonstrate that the
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
…
strength of this non-classical CH O hydrogen bond may be tuned in response to the
electron-withdrawing or electron-donating ability of substituents positioned remotely on
the aryl ring.
Acid-catalyzed equilibration of a representative series of anancomeric 2-t-butyl-5-
aryl-1,3-dioxane isomers (Table 1) reveals that substituents on the phenyl ring affect the
conformational energy of a 5-phenyl-1,3-dioxane in a predictable and quite reasonable
way: electron-withdrawing substituents decrease the conformational energy of the phenyl
group while electron-donating substituents increase the conformational energy of the
group. Moreover, the effect of substituents on the conformational energy of a 5-phenyl-
1,3-dioxane is correlated in a very linear fashion (r = 0.98) to Hammett σm parameters
(Figure 3). Consequently, the conformational energy of a 5-phenyl group is adjustable, or
tunable, in a predictable and rather precise way by reference to Hammett constants that
account for the effect of substituents on the acidity of benzoic acids.
In a larger sense, the results of this investigation of the conformational behavior of
…
5-phenyl-1,3-dioxanes reinforces the notion that non-classical CH X hydrogen bonds
are often relevant to an understanding of broader conformational issues involving
heterocyclic systems bearing aryl substituents.
EXPERIMENTAL SECTION
22
ACS Paragon Plus Environment

Page 23 of 49
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
General Procedures. Anhydrous solvents were obtained as follows: dry Et2O and
THF were freshly distilled from a dark-purple solution of sodium and benzophenone;
cyclohexane was dried over anhydrous magnesium sulfate, filtered, and freshly distilled
from a dark blue solution of sodium/benzophenone/tetraglyme; acetonitrile was distilled
from calcium hydride; dry CHCl3 was obtained by stirring with anhydrous potassium
carbonate then passage through a short column of activated alumina. Reactions involving
organometallic reagents were conducted in flame-dried glassware under an argon
atmosphere using standard techniques for handling air sensitive reagents,15 solvents
were deoxygenated by bubbling dry argon gas through the neat liquid for 10 minutes
before use, and t-butyllithium was titrated immediately prior to use utilizing the method of
Watson and Eastham.16 Sodium hydride, purchased as a 60% dispersion in mineral oil,
was washed with pentane to remove the mineral oil coating prior to use. NMR spectra
were recorded in CDCl3 on a 400 or 500 MHz spectrometer, and chemical shifts are
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
reported in ppm. Proton spectra are referenced to the residual H signal of CHCl3 at δ =
7.26 and are reported relative to TMS at δ = 0.00; carbon spectra are referenced to the
13C signal for CDCl3 at δ = 77.23 and are reported relative to TMS at δ = 0.00; fluorine
spectra are referenced to a fluorobenzene internal standard at δ= –113.15 and are
reported relative to CCl3F at δ = 0.00. Residual acid present in the CDCl3 NMR solvent
was neutralized with the addition of and storage over anhydrous potassium carbonate to
prevent epimerization of products. HRMS molecular mass determinations were performed
on a TOF mass spectrometer using a direct analysis in real time (DART) ionization
method. Refractive indices and melting points are uncorrected.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 49
1
2
3
4
Synthesis of Ethyl Esters
5
6
7
8
Ethyl 2-(4-chlorophenyl)acetate.17 Following the general method of Xu and co-
workers,18 100 mL of absolute ethanol was added to a 250 mL round-bottomed flask
containing a magnetic stir bar followed by the addition of 21.32 g (125.0 mmol) of 4-
chlorophenylacetic acid and 9.80 mL (138 mmol) of acetyl chloride. The flask was fitted
with a condenser and heated in an oil bath to 50 °C for 1.5 h then allowed to cool to room
temperature. Solvent was removed under reduced pressure, the residue was taken up in
100 mL of Et2O and washed with saturated aqueous NaHCO3 (3 x 50 mL), brine (1 x 25
mL), dried over Na2SO4 and concentrated to afford 22.62 g (91%) of the title compound
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
1
as a light yellow oil: H NMR (400 MHz, CDCl3) δ 1.26 (t, J = 7.1 Hz, 3H), 3.59 (s, 2H),
4.16 (q, J = 7.0 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 14.3, 40.8, 61.1, 128.8, 130.7, 132.7, 133.1, 171.2.
Ethyl 2-(4-methoxyphenyl)acetate.19 Following the representative procedure,
20.77 g (125.0 mmol) of 4-methoxyphenylacetic acid yielded 23.51 g (97%) of the title
21
20
1
compound as a light yellow oil: nD = 1.5080 (lit.20 nD = 1.5064); H NMR (400 MHz,
CDCl3) δ 1.24 (t, J = 7.2 Hz, 3H), 3.55 (s, 2H), 3.76 (s, 3H), 4.14 (q, J = 7.1 Hz, 2H), 6.86
13
(d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H); C NMR (100 MHz, CDCl3) δ 14.2, 40.5,
55.1, 60.7, 113.9, 126.3, 130.2, 158.7, 171.8.
Ethyl 2-(4-trifluoromethylphenyl)acetate.21 Following the representative
procedure, 20.42 g (100.0 mmol) of 4-trifluoromethylphenylacetic acid gave 21.47 g
(93%) of the title compound as a white crystalline solid: mp 37.1 – 38.2 °C (ethanol) (lit.22
mp 34 – 35 °C); 1H NMR (400 MHz, CDCl3) δ 1.26 (t, J = 7.2 Hz, 3H), 3.67 (s, 2H), 4.17
(q, J = 7.2 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H); 13C NMR (100 MHz,
24
ACS Paragon Plus Environment

Page 25 of 49
The Journal of Organic Chemistry
1
2
3
4
CDCl3) δ 14.3, 41.3, 61.3, 124.3 (q, JC-F = 272 Hz), 125.6 (q, JC-F = 3.7 Hz), 129.6 (q, JC-F
5
6
7
= 32.5 Hz), 129.9, 138.3, 171.0; 19F NMR (376 MHz, CDCl3) δ –62.6.
8
9
Ethyl 2-(3,5-bis(trifluoromethyl)phenyl)acetate.23 Following the representative
procedure, 34.02 g (125.0 mmol) of 3,5-bis(trifluoromethyl)phenylacetic acid afforded
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
31.42 g (84%) of the title compound as a light-yellow oil: nD21 = 1.4239; H NMR (400
MHz, CDCl3) δ 1.26 (t, J = 7.2 Hz, 3H), 3.74 (s, 2H), 4.18 (q, J = 7.2 Hz, 2H), 7.76 (s, 2H),
7.79 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.1, 40.8, 61.6, 121.5 (septet, JC-F = 3.8 Hz),
123.5 (q, JC-F = 272 Hz), 129.9 (q, JC-F = 3.7 Hz), 132.0 (q, JC-F = 33.2 Hz), 136.8, 170.1;
19F NMR (376 MHz, CDCl3) δ –63.0; HRMS (DART-TOF) m/z calcd for C12H10F6O2 [M +
H]+ 301.0663, found 301.0677.
Ethyl 2-(4-bromophenyl)acetate.19 Following the representative procedure, 16.58
g (77.0 mmol) of 4-bromophenylacetic acid gave 16.55 g of the title compound as a clear,
colorless oil that crystallized upon standing: mp 30.5 – 31.4 °C (ethanol) (lit.24 mp 31 – 34
°C); 1H NMR (400 MHz, CDCl3) δ 1.24 (t, J = 7.2 Hz, 3H), 3.55 (s, 2H), 4.14 (q, J = 7.2
13
Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H); C NMR (100 MHz, CDCl3)
δ 14.2, 40.8, 61.1, 121.1, 131.1, 131.7, 133.2, 171.0.
Synthesis of Diethyl Arylmalonates
Diethyl (4-bromophenyl)malonate.19 Following the general method of Enoua and
co-workers with minor modifications,25 a dry 250 mL round-bottomed flask containing a
magnetic stir bar was flushed with dry nitrogen and charged with 5.92 g (246.9 mmol) of
oil-free sodium hydride, 150 mL of anhydrous THF and 36.47 g (308.7 mmol) of diethyl
carbonate. Carefully, 15.01 g (61.7 mmol) of ethyl 2-(4-bromophenyl)acetate in 40 mL of
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 49
1
2
3
4
5
6
7
8
9
anhydrous THF was added dropwise over a period of 10 min. The flask was then fitted
with a condenser and the reaction mixture was heated at reflux. The reaction progress
was monitored colorimetrically; the initial off-white solution developed a bright orange
color over the course of the reaction, and upon persistence of this color (ca. 4 h for most
substrates) the reaction was cooled to room temperature. An ice-water bath was placed
under the reaction flask and saturated, aqueous ammonium chloride was added
dropwise through the condenser until the evolution of hydrogen gas ceased. The mixture
was then poured into a 500 mL separatory funnel and 100 mL of Et2O was added. The
organic layer was collected and the aqueous layer was extracted with Et2O (2 x 75 mL).
The combined organic layers were rinsed with saturated, aqueous ammonium chloride (2
x 75 mL), saturated, aqueous NaHCO3 (2 x 75 mL), brine (1 x 50 mL), dried over Na2SO4,
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
and concentrated. The resulting orange oil was distilled (Kugelrohr, bath temperature =
23
195 °C, 20 mm) to yield 17.50 g (90%) of the title compound as a colorless oil: nD
=
1
1.515; H NMR (400 MHz, CDCl3) δ 1.25 (t, J = 7.2 Hz, 6H), 4.14–4.27 (m, 4H), 4.56 (s,
1H), 7.28 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 14.1,
57.5, 62.1, 122.6, 131.2, 131.9, 132.0, 167.8.
Diethyl 2-(4-trifluoromethylphenyl)malonate.26 Following the representative
procedure with minor modification, 10.00
g
(43.0 mmol) of ethyl 2-(4-
trifluoromethylphenyl)acetate afforded a light orange oil that was purified by passage
through 50 g of silica gel with 15% Et2O in pentane as eluent. Removal of the solvent
under reduced pressure gave a light-yellow oil that crystallized upon standing.
Recrystallization from 50 mL of pentane yielded 8.99 g (69%) of the title compound as a
white crystalline solid: mp 28.6 – 29.0 °C (pentane); 1H NMR (400 MHz, CDCl3) δ 1.26 (t,
26
ACS Paragon Plus Environment

Page 27 of 49
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
J = 7.2 Hz, 6H), 4.16–4.29 (m, 4H), 4.68 (s, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.2
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 14.1, 57.9, 62.3, 124.2 (q, JC-F = 272 Hz), 125.6 (q,
JC-F = 3.7 Hz), 130.0, 130.6 (q, JC-F = 32.6 Hz), 136.9, 167.7; 19F NMR (376 MHz, CDCl3)
δ –62.8. HRMS (DART-TOF) m/z calcd for C14H15F3O4 [M + H]+ 305.1001, found
305.0990.
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
Diethyl
2-(3,5-bis(trifluoromethyl)phenyl)malonate.27
Following
the
representative procedure with minor modification, 6.00 g (20.0 mmol) of ethyl 2-(3,5-
bis(trifluoromethyl)phenyl)acetate afforded a crude yellow oil that was purified by passage
through 40 g of silica gel using 20% ethyl acetate in hexanes as eluent. Removal of the
solvent afforded 6.30 g (85%) of the title compound as a light yellow oil: nD21 = 1.4250; 1H
NMR (400 MHz, CDCl3) δ 1.27 (t, J = 7.1 Hz, 6H), 4.16–4.32 (m, 4H), 4.74 (s, 1H), 7.86
(s, 1H), 7.91 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 14.0, 57.6, 62.7, 122.5 (apparent
septet, JC-F = 3.7 Hz), 123.3 (q, JC-F = 272 Hz), 130.0 (apparent q, JC-F = 3.6 Hz), 132.0 (q,
19
JC-F = 33.5 Hz), 135.3, 167.0; F NMR (376 MHz, CDCl3) δ –62.9; HRMS (DART-TOF)
m/z calcd for C15H14F6O4 [M + H]+ 373.0875, found 373.0867.
Diethyl 2-(4-methoxyphenyl)malonate.27 Following the representative procedure,
with the modification that the reaction mixture was heated at reflux for 7 h before work-up,
7.50 g (38.6 mmol) of ethyl 2-(4-methoxyphenyl)acetate afforded a light-yellow oil that
was purified by column chromatography (100 g SiO2, 0 → 10% Et2O/hexanes; the
product eluted in fractions after 6% Et2O/hexanes) to yield 6.20 g (60%) of the title
20
20
1
compound as a colorless oil: nD = 1.4975 (lit.28 nD = 1.4988); H NMR (400 MHz,
CDCl3) δ 1.26 (t, J = 7.1 Hz, 6H), 3.80 (s, 3H), 4.14–4.28 (m, 4H), 4.55 (s, 1H), 6.89 (d, J
13
= 8.7 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H); C NMR (100 MHz, CDCl3) δ 14.2, 55.5, 57.4,
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 49
1
2
3
4
61.9, 114.2, 125.2, 130.59, 159.7, 168.6.
5
6
7
8
Diethyl 2-(4-chlorophenyl)malonate. Following the procedure of Meyer and
Levene for the synthesis of diethyl phenylmalonate,29 20.99 g (106 mmol) of ethyl 2-(4-
chlorophenyl)acetate afforded 8.65 g (30%) of the title compound as a colorless oil after
distillation: bp 175 – 180 °C (10 mm) [lit.25 bp 170 – 180 °C (27 mbar)]; nD21 = 1.4970 (lit.30
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
25
1
nD = 1.4999); H NMR (400 MHz, CDCl3) δ 1.25 (t, J = 7.1 Hz, 6H), 4.10–4.27 (m, 4H),
13
4.58 (s, 1H), 7.30 – 7.36 (m, 4H); C NMR (100 MHz, CDCl3) δ 14.1, 57.4, 62.1, 128.9,
130.8, 131.4, 134.4, 167.9.
Synthesis of 2-Aryl-1,3-propanediols
2-(4-Trifluoromethylphenyl)-1,3-propanediol.26 A solution of 6.95 g (22.8 mmol)
of diethyl (4-trifluoromethylphenyl)malonate in 50 mL of dry Et2O was added to a 0 °C
suspension of 1.30 g (34.2 mmol) of lithium aluminum hydride in 150 mL of Et2O. The
resulting mixture was stirred at room temperature overnight and then hydrolyzed by
sequential, dropwise addition of 1.5 mL of water, 1.5 mL of a 1 M aqueous solution of
sodium hydroxide, and 6 mL of water. The mixture was filtered through a pad of Celite
and the solids were washed with three 150-mL portions of Et2O. The combined filtrate
and washings were dried (Na2SO4) and concentrated under reduced pressure to yield a
thick oil which was purified by column chromatography (100 g SiO2, 15 → 80%
Et2O/pentane, product eluted in fractions after 60% Et2O/pentane). Combining relevant
fractions and removal of the solvent yielded a solid which was recrystallized from pentane
to afford 2.79 g (56%) of the title compound as a white crystalline solid: mp 48.8–50.0 °C
(pentane); 1H NMR (400 MHz, CDCl3) δ 2.75 (br s, 2H), 3.05–3.18 (m, 1H), 3.87–4.04 (m,
28
ACS Paragon Plus Environment

Page 29 of 49
The Journal of Organic Chemistry
1
2
3
4
4H), 7.34 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 49.6,
5
6
7
65.6, 124.3 (q, JC-F = 272 Hz), 125.8 (apparent q, JC-F = 3.6 Hz), 128.7, 129.7 (q, JC-F =
19
8
9
32.5 Hz), 144.0; F NMR (376 MHz, CDCl3) δ –62.6; HRMS (DART-TOF) m/z calcd for
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
C10H11F3O2 [M + H]+ 221.0789, found 221.0800.
2-(4-Bromophenyl)-1,3-propanediol.19 A solution of 15.80 g (50.1 mmol) of
diethyl (4-bromophenyl)malonate in 75 mL of dry Et2O was reduced with 2.85 g (75.2
mmol) of lithium aluminum hydride in 150 mL of Et2O. The reaction mixture was worked
up as described above, the solids were extracted overnight with Et2O using a Soxhlet
extractor, and the resulting oil was purified by column chromatography (100 g SiO2, 20 →
100% Et2O/pentane, product eluted in fractions after 60% Et2O/pentane). The clear oil
obtained after solvent removal crystallized upon standing and was recrystallized from
pentane/ Et2O to afford 5.50 g (48%) of the title compound as a white crystalline solid: mp
65.8–66.5 °C (pentane/ Et2O); 1H NMR (400 MHz, CDCl3) δ 2.44 (br s, 2H), 3.02 (quintet,
J = 6.4 Hz, 1H), 3.89 (dd, J = 10.7 Hz, J = 5.5 Hz, 2H), 4.02 (dd, J = 10.7 Hz, J = 7.6 Hz,
2H), 7.11 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 49.3,
65.8,121.2, 130.0, 132.1, 138.7; HRMS (DART-TOF) m/z calcd for C9H11BrO2 [M + H]+
231.0021, found 231.0042.
2-Phenyl-1,3-propanediol.31 A solution of 5.91 g (25.0 mmol) of diethyl
phenylmalonate in 20 mL of dry Et2O was reduced with 1.42 g (37.5 mmol) of lithium
aluminum hydride in 100 mL of Et2O. The reaction mixture was worked up as described
above to afford an oil that crystallized upon standing. The solid was triturated with
pentane to yield 3.18 g (84%) of the title compound: mp 51.8 – 52.3 °C (pentane) (lit.3 mp
50 – 51.5 °C); 1H NMR (400 MHz, CDCl3) δ 2.59 (br s, 2H), 3.02–3.12 (m, 1H), 3.86–4.03
29
ACS Paragon Plus Environment