Investigation of Electrostatic Interactions towards Controlling Silylation-Based Kinetic Resolutions

Article abstract of DOI:10.1002/ejoc.201900754

Electrostatic interactions between a silylated isothiourea intermediate and an ester π system were explored by determining how variations in sterics and electronics affect the selectivity of a silylation-based kinetic resolution. Sterics on the π systems affect the selectivity factors of alkyl 2-hydroxycyclohexanecarboxylates, resulting in a strong correlation of selectivity factors to Charton values. Induction effects of electron-withdrawing substituents on phenyl esters significantly enhance selectivity supporting an edge to face π–π interaction. The linear free energy relationships that were uncovered will aid in future incorporation of intermolecular electrostatic interactions towards controlling asymmetric reactions.

Full text of DOI:10.1002/ejoc.201900754

A Journal of
Accepted Article
Title: Investigation of electrostatic interactions towards controlling
silylation-based kinetic resolutions
Authors: Tian Zhang, Brandon Redden, and Sheryl Wiskur
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900754
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10.1002/ejoc.201900754
European Journal of Organic Chemistry
COMMUNICATION
Investigation of electrostatic interactions towards controlling
silylation-based kinetic resolutions
Tian Zhang,[a] Brandon Redden,[a] and Sheryl L. Wiskur*[a]
Abstract: Electrostatic interactions between a silylated isothiourea
intermediate and an ester π system were explored by determining
how variations in sterics and electronics affect the selectivity of a
silylation-based kinetic resolution. Sterics on the π systems affect the
selectivity factors of alkyl 2-hydroxycyclohexanecarboxylates,
resulting in a strong correlation of selectivity factors to Charton values.
Induction effects of electron withdrawing substituents on phenyl esters
significantly enhance selectivity supporting an edge to face π-π
interaction. The linear free energy relationships that were uncovered
will aid in future incorporation of intermolecular electrostatic
interactions towards controlling asymmetric reactions.
(Scheme 1). Our method employs an isothiourea catalyst (1 or
2)[9] and a triarylsilyl chloride (3a or 3b) to obtain efficient
separation of the alcohol enantiomers.
1
2
or (25mol %)
3a)
3b
)
Ph3SiCl (
or (p-iPrPh)3SiCl (
OH
Alkyl
OH
Alkyl
OSiAr3
Alkyl
iPr2NCHEt2 or iPr2NEt
R
THF, MS 4 Å, -78 °C
R
R
N
N
S
S
N
N
1
2
2° alcohols lactones/lactams cyclohexanols
OH
Introduction
OH
OH
R'
R'
O
Ar
Intermolecular interactions such as hydrogen bonding, π-π
stacking, and ionic forces have been shown to play a large role in
controlling the selectivity and reactivity of organocatalyzed
reactions, in many cases working cooperatively to obtain a
favorable outcome.[1] Electrostatic interactions such as π-π
interactions and cation-π interactions[2] have been shown to aid in
controlling the selectivity of asymmetric reactions through an
electrostatic interaction between a substrate and a catalyst.[3] We
have theorized that these type of electrostatic interactions are
also controlling the selectivity of our silylation-based kinetic
resolutions, given that our substrates need to have a π system
within the structure to obtain any selectivity.[4] While exploring the
kinetic resolution of trans 2-hydroxy cyclohexane carboxylate
esters with isothiourea catalysts, linear free energy relationships
were observed that correlates selectivity with both the size of the
ester substituent and the electronics of the aryl group on the ester,
indicating sterics and electronics affect the strength of this
interaction. While we originally hypothesized that a cation- π
interaction was the dominating factor, electronics suggest that a
π-π type interaction is more likely the controlling factor. Herein,
we highlight the selectivity observed with variations in this
substrate class, and how sterics and electronics on the ester
affect a potential electrostatic interaction with the π system.
Acylation-based kinetic resolutions have dominated the way
secondary alcohols are resolved over the last 20 years,[5] but
recently silylation-based kinetic resolutions have emerged as a
competitive alternative with increasing diversity in the types of
alcohols that can be resolved.[6] We have successfully resolved
cyclic alcohols,[7] β-hydroxy lactones and lactams,[8] and 2-aryl
cyclohexanols[4] with synthetically useful levels of selectivity
X
n
X = O or NAr
(s up to 25)
(s upto 100)
(s up to 50)
Scheme 1. Previous silylation-based kinetic resolutions performed by our group.
In order to obtain selectivity in our silylation methodology, the
substrates need to have a π system within the structure. For
example, by changing the substituent on 2-substituted
cyclohexanols from a phenyl ring into a cyclohexane ring, the
selectivity factor drops from 10 to 2.[4] We hypothesize that an
electrostatic cation-π or π-π interaction between the silylated
cationic catalyst intermediate and the π-system of the substrate
help to control the orientation of the two, which aids in controlling
selectivity. These interactions are defined as electrostatic, non-
covalent interactions between either a cation and a π system or
two π systems, and the attractive force for the stronger cation- π
interaction is comparable in strength to a hydrogen bond.[10] The
attractive interaction forms between an electron deficient
structure and the negatively charged surface of a π system,
frequently an aromatic group. However, it can also be as simple
as an alkene or acyl group. It has been suggested that this
interaction aids in controlling selectivity in other asymmetric
reactions,[3] including work by Birman using the same isothiourea
catalysts for acylation-based kinetic resolutions.[11] In order to
obtain
a more thorough understanding how sterics and
electronics of the π system affect this interaction, we began to
explore trans 2-ester substituted cyclohexanols. The ester group
provides the needed electronics, and it can be easily derivatized
to alter the electronics and sterics of the π-system.
[a]
Prof. Dr. Sheryl L. Wiskur
Department of Chemistry and Biochemistry
University of South Carolina
631 Sumter St., Columbia, SC 29208
E-mail: wiskur@mailbox.sc.edu
Results and Discussion
Optimized reaction conditions for the kinetic resolution were
determined using trans-ethyl 2-hydroxycyclohexanecarboxylate
((±)-4) as the substrate. The results are shown in Table 1. Chiral
Homepage: http://artsandsciences.sc.edu/chemistry/groups/wiskur/
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900754
European Journal of Organic Chemistry
COMMUNICATION
catalysts are employed to activate a silyl chloride to preferentially
silylate one alcohol enantiomer over the other, generating silyl
ethers 5a-b and recovering enantiomerically enriched alcohol (+)-
4. Similar to our previous work, the catalyst with the fused
aromatic ring, benzotetramisole (2),[11] gave higher selectivity than
the less conjugated version (tetramisole, 1) (Table 1, Entry 1 vs 2,
Entry 3 vs. 4). In a previous study, we noted that three phenyl
groups on the silyl chloride is needed in order to obtain useful
levels of selectivity,[7] and electron-donating isopropyl groups in
the para position also resulted in improved selectivity.[13] These
factors are also important in obtaining good selectivity with this
substrate. When tris(4-isopropylphenyl)silyl chloride (3b) was
utilized, selectivity increased versus employing the unsubstituted
triphenylsilyl chloride (3a) (entry 2 versus 4). Electron donating
groups on the silyl group are hypothesized to stabilize the reactive
silicon/catalyst intermediate.[13]
correlation between the steric effect near the π-system and the
selectivity factors (Ψ = -0.7), showing that as sterics increase
selectivity decreases. The sterics obviously have a negative
impact regarding how the substrate and the reactive intermediate
organize in the transition state to obtain selectivity. The sterics
also play a negative effect on reactivity, with the conversion of the
reaction decreasing as sterics increase. In fact, the t-butyl
substrate has very little conversion over a 24-hour period (Table
2, entry 4).
Table 2. Substrate scope of the silylation-based kinetic resolution of trans-
alkyl-2-hydroxycyclohexanecarboxylate.
2 (25 mol%)
(p-iPrPh)3SiCl (3b) (0.6 equiv)
iPr2NEt (0.6 equiv)
O
OH
O
OH
O
OH
O
OSi(p-iPrPh)3
R
THF, MS 4 Å, -78 °C
R
R
R
Table 1. Optimization of reaction conditions for resolution of trans-ethyl 2-
n
n
n
n
hydroxycyclohexanecarboxylate.
er of
recovered
alcohol
recovered
alcohol
entry[b]
conv (%)[a]
36
s[a]
Catalyst (25 mol %)
R3SiCl (3a-b ) (0.6 equiv)
O
O
O
O
OH
OH
OH
OH
O
OH
O
OH
O
OH
O
OSiR3
1
72:28
55:45
14
10
EtO
iPr2NEt (0.6 equiv)
THF, MS 4 Å, -78 °C
EtO
EtO
(±)-4
EtO
EtO
(+)-4
5a-b
2
3
iPr
35
Entry[b] catalyst
R
t (h) conv (%)[a] s[a]
O
O
O
1
2
1
2
a
)
1
Ph (
24
24
48
48
47
44
18
36
3
11
3
2
Ph (a)
3[c]
4
p-iPr-Ph (
)
b
66:34
52:48
30
6
8.4
4.7
b
p-iPr-Ph (
)
14
[a] Conversions and selectivity factors are based on the ee of the recovered
starting materials and products. See ref [12]. [b] Selectivity factors are an
average of two runs. Conversions are from a single run. [c] Conversion and
[c]
4
tBu
selectivity factor is based on the ee of the recovered starting material and 1
H
NMR conversion.
O
OH
[c]
5
64:36
58:42
41
3
With the optimized reaction conditions obtained, the effect of
altering the sterics on the ester group was explored (Table 2).
O
H3CO
When
the
ethyl
group
of
trans
ethyl
2-
O
O
OH
OH
[c]
6
20
43
4.4
27
hydroxycyclohexanecarboxylate (4) was changed to an isopropyl
group, a decrease in the selectivity factor was observed (from s =
14 to 10) presumably from an increase in steric hindrance of the
ester (Table 2, entry 2). In order to provide evidence that sterics
on the ester correlate to the selectivity factor, two more 2-ester
cyclohexanol derivatives were synthesized through the
esterification of 2-hydroxycyclohexanecarboxylate and tested
under the optimized conditions. As predicted, substrates with
cyclohexyl and t-butyl groups also followed the same trend of
decreasing selectivity as the alkyl group on the ester increased in
size (Table 2, entry 3 and 4). The sensitivity of these selectivity
factors (Table 2, entries 1-4) to steric hindrance was then
investigated using Charton (υ) values in a linear free energy
relationship[14] to establish if there is a correlation between the
steric effect and selectivity. Charton values are substituent
parameters that use the van der Waals radius of the substituent
to study sterics.[15] The log of the selectivity factors for the different
substrates were plotted against the Charton values associated
with each alkyl group (Figure 1). Indeed, there is a strong linear
O
O
Cl
[c]
82.5:17.5
7
F3C
O
O
OH
OH
OH
[c]
8
69:31
60:40
61:39
29
38
45
34
3
O
O
9
Et
O
10
2.7
EtO
[a] Conversions and selectivity factors are based on the ee of the recovered
starting materials and products. See ref [12]. Selectivity factors are an
average of two runs. Conversions are from a single run. [b] Reactions were
run for 48 h at a concentration of 0.42 M with respect to alcohol on a 0.4 mmol
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10.1002/ejoc.201900754
European Journal of Organic Chemistry
COMMUNICATION
scale. [c] Conversion and selectivity factor is based on the ee of the recovered
In order to provide more evidence that the substituents are
contributing to the interaction through induction, not resonance
the Swain-Lupton dual parameter approach was used to
determine the percent contribution of each effect, by using
substituent constants for both field effects and resonance.[20] The
log of the selectivity factor is set equal to the sum of the
substituent constants for field effects (F) and resonance (R), with
sensitivity factors for each (ƒ and r respectively) (Eq. 1). Using a
least-squares regression analysis, the experimental data is
plotted against the predicted data and the sensitivity factors are
solved for, ultimately looking for a slope of one. As expected, the
sensitivity factor for field effects was about 2.5 times higher than
the sensitivity constant for resonance, indicating that the field
effects contribute more significantly towards controlling selectivity
(Figure 3).
starting material and 1H NMR conversion.
In order to modulate the electronics of the ester with the intention
of altering the strength of the electrostatic interaction controlling
selectivity, phenyl esters were synthesized with either a hydrogen
or an electron withdrawing group in the para position on the
phenyl ring (Table 2, Entries 5-8). It is known that the phenyl
group on a phenyl ester is not in resonance with the ester group,
but is rotated such that the plane of the phenyl group is
perpendicular to the plane of the s-trans ester.[16] Since
Neuvonen and coworkers have shown that electron donating and
withdrawing substitutents on these phenyl groups affect the
polarity of the carbonyl,[17] we hypothesized that the selectivity of
the kinetic resolution would be affected also with different
substituents. When just a phenyl group was employed, the
selectivity was pretty low (Table 2, Entry 5). By adding a methoxy
group, which is electron donating in Neuvonen’s work, the
selectivity slightly increased to s = 4.4 (Table 2, Entry 6), therefore
weakly enhancing the electrostatic interaction. When the para
position was substituted with strong electron withdrawing groups
such as a chloro or a trifluoromethyl group, the selectivity
significantly increased to s = 27 and 34 respectively (Table 2,
Entries 7 and 8). While stronger electron withdrawing groups
increase the electron density on the carbonyl carbon which would
help promote a cation- π interaction, electron donating groups
decrease the electron density on the carbonyl which would
ultimately decrease the strength of the interaction with the cationic
catalyst which does not support the methoxy data.
2
CF3
1.5
1
Cl
Log (s)
y = 2.6x+ 0.4
R² = 0.98
H
OCH3
0.5
0
0
0.25
0.5
σm
1.5
Et
Figure 2. Linear free energy relationship employing σm versus selectivity for the
induction of the ester substituent.
1.2
iPr
C6H11
0.9
tBu
Log (s)
0.6
log(s) = ƒF + rR
Eq. 1
y = ‐0.7x+ 1.5
R² = 0.99
0.3
0
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Charton(ν)
Figure 1. Linear free energy relationship employing Charton values versus
selectivity for the sterics of the ester substituent.
A linear free energy relationship (LFER) was found for the four
substrates when sigma meta (σm) substituent parameters[18] were
plotted against the log of the selectivity factor showing that as
electron withdrawing groups become stronger selectivity
increased, resulting in a significant sensitivity constant (ρ) of 2.6
(Figure 2). Methoxy is an electron withdrawing group when
employing sigma meta, which is consistent with the increase in
selectivity over just phenyl. Edge to face π-π interactions are
enhanced when one π system is electron deficient,[19] suggesting
that the selectivity defining interaction for the phenyl esters is a π
interaction with one of the aryl groups on the catalyst or silicon.
Figure 3. Comparison of the experimental log(s) using the selectivity factors
from Table 1 (entries 5-7) versus predicted log(s) calculated from Eq. 1.
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COMMUNICATION
General procedure for the kinetic resolution of trans-alkyl-2-
hydroxycyclohexanecarboxylate To an oven dried 1-dram vial with an
oven dried Teflon coated stir bar and activated 4Å molecular sieves, the
racemic alcohol substrate (0.4 mmol) and catalyst (0.1 mmol) were added.
The vial was then purged with argon and sealed with a septa. The N, N-
diisopropylethylamine (0.24 mmol) was added via syringe and the resulting
mixture was dissolved in THF (0.55 mL) to make a 0.72 M concentration
solution with respect to the alcohol. The vial was then cooled to -78 ºC for
30 mins. The cooled mixture was then treated with a 0.65 M solution of
silyl chloride in THF (0.4 ml, 0.26 mmol) and was left to react for 48 h at -
78 ºC. The resulting solution was 0.42 M with respect to the alcohol. After
48 hours, the reaction was quenched with 0.3 ml of methanol. The solution
was allowed to warm to room temperature and the crude contents were
diluted with diethyl ether and transferred to a 4-dram vial. Solvent was
removed by rotary evaporator and the crude mixture was purified via silica
gel chromatography (5% EtOAc in hexanes increasing to 10% and 25%
EtOAc in hexanes). The silylated alcohol was concentrated and saved for
analysis and the unreacted alcohol could either be analyzed directly by
HPLC or be converted to the benzoate ester for HPLC analysis.
The last two entries in table 2 highlight the importance of ring size
and positioning of the π system. A six membered ring is needed
in order to obtain selectivity, as seen in entry 10 (vs. entry 1)
where the selectivity factor dropped to 2 when a cyclopentanol
substrate was employed. When the orientation of the ester on the
cyclohexanol was reversed, the selectivity of the reaction was
very low (entry 9, s = 3). We hypothesize that the intramolecular
hydrogen bonding between the ester carbonyl and hydroxyl group
of 4 forms a stable six-membered ring which aids in controlling
selectivity, by favoring a chair conformation with both the hydroxyl
and ester group in an equatorial position and prevents free
rotation of the ester. When the orientation of the ester is switched
in entry 9, the intramolecular hydrogen bond forms a less
energetically favorable seven membered ring, weakening that
interaction (Figure 4). Ultimately, the π system is moved further
from the reacting alcohol, and the ester is more likely to be freely
rotating. This prevents optimal electrostatic interactions, reducing
the selectivity of the kinetic resolution.
Acknowledgments
Table 2, entry 1
H
Table 2, entry 9
H
O
Support from the University of South Carolina and the Office of
the Vice President for Research Aspire Awards is gratefully
acknowledged.
O
O
O
Et
VS
O
Et
O
Keywords: kinetic resolutions • linear free energy relationship •
favorable
unfavorable
6-membered
H-bonding ring
7-membered
H-bonding ring
noncovalent interactions • cation-pi interactions
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Conclusions
In conclusion, we have investigated potential electrostatic
interactions between the proposed, reactive catalytic species and
trans 2-ester substituted cyclohexanols by varying sterics and
electronics on the ester π system. The electrostatic attraction
helps align the substrate to the catalyst in an orientation that
allows for increased selectivity. An increase in sterics adjacent to
the π-system affects the ability to orient favorably, resulting in a
decrease in selectivity which correlates well with Charton
substituent constants. Substituting the ester with aryl groups
affects the selectivity, mainly through field effects deduced from a
Swain-Lupton analysis. The data suggests that an edge to face
π-π interaction is dominating given that electron withdrawing
groups dramatically increase the selectivity of the reaction.
Finally, the ability of the hydroxyl group to form a favorable
hydrogen bond to the carbonyl of the ester (6- vs 7-membered
rings) is an aspect that promotes an increase in selectivity. Future
work will focus on computational modeling of these and similar
systems, and looking at other systems to see if similar trends are
followed.
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Experimental Section
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10.1002/ejoc.201900754
European Journal of Organic Chemistry
COMMUNICATION
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COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Electrostatic Control*
Tian Zhang, Brandon Redden, Sheryl L.
Wiskur*
What attractiveinteractions
control selectivity?
Page No. – Page No.
Investigation of electrostatic
The intermolecular interactions that aid in controlling asymmetric reactions are
investigated. Alterations in the electronics and sterics of a π system are studied to
understand the effect on selectivity that results from electrostatic interactions
between the catalyst and the substrate.
interactions towards controlling
silylation-based kinetic resolutions
*physical organic interactions
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