A dual-catalysis anion-binding approach to the kinetic resolution of amines: Insights into the mechanism via a combined experimental and computational study

Article abstract of DOI:10.1021/jacs.5b00190

Racemic benzylic amines undergo kinetic resolution via benzoylation with benzoic anhydride in the presence of a dual catalyst system consisting of a readily available amide-thiourea catalyst and 4-dimethylaminopyridine (DMAP). An evaluation of various exp

Full text of DOI:10.1021/jacs.5b00190

Article
pubs.acs.org/JACS
A Dual-Catalysis Anion-Binding Approach to the Kinetic Resolution
of Amines: Insights into the Mechanism via a Combined
Experimental and Computational Study
Nisha Mittal,‡ Katharina M. Lippert,# Chandra Kanta De,‡ Eric G. Klauber,‡ Thomas J. Emge,‡
Peter R. Schreiner,*,# and Daniel Seidel*,‡
‡Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854,
United States
#Institute of Organic Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 58, 35392 Giessen, Germany
S
* Supporting Information
ABSTRACT: Racemic benzylic amines undergo kinetic reso-
lution via benzoylation with benzoic anhydride in the presence of
a dual catalyst system consisting of a readily available amide-
thiourea catalyst and 4-dimethylaminopyridine (DMAP). An
evaluation of various experimental parameters was performed in
order to derive a more detailed understanding of what renders
this process selective. The catalyst’s aggregation behavior and
anion-binding ability were evaluated in regard to their relevance
for the catalytic process. Alternate scenarios, such as catalyst
deprotonation or the in situ formation of a neutral chiral
acylating reagent were ruled out. Detailed computational studies at the M06/6-31G(d,p) level of theory including solvent
modeling utilizing a polarized continuum model provide additional insights into the nature of the ion pair and reveal a range of
important secondary interactions that are responsible for efficient enantiodiscrimination.
Scheme 1. Anion-Binding Concept for Asymmetric Acyl
Transfer
INTRODUCTION
■
Enantiopure amines are important building blocks with a
plethora of applications.1 While enantioselective methods for
the synthesis of chiral amines continue to be developed at a
rapid pace,1 the classic separation of racemic amines via their
diastereomeric salts remains a frequently used approach,
especially in large scale preparations.2 Although often highly
reliable, a disadvantage of this strategy is that it requires the use
of stoichiometric amounts of chiral acids as resolving
reagents.2,3 An attractive alternative is the use of chiral catalysts
that facilitate the kinetic resolution of racemic amines via
acylation and other methods.4 In contrast to their enzymatic
counterparts,4y,5 the kinetic resolution of racemic amines via
small-molecule-based approaches has remained challenging.
Solutions to this problem have started to appear only recently
and still lag behind the advances that have been achieved in the
corresponding kinetic resolutions of alcohols.4,6 This is at least
in part due the inherent nucleophilicity of amines and their
resulting propensity to react with common acylating reagents
without the need for intervention by a catalyst.
and a chiral anion receptor/hydrogen bonding (HB)
catalyst.11−13 Mixtures of DMAP and various acylating reagents
are known to exist in equilibrium with their corresponding
acylpyridinium salts (e.g., ion pair I).14 These acylpyridinium
salts are rendered chiral upon interaction of the counteranion
with a chiral anion receptor such as a thiourea catalyst to form
ion pair II.15,16 Furthermore, the chiral anion receptor is
thought to impact the equilibrium between DMAP and its
acylpyridinium salt. Ion pair II is expected to be more
electrophilic and/or soluble than ion pair I. Consequently,
reactions with substrates such as amines should more readily
occur with ion pair II than with ion pair I. While the
applicability of this concept to the kinetic resolution of amines
has been demonstrated as mentioned above, questions remain
as to the exact nature of ion pair II and the role of all reaction
We have recently reported a new concept for asymmetric
nucleophilic catalysis and demonstrated its applicability in the
kinetic resolution of various classes of amines,7 the desymmet-
rization of meso-diamines,8 and other asymmetric acyl-transfer
reactions.9 As outlined in Scheme 1, a chiral acylating reagent is
generated in situ via the interplay of three components: 4-
dimethylaminopyridine (DMAP),10 an achiral acylating reagent,
Received: January 7, 2015
© XXXX American Chemical Society
A
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Scheme 2. Evaluation of Catalysts in the Kinetic Resolution of a Benzylic Amine
components in the enantiodetermining step of the reaction. In
fact, it has thus far remained unclear whether a species
corresponding to ion pair II is actually involved in the catalytic
process. Here we report the results of experiments and
computations that shed light on these questions.
unsubstituted phenyl ring. While compound 1g contains the
most electron-deficient aryl ring studied, the low solubility of
this species likely accounts for its poor performance.
Interestingly, simple acetamide 1i performed relatively better
than most of the aryl-amide catalysts. The presence of a free
amide NH-proton was found to be essential, as replacement for
an imide or an N-alkyl amide led to inferior performance (cf.,
1d, 1j, and 1k). Similarly, replacement of amide for the
corresponding amine led to a significant drop in catalyst
efficiency (cf., 1f and 1l). Catalyst 1m, containing both thiourea
and DMAP moieties, was essentially inactive. Thioamide-
thiourea 1n was considered to be a promising candidate for
improved catalysis due to its more acidic NH-proton. However,
1n was found to be inferior to catalyst 1b. This implies an
important role for the amide-carbonyl group which may be
involved in secondary interactions.
Impact of the Acylating Reagent. An evaluation of
various acylating reagents as summarized in Table 1 provides
compelling support for the intermediacy of a type II ion pair
(Scheme 1). Benzoylation with benzoyl fluoride, chloride, or
bromide showed a clear trend favoring the smallest halide while
establishing a strong counteranion effect (Table 1, entries 1−
3). However, these results were inferior to those of benzoic
anhydride (entry 4). Substituted benzoic anhydrides, without
exception, provided poorer results without showing a
discernible trend with regard to electronics (entries 5−9).
Acetyl chloride and acetic anhydride were also tested (entries
10, 11). Although acetic anhydride performed relatively better,
both were inferior to benzoic anhydride. Consistent with the
better leaving group ability of benzoate vs acetate, acylation
with the mixed acetic benzoic anhydride provided exclusively
acetylated product 3g (eq 3). The s-factor was substantially
lower than in the case of benzoic anhydride (6.8 vs 13). In
agreement with the computational results (vide infra), this
observation illustrates not only the importance of the
RESULTS AND DISCUSSION
■
Evaluation of Catalysts. In our original study on the
kinetic resolution of benzylic amines via benzoylation, the
Nagasawa bis-thiourea 1a,17 used in combination with DMAP,
was identified as an effective catalyst system.7a Catalyst loadings
of 20 mol % of each, 1a and DMAP, provided a selectivity
factor (s-factor) of 10 for the benzoylation of racemic 1-
phenylethanamine (not shown).18 To determine which
structural catalyst components are important for efficient
catalysis, a range of potential catalysts was tested in the
resolution of 1-phenylethanamine 2a (Scheme 2). To amplify
potentially subtle differences between the catalysts, reactions
were performed at a 5 mol % catalyst loading, using 0.5 equiv of
benzoic anhydride as the acylating reagent (50% maximum
conversion). All reactions were conducted in the presence of 4
Å molecular sieves at −78 °C in toluene (0.01 M
concentration) and quenched after 2 h. Under these conditions,
1a provided an s-factor of 8.5 (44% conversion). Amide-
thiourea catalyst 1b displayed improved performance (s-factor
= 13 at 41% conversion). Importantly, the presence of DMAP
was found to be crucial. Although 1b displayed catalytic activity
in the absence of DMAP, a significantly reduced s-factor of 1.9
resulted. A 3,5-bis(trifluoromethyl)phenyl thiourea moiety was
found to be a crucial component of any catalyst.19 For instance,
structurally related diamide 1c was completely ineffective. A
comparison of catalysts 1d−f illustrates that the presence of
substituents (in particular electron withdrawing groups) on the
para-position of the aryl-amide ring is preferable to an
B
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a
a
Table 1. Evaluation of Different Acylating Reagents
Table 3. Evaluation of Solvent
entry
acylating reagent
product
conversion (%)
s-factor
entry
solvent
conversion (%)
s-factor
1
PhCOF
3a
3a
3a
3a
3b
3c
3d
3e
3f
34
50
39
41
47
24
50
38
3.6
43
43
3.1
2.4
1.0
13
1
2
3
4
5
6
toluene
hexanes
41
17
50
42
19
38
13
2
PhCOCl
1.0
12
3
PhCOBr
toluene/hexanes (1:1)
4
(PhCO)2O
mesitylene/hexanes (1:1)
5.6
1.5
1.4
5
(4-CF3−PhCO)2O
(4-Br-PhCO)2O
(4-F-PhCO)2O
(4-Me-PhCO)2O
(4-MeO-PhCO)2O
MeCOCl
7.5
1.2
12.9
12.8
4.8
1.4
6.7
EtOAc
MTBE
6
a
7
See footnote in Table 1.
8
9
constant of the reaction medium, a 1:1 mixture of toluene and
hexanes was evaluated. The outcome was nearly identical to
that in neat toluene (entry 3). A 1:1 mixture of toluene and
mesitylene resulted in a markedly reduced s-factor (entry 4).
Neat mesitylene could not be evaluated due to its melting point
of −44.8 °C. As anticipated, the more polar solvents ethyl
acetate (EtOAc, entry 5) and methyl tert-butyl ether (MTBE,
entry 6) provided inferior results.
10
11
3g
3g
(MeCO)2O
a
Reactions were performed on a 0.2 mmol scale. The s-factors were
determined by HPLC analysis; see Supporting Information for details.
Impact of the Catalyst Loading. Upon studying the effect
of catalyst loading on the resolution of 2a (Table 4), we made
a
Table 4. Evaluation of Catalyst Loading
counteranion but also the nature of the substituent on the
acylpyridinium cation.
Impact of the Reaction Temperature. To exclude the
possibility of unusual temperature dependence, the title
reaction was conducted at various temperatures (Table 2). As
anticipated, lower s-factors were obtained upon increasing the
reaction temperature from the optimal −78 to −40 °C.
s-
entry 1b (mol %) DMAP (mol %) time (h) conversion (%) factor
1
2
3
4
10
5
10
5
2
2
4
4
50
41
48
43
8.6
13
a
Table 2. Evaluation of Reaction Temperature
2
2
8.6
5.1
1
1
a
See footnote in Table 1.
the intriguing discovery that a reduction in catalyst loading
from 10 to 5 mol % led to an improvement in s-factor from 8.6
to 13 (entries 1 and 2). While such a phenomenon is not
without precedent,20 it is quite rare to achieve improved
selectivities upon reduction of the catalyst loading. Interest-
ingly, a catalyst loading of 2 mol % provided a nearly identical
result to that obtained with 10 mol % (compare entries 1 and
3). A catalyst loading of 1 mol % led to a further drop in
selectivity although an appreciable level of selectivity was
maintained (entry 4). The trend in going from 5 over 2 to 1
mol % of catalyst loading is readily rationalized by an
increasingly competitive background reaction. On the other
hand, the reduction in s-factor at higher catalyst loadings is
consistent with catalyst aggregation20b,21 (vide infra).
Catalyst Aggregation Behavior. Two sets of single
crystals of catalyst 1b suitable for X-ray crystallography could
be obtained. The first solid-state structure of 1b is depicted in
Figure 1 (crystals obtained by diffusion of hexanes into a
dichloromethane solution of 1b) and is characterized by a
chain-type aggregation with multiple intra- and intermolecular
H-bonding interactions.
entry
temperature (°C)
conversion (%)
s-factor
1
2
3
−78
−60
−40
41
50
50
13
10
7.5
a
See footnote in Table 1.
Impact of the Reaction Medium. Toluene appears to
hold a privileged place in catalytic enantioselective reactions
that proceed via catalyst−substrate ion pairing.15,4m This is
consistent with the notion that the nature of an ion pair
strongly depends on the reaction medium, with nonpolar
solvents favoring tight (contact) ion pairs whereas more polar
solvents result in solvent-shared or solvent-separated ion
pairs.15i Different solvents were evaluated as part of the present
study (Table 3). A reaction performed in hexanes resulted in
poor conversion and no measurable degree of selectivity (entry
2). This is likely attributable to the poor solubility of catalyst 1b
in hexanes, and the increased tendency toward self-association
of polar substrates such as 1b in nonpolar solvents. In an effort
to restore catalyst solubility and still reduce the dielectric
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engaged in NH···S H-bonding interaction with thioureas from
neighboring dimers. The NH-protons of the amide of the
second dimer are involved in NH···O H-bonding interactions
with ethyl acetate.
To determine whether catalyst aggregation also occurs in
solution,22 1H NMR spectra of 1b were recorded at varying
concentrations. This study was initially conducted in CDCl3.
Due to the low solubility of 1b, 0.04 M was the highest possible
concentration at which spectra could be recorded. Figure 3
Figure 1. Aggregation scheme in the crystal structure of 1b,
characterized by a 1D array of molecules arranged in the crystallo-
graphic ac plane. The 1b molecules are oriented left−right across the
page and engage in two distinct and alternating H-bonding motifs
across the page: (A) pairwise NH···O H-bonding interactions to form
a dimer, (B) pairwise NH···S H-bonding interactions to bridge
adjacent dimers. The HNCNH group is in the exo conformation and
allows one intramolecular NH···S interaction. The van der Waals,
vdW, radii used are 1.80, 1.52, and 1.2 Å for S (yellow), O (red), and
H (white), respectively. The C atoms are gray and the N atoms are
blue. For clarity, the H atoms of the cyclohexyl ring are omitted and
the 3,5-bis(trifluoromethyl)phenyl group is depicted by a green ball.
The solid-state structure of 1b as depicted in Figure 2 is
markedly different (crystals obtained in the presence of ethyl
acetate) in that it contains two slightly different catalyst dimers.
Catalyst dimerization occurs via bifurcated hydrogen bonding
of both thiourea NH-protons with the amide carbonyl group of
a second molecule. Two such interactions are present in each
dimer. In one type of dimer, the NH-protons of the amide are
Figure 3. Graphical representation of chemical shift dependence of
NH-protons of catalyst 1b in CDCl3. A more limited dilution study of
catalyst 1b was also performed in toluene, the solvent used in the
reaction. Here the signal corresponding to the NH1-proton was not
readily observable.23
shows the dependence of the concentration on the chemical
shift of the three different types of NH-protons. Upon
decreasing the concentration of 1b, the NH1 and NH2
thiourea protons experience a significant upfield shift. An
upfield shift is also observed for the NH3 proton, albeit to a
much lesser extent. These observations are consistent with
aggregation via H-bonding at higher concentrations, and a
significant degree of deaggregation at lower concentrations.19
Interestingly, the NH3 proton does not appear to be involved
directly (via HB) in the aggregation process which points to
isolated catalyst dimers (cf., dimers in Figure 2).
With regard to the aggregation behavior of the Nagasawa
catalyst (1a), Eckert-Maksic, Friscic, and co-workers have
́ ̌ ̌ ́
previously obtained an X-ray crystal structure of 1a·2(i-
PrOH).24 For comparison purposes, this structure is shown
in Figure 4. Its main characteristic is the presence of bifurcated
H bonds of both thiourea NH-protons with the thiourea sulfur
atom of a neighboring bisthiourea molecule.
1
We also studied the aggregation behavior of 1a by H NMR
(Figure 5). Due to partial overlap of NH-signals with aromatic
protons in deuterated toluene, C6D6 was selected for this study.
Similar to what was seen for 1b, both types of thiourea protons
of 1a experience an upfield shift upon lowering of the solvent
molarity. The magnitude of this shift was found to be roughly
equal for NH1 and NH2 and is consistent with the type of
aggregation observed in the solid state (cf., Figure 4). The
corresponding study in CDCl3 provided a similar result.23
Importantly, these studies indicate that the catalysts should
exist largely in their nonaggregated forms at the concentrations
Figure 2. Aggregation scheme in the crystal structure of 1b·EtOAc,
characterized by a 1D array of molecules arranged in the crystallo-
graphic ab plane. The vdW radii and atom and 3,5-bis-
(trifluoromethyl)phenyl group representations are as in Figure 1
D
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solution containing 1a, triethylamine, and benzoic acid in a
1:1:1 ratio. The resulting X-ray crystal structure is shown in
Figure 6.
Figure 4. Aggregation scheme in the crystal structure of 1a·2(i-
PrOH),24 characterized by a 1D array of molecules arranged along the
crystallographic b axis with adjacent 1a molecules oriented in a head-
up/head-down fashion, so that both S atoms can accept H-bonds: one
from one HNCNH group of an adjacent molecule of 1a, and one from
the first i-PrOH solvate. The other HNCNH group of the molecule
terminates connectivity through H-bonding to the second unique i-
PrOH solvate. Because of the involvement of two unique i-PrOH
molecules, the overall motif is that of a 1D polymeric array. The vdW
radii and atom and 3,5-bis(trifluoromethyl)phenyl group representa-
tions are as in Figure 1
Figure 6. Aggregation scheme in the crystal structure of the
+
−
triethylammonium benzoate cocrystal of (1a)2·(HNEt3 PhCO2 ),
characterized by a 2D array of molecules arranged in the crystallo-
graphic ab plane. The 1a molecules are oriented up−down across the
page and engage in HNCNH···S H-bonding as in the bis-2-propanol
solvate of 1a (Figure 4). Contrasting the motif in Figure 4: (A) the
two O atoms of the benzoate ion act as acceptors for three H-bonds
each, bridging one linear array of 1a molecules to the adjacent ones in
the b axis direction, and (B) one of the two S atoms per 1a molecule
does not engage in H-bonding. The vdW radii and atom and 3,5-
bis(trifluoromethyl)phenyl group representations are as in Figure 1.
Catalyst/anion interactions were also studied in solution and
1
monitored by H NMR. The results of the titration of 1b with
tetrabutylammonium benzoate (TBAB) are shown in Figure 7.
A substantial shift was seen for all three NH-signals upon
increasing the mole fraction of benzoate. However, the NH-
signals of the thiourea functionality (NH1 and NH2)
experienced a more substantial downfield shift than that of
NH3. This is consistent with the results obtained from the
computational analysis (vide infra), which suggest intra-
molecular hydrogen bonding of NH3 to the thiourea sulfur
atom, but no direct involvement of NH3 in anion binding. The
data indicate 1:1 binding of the catalyst to the benzoate anion
based on the observation that the chemical shifts for all three
NH’s remains nearly constant upon reaching a mole ratio of
one. A 1:1 binding stoichiometry was confirmed via a UV−vis
titration and Job plot analysis.23 A related study with
tetrabutylammonium acetate provided qualitatively similar
results.23
Figure 5. Graphical representation of chemical shift dependence of
NH-protons of catalyst 1a in C6D6.
relevant for catalysis. It should be noted that in a related study
by Miller et al. on the kinetic resolution of alcohols with a
peptide catalyst, poorer catalyst performance at higher than
optimal concentrations was attributed in part to catalyst
aggregation.25
Catalyst Anion Binding. Numerous attempts were under-
taken to cocrystallize catalysts 1a and 1b with various
carboxylate or acylpyridinium salts in order to obtain insights
into how these species interact.26 While these efforts met with
limited success, X-ray quality crystals were obtained from a
Catalyst Deprotonation Study. In light of recent thiourea
deprotonation studies,27 it appeared plausible that different
types of ion pairs could play a role in the resolution process
(Scheme 3). Given the presence of relatively basic substrates,
deprotonation of the proposed ion pair 4 could result in
alternate ion pair 5. To determine the likelihood of 5 being
E
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(Figure 8). Again, significant spectral changes were observed,
consistent with the deprotonation of the thiourea moiety. In
particular, the downfield shift of C6 and the upfield shift of C9
support this notion. Considering that strongly basic conditions
are required for the deprotonation of 1b and that its pKa value
is approximately 17−18,27b we rule out the involvement of the
conjugate base of 1b in the catalytic process.
Acylation of the Catalyst. Upon studying potential
interactions between catalyst 1b with DMAP and benzoic
anhydride, we observed the slow benzoylation of 1b at room
temperature to give 6 (Scheme 4). Since 6 could conceivably
Scheme 4. Acylation of 1b
Figure 7. Graphical representation of chemical shift dependence of
NH-protons on the mole ratio of TBAB/1b in CDCl3.
Scheme 3. Different Ion Pairs of Potential Relevance
act as a chiral acylating reagent, we decided to evaluate its
potential role in the catalytic cycle. Thus, 6 was used in place of
catalyst 1b in the kinetic resolution of 2a under standard
conditions (eq 7). Less than five percent conversion was
observed, which can be attributed to background reactivity.
Consequently, neutral acylating reagents such as 6 appear to
play no role in the catalytic cycle.
involved in the catalytic process, 1b was exposed to a number
of different bases, including triethylamine, DMAP, Hunig’s
̈
base, and 1-phenylethanamine. While in some cases the
apparent disappearance of one of the thiourea NH-signals in
COMPUTATIONAL METHODS
■
1
the H NMR was noted, virtually no change was observed in
We employed the M06 density functional28 in conjunction with
a double-ζ basis set [6-31G(d,p)], a level of theory which has
proven to be quite suitable for the description of ion pairs and
hydrogen binding interactions owing to the inclusion of
medium-range correlation effects.19 Interaction energies are
not corrected for basis set superposition errors because this
often leads to overcorrections.29 All stationary structures were
characterized by computing analytical second derivatives to
define minima (number of imaginary frequencies = 0) on the
respective potential energy hypersurface and to compute zero-
the corresponding 13C and 19F NMR spectra. Since significant
changes in the 13C NMR were observed upon deprotonation of
1,3-bis(3,5-bis(trifluoromethyl)phenyl)thiourea,27 we conclude
1
that the observed changes in the H NMR spectra are due to
hydrogen bonding and/or a fast exchange process.
When the stronger base BEMP was added to a solution of 1b
in deuterated toluene, a significant change in the 13C NMR
spectrum was noted. Due to the poor solubility of 1b in
toluene, an identical experiment was performed in THF-d8
Figure 8. Changes in the 13C NMR of 1b in THF-d8 upon addition of 2 equiv of BEMP.
F
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Figure 9. Overview of the lowest-lying complexes and conformers of 2 computed at the M06/6-31G(d,p) level of theory. Energies are given in kcal
mol−1; distances are given in Å. Values in parentheses were computed with the PCM model for toluene, employing UAHF radii.
Figure 10. Overview of the lowest-lying quaternary complexes computed at the M06/6-31G(d,p) level. Energies are given in kcal mol−1; distances
are given in Å. Values in parentheses were computed with the PCM model for toluene, employing UAHF radii. Despite numerous attempts, the
PCM computations did not converge for 1a·DMAP·benzoic anhydride (S)-2a.
point vibrational energy (ZPVE) differences. Solvent effects
were included using the polarized-continuum model (PCM)
within the self-consistent reaction-field (SCRF) model by
optimizing the stationary structures in a particular solvent, and
frequency computations for the determination of solvent effects
were also performed using the M06/6-31G(d,p) method using
a self-consistent reaction-field (SCRF) model.30 The PCM used
the United Atom Topological (UAHF) Model applied on radii
optimized at the HF/6-31G(d) level of theory.30b,31 All ΔH0
values are ZPVE-corrected. We utilized the Gaussian09
program package for all computations.32 All structures were
visualized with CYLview.33
Computations and Comparisons with 2D-NMR Ex-
periments. We computed a large series of ion pair
configurations for benzoic anhydride interacting with DMAP
(Figure 9). The lowest-lying complex corresponds to a
pyridinium salt with the benzoate and benzoyl rings on the
pyridine’s nitrogen on the same side. The dissociation energies
of the complex are substantial and negative at rt as well as at
195 K. Thus, the formation of the DMAP salt with benzoic
anhydride is likely to be unfavorable14f as also evident from the
absence of NOE signals in toluene-d8 at rt; however, this could
also be due to long proton−proton distances and fast exchange.
DOSY NMR-spectroscopy also did not reveal evidence of ion
pair formation.34
The lowest-lying conformer of Nagasawa’s catalyst 1a17a
(Figure 9) displays Z,Z- and Z,E-orientations of the NH-bonds
of the two thiourea moieties. The preferred conformation in
solution remains difficult to determine due to the inseparability
1
of the NH and o-protons in the H NMR-spectra. The lowest-
lying ternary complex shows a clear preference for complex
formation of the bis(thiourea) with the DMAP salt in 1a·
DMAP·benzoic anhydride (Figure 9): The Z,Z-oriented NH
protons of one thiourea moiety coordinate through double
hydrogen-bonding to the oxygen of benzoate. The acidified o-
proton of the thiourea’s aryl-ring also coordinates to oxygen,19
while the second thiourea motif binds to the sulfur atom of the
other thiourea moiety. Additionally, the oxygens coordinate to
the phenyl protons of DMAP in ortho- and para-positions. The
benzoyl group is stereochemically fixed through π−π stacking
with one of the thiourea aryl rings. The 1a·DMAP·benzoic
anhydride complex is favored at lower temperatures because of
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Figure 11. Conformer 1b and the lowest-lying ternary complex of 1b·DMAP·benzoic anhydride computed at the M06/6-31G(d,p) level. Energies
are given in kcal mol−1; distances are given in Å. Values in parentheses were computed with PCM model for toluene, employing UAHF radii.
a positive dissociation energy D195 = +10.4 kcal mol−1 (D195
=
Of course, it would be highly desirable to actually determine
the transition structures for these reactions, but this is currently
technically not possible owing to the enormous number of
possible configurations of the various complexes, especially
when considering their large number of rotational degrees.
+3.6 kcal mol−1 in solution). The analysis of the 2D-NMR
spectra of these ternary complexes was complicated by the
1
appearance of new signals. A H, 15N HSQC spectrum (60.8
MHz) of complex 1a·DMAP·benzoic anhydride (each com-
pound c = 10 mM) in toluene-d8 at 298 K) revealed no signals
for the N−H bonds probably due to fast exchange.
CONCLUSIONS
Adding the (R)-configured amine (Figure 10), the lowest-
lying quaternary complex 1a·DMAP·benzoic anhydride (R)-2a
displays Z,Z-oriented NH-protons; one thiourea moiety
coordinates to benzoate through double hydrogen-bonding.
The second thiourea function coordinates to the first thiourea
moiety also through double hydrogen-bonding. At the same
time, benzoate binds to the o- and p-protons of the pyridinium
cation, which now prefers an orientation that is opposite to that
of 1a·DMAP·benzoic anhydride. The alternative orientation
allows 3-fold π−π stacking of one thiourea aryl, DMAP’s
pyridine, and the phenylethylamine ring. This quaternary
complex structurally precedes the transfer of the benzoyl group
in the transition state. The computations show that the
■
Examination of multiple reaction parameters in the kinetic
resolution of a benzylic amine via benzoylation has provided
important insights into the mechanism of this transformation.
The catalyst pair, consisting of a bis-thiourea (or an amide-
thiourea) catalyst and DMAP, upon interaction with benzoic
anhydride, forms a chiral ion pair that acts as the acyl-transfer
reagent. A key feature of this ion pair is the binding of a catalyst
thiourea subunit to the benzoate counteranion of the DMAP-
derived N-benzoylpyridinium salt. This notion is corroborated
by the demonstrated ability of the catalyst to bind benzoate in
1:1 fashion. The potential involvement of neutral chiral
acylating reagents or alternative ion pairs (e.g., those resulting
from deprotonation of the thiourea catalyst) were ruled out.
Catalyst aggregation, as observed in the solid state and in
solution, is responsible, at least in part, for the fact that reduced
catalyst loadings provide better selectivities in some instances.
Computational investigations provided detailed insights into
the nature of the chiral ion pairs. In addition, evaluation of the
two diastereomeric quaternary complexes helped rationalize the
experimental observation that the R-enantiomer of 1-phenyl-
ethanamine is benzoylated preferentially over the correspond-
ing S-enantiomer. Interestingly, for both the bis-thiourea and
the amide-thiourea catalyst, dual intramolecular hydrogen
bonding to the sulfur atom of a thiourea subunit was found
to activate this moiety for anion binding via acidification of the
two N−H bonds. While the closely related intramolecular
activation of a thiourea by another urea unit has already been
exploited by others,35 our results suggest that this mode of
activation may be more prevalent than previously considered
and could in fact become an important design element in the
development of new organocatalysts.
quaternary complex is more favored at 195 K as at rt (D195
=
19.0 kcal mol−1 vs D298 = 3.1 kcal mol−1 in gas phase). With the
(S)-configured amine, the quaternary complex is energetically
less favorable.
In contrast to 1a, catalyst 1b, which bears a thiourea and an
amide function, prefers both in the gas phase and in toluene an
E,Z-orientation of the thiourea moiety (Figure 11). The lowest
lying ternary complex 1b·DMAP·benzoic anhydride contains a
Z,Z-oriented thiourea moiety, which binds to the oxygens of
benzoate with its acidified o-proton in a double hydrogen-
bonding fashion (Figure 11). Simultaneously, the amide
function binds through the NH-bond to the sulfur atom of
the thiourea moiety. Benzoate coordinates with the oxygens to
the o-proton of DMAP’s pyridine ring, and the two aryl groups
of the catalyst stereochemically fix DMAP and the benzoyl
moiety. The dissociation energy is negative at rt but positive at
195 K (+12.6 kcal mol−1 in the gas phase and +5.2 kcal mol−1
in toluene).
The computations thus reveal that the quaternary complexes
configured (R) in the amine, which are likely to precede the
corresponding transition structures, are energetically favored,
which is in excellent agreement with the experimental findings.
H
DOI: 10.1021/jacs.5b00190
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
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ASSOCIATED CONTENT
* Supporting Information
EExperimental procedures, characterization data, and CIF files.
Cartesian coordinates, energies, and thermodynamic correc-
tions for all calculated structures. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
*prs@org.chemie.uni-giessen.de.
*seidel@rutchem.rutgers.edu.
Notes
■
The authors declare no competing financial interest.
(5) Selected reviews on enzymatic amine acylation: (a) Hohne, M.;
̈
Bornscheuer, U. T. ChemCatChem. 2009, 1, 42. (b) Turner, N. J. Nat.
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Opin. Drug Discovery Dev. 2009, 12, 784. (d) Lee, J. H.; Han, K.; Kim,
M.-J.; Park, J. Eur. J. Org. Chem. 2010, 999.
ACKNOWLEDGMENTS
■
This material is based upon work supported by the National
Science Foundation under grant no. CHE-1300382 to D.S. D.S.
is grateful to the Alexander-von-Humboldt-Foundation for a
research fellowship for experienced researchers. We thank Mr.
Chenfei Zhao (Rutgers University) for performing a number of
experiments for Table 1.
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DOI: 10.1021/jacs.5b00190
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