Crystal structures and chiral recognition of the diastereomeric salts prepared from 2-methoxy-2-(1-naphthyl)propanoic acid

Article abstract of DOI:10.1039/c1ce05155e

This paper is the first to report the structures of crystalline diastereomeric salts 8 and 9 prepared from (R)-2-methoxy-2-(1-naphthyl)propanoic acid [(R)-MαNP acid, (R)-1] and (S)-1 with (R)-1-phenylethylamine [(R)-PEA, (R)-7], respectively. These crysta

Full text of DOI:10.1039/c1ce05155e

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PAPER
Crystal structures and chiral recognition of the diastereomeric salts prepared
from 2-methoxy-2-(1-naphthyl)propanoic acid†
a
Akio Ichikawa, Hiroshi Ono,b Takuya Echigo‡c and Yuji Mikatad
*
Received 1st February 2011, Accepted 25th March 2011
DOI: 10.1039/c1ce05155e
This paper is the first to report the structures of crystalline diastereomeric salts 8 and 9 prepared from
(R)-2-methoxy-2-(1-naphthyl)propanoic acid [(R)-MaNP acid, (R)-1] and (S)-1 with (R)-1-
phenylethylamine [(R)-PEA, (R)-7], respectively. These crystal structures helped elucidate a novel chiral
recognition mechanism characteristic of MaNP salts. The less-soluble diastereomeric salt 8 prepared
from (R)-1 and (R)-7 formed an ammonium–carboxylate ion pair by means of a methoxy-assisted salt
bridge and an aromatic CH/p interaction. The more-soluble diastereomeric salt 9 prepared from (S)-1
and (R)-7 formed an ion pair by a methoxy-assisted salt bridge in which the 1-naphthyl and phenyl
groups did not overlap. Instead, salt 9 formed a close ion pair by means of a salt bridge, a CH/O
hydrogen bond, and a p/p interaction. These crystal structures suggest that the molecular length from
the MaNP plane containing the carboxy and methoxy groups is critical to the crystallisation of
diastereomeric salts. The crystal packing in both salts was investigated with regard to the weak
interactions (i.e., salt bridges, NH/O and CH/O hydrogen bonds, and aromatic CH/p, CH/p,
and p/p interactions). Finally, diastereomeric amides 11 and 12 were prepared from (S)-2-methoxy-2-
(2-naphthyl)propanoic acid [(S)-MbNP acid, (S)-2] and (R)-2 with (S)-1-(1-naphthyl)ethylamine [(S)-
10]. The solution-phase structures of the MbNP amides, and their separation, was investigated by
NMR spectroscopy and high-performance liquid chromatography (HPLC). The less-stereochemically
demanding and longer 2-naphthyl group made the MbNP amide more flexible and less polar than the
MaNP amide. Acid 2 was more efficient than acid 1 in separating amides 11 and 12.
3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid (MTPA, 4),5
Introduction
while the analytical properties of acid 3 were slightly superior to
2-Aryl-2-methoxypropanoic acids [e.g., MaNP acid, 1; MbNP
those of 1.6 Prior to these studies, Riguera et al.7 and Kusumi
acid, 2; and 2-methoxy-2-(9-phenanthryl)propanoic acid, M9PP
et al.8 independently developed the important chiral resolving
acid, 3] are powerful chiral resolving agents whose diastereo-
agent 2-methoxy-2-(2-naphthyl)acetic acid (2NMA, 5).
meric esters can be used to rapidly resolve biofunctional mole-
Recently, the high crystallinity of 2-aryl-2-methoxypropanoic
1
cules and to elucidate stereochemistry by H NMR anisotropy
acids 1–3 and their derivatives was demonstrated.1,3,9–11 These
(Fig. 1).1–4 For these purposes, acid 1 was superior to Mosher’s
properties make acids 1–3 useful as stereochemical internal
standards for X-ray crystallography, which is considered the
most reliable method for elucidating stereochemistry.1
A
aDivision of Insect Sciences, National Institute of Agrobiological Sciences,
1-2 Owashi, Tsukuba, Ibaraki, 305-8634, Japan. E-mail: ichikawa@affrc.
go.jp
bAnalytical Science Division, National Food Research Institute, 2-1-12
Kannondai, Tsukuba, Ibaraki, 305-8642, Japan
cPost-harvest Science and Technology Division, Japan International
Research Center for Agricultural Sciences, 1-1 Owashi, Tsukuba,
Ibaraki, 305-8686, Japan
dKYOUSEI Science Center for Life and Nature, Nara Women’s
University, Nara, 630-8506, Japan
herringbone motif12,13 was observed in both crystalline (S)-3 and
a diastereomeric amide derived from (R)-1 and (S)-10.11 This
motif suggests that aromatic CH/p interactions played an
important role in the crystallisation. In addition, the molecular
lengths of the acid and alcohol moieties from the MaNP plane
were critical in the crystallisation of both the diastereomeric
MaNP esters10 and the MaNP amide.11
Fig. 2 shows the conformations of 2-aryl-2-methoxypropanoic
acid and its derivatives as elucidated by X-ray crystallography
and NMR spectroscopy. In crystalline (S)-3, the hydroxy and
carbonyl groups were syn, as were the carbonyl and methoxy
groups. The aromatic hydrogen atom at the 10-position and the
methyl group were also syn.11 The carboxy groups of (S)-3
† Electronic supplementary information (ESI) available. CCDC
reference numbers 801460, 801461, 807172, 807173, 813345 and
813714. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c1ce05155e
‡ Present address of T. Echigo: Environment and Energy Materials
Research Division, National Institute for Materials Science, 1-1 Namiki,
Tsukuba, Ibaraki 305-0044, Japan
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Fig. 1 Structures of chiral resolving agents and their derivatives.
formed a chain-like motif called a catemer.14 A similar structure
was observed in crystalline (S)-1.9
analyses suggested that this conformation was also predominant
when the compounds were dissolved in chloroform-d. Large
high-field shifts were observed at the alcohol substituent R1. The
more polar diastereomeric MaNP ester, in which the larger and
more hydrophobic substituent overlapped the 1-naphthyl group,
yielded crystals.10
The crystalline conformation of the (S)-MaNP ester was
similar to those of acids (S)-1 and (S)-3 as follows (Fig. 2).3,9–11
The methine group of the alcohol moiety and the carbonyl group
were syn. The carbonyl and methoxy groups were also syn,
forming the MaNP plane, and the methyl group and the
X-Ray crystallographic data and NMR spectra of the (R)-
MaNP amide3,11 suggested that the methine group of the amine
1
aromatic hydrogen atom at the 2-position were syn. H NMR
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Fig. 2 Conformations of 2-aryl-2-methoxypropanoic acid and derivatives.
moiety and the carbonyl group were syn, while the carbonyl and
the methoxy groups were anti (Fig. 2). In addition, the methyl
group of the MaNP moiety and the aromatic hydrogen atom at
the 2-position were syn. Smaller or even irregular Dd values were
aromatic hydrogen atom at the 2-position were syn, indicating
the strict conformational requirement of 1-naphthyl group.
The less-soluble diastereomeric salt 8 formed an ammonium–
carboxylate ion pair by a methoxy-assisted salt bridge and an
aromatic CH/p interaction22–25 acting as supramolecular syn-
thons22 [Fig. 3 and 4 (A)]. The MaNP anion and the ammonium
ion acted as a proton acceptor and donor (or electron donor and
acceptor), respectively.26 A methoxy-assisted salt bridge was also
observed in salt 9. However, the naphthyl and phenyl groups of
the ion pair did not overlap [Fig. 4 (B)]. Instead, salt 9 formed
another ammonium–carboxylate ion pair by means of a normal
salt bridge, a CH/O hydrogen bond, and a p/p interaction
[Fig. 4 (C)].
1
observed in the H NMR spectra of the MaNP amides.11
In 1978, Goto et al. synthesised (R)-1 and (R)-2 with (R)-7 via
diastereomeric salt formation, and applied them to the enan-
tioresolution of amino acid methyl esters.15 Nevertheless, the
crystal structures of the MaNP and MbNP salts and the chiral
recognition mechanisms of the crystals have yet to be clarified.
Diastereomeric salt formation is a metal-free process that also
serves to remove contaminants.16 More than half of all chiral
pharmaceuticals have been estimated to be produced by the
crystallisation of diastereomeric salts.17 Saigo elucidated a chiral
recognition mechanism during preferential and diastereomeric
crystallisations and applied the process to the preparation of
enantiopure compounds.18,19 Several natural and synthetic acids
have been used as chiral resolving agents in the enantioresolution
of amines by forming the diastereomeric salts.20 Among them,
mandelic acid 6 is one of the most important chiral resolving
agents.16,20,21
The crystal packing of salts 8 and 9 was also investigated with
regard to the weak interactions (i.e., salt bridges, NH/O and
CH/O hydrogen bonds, and aromatic CH/p, CH/p, and
p/p interactions).27–29 The identification of these weak inter-
molecular interactions in the crystals will be useful in under-
standing ligand–receptor interactions in biofunctional molecules
and can be used toward the rational design of agrochemicals and
pharmaceuticals.
Acids 1–3 possess non-racemisable chiral centres and relatively
large aromatic groups. These properties make them useful for
large-scale preparations of single-enantiomer biofunctional
molecules, agrochemicals, and pharmaceuticals using the dia-
stereomeric salt formation method. For this reason, the eluci-
dation of chiral recognition mechanisms is important for the
crystal engineering12–14 of diasteremeric salts prepared from acids
1–3.
Unlike acids 1 and 3, many of the analytical properties of acid
23,15,30,31 have not been characterised. For this reason, solution-
phase structures of diastereomeric MbNP amides 11 and 12 were
determined by two-dimensional NMR analyses. The 2-naphthyl
group of acid 2 was stereochemically less demanding and longer
In both the crystalline MaNP salts [i.e., the less-soluble dia-
stereomeric salt 8, prepared from (R)-1 and (R)-7;15 and the
more-soluble diastereomeric salt 9, prepared from (S)-1 and (R)-
7], the conformation of the MaNP anion was similar to those of
MaNP acid and its esters as follows (Fig. 2). The three oxygen
atoms of the caboxylato (–COOꢀ) and methoxy groups were
almost in the MaNP plane, and the methyl group and the
Fig. 3 Methoxy-assisted salt bridge as a supramolecular synthon.
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Fig. 4 Chiral recognitions in salts 8 and 9.
than the 1-naphthyl group of acid 1. Therefore, the conformation
of the MbNP moiety was more flexible than the MaNP moiety
(Fig. 2): the methyl group was syn to the aromatic hydrogen
atoms at the 1- and 3-positions of the conformers L and M,
respectively. In addition, MbNP amides 11 and 12 were less polar
than the corresponding MaNP amides,11 and yielded a higher-
The conformation of the (R)-MaNP anion was similar to those
of (R)-1 and the (R)-MaNP ester. Table 2 shows the dihedral
angles, interatomic distances, and interatomic angles of salt 8.
The three oxygen atoms of the carboxylato and methoxy groups
were almost in the MaNP plane. The dihedral angles O1–C1–
C2–O3 and C4–O3–C2–C1 were ꢀ27.17(19)ꢁ and +177.82(14)ꢁ,
respectively. The methyl group was in the aromatic plane with
the dihedral angle C3–C2–C5–C6 ¼ ꢀ0.1(2)ꢁ. As already
reported for the MaNP esters,9,10 short distances were observed
between the aromatic hydrogen atom H13 and the carboxylate
1
resolution separation in normal-phase HPLC.3 The H NMR
anisotropy method, which can be used to assign relative stereo-
chemistry, was applied to amides 11 and 12.
ꢀ
oxygen atom O1 [d1 ¼ 2.875(19) A], and between H13 and the
Results and discussion
methoxy oxygen atom O3 [d2 ¼ 2.43(3) A].33 For this reason, the
ꢀ
ammonium group was slightly offset from the MaNP plane
[Fig. 4 (A)]. The same was true for salt 9 [Fig. 4 (B)]. In the PEA
cation, the dihedral angle C16–C15–C17–C18 was ꢀ66.64(19)ꢁ.
Recently, He et al. reported the crystal structures of diastereo-
meric salts prepared from chlorine-substituted mandelic acid
and (R)-7.32
Crystal conformation of the less-soluble diastereomeric salt 8
Salt 815 was prepared from (R)-1 and (R)-7 and was recrystallised
from a mixture of methanol and chloroform. Table 1 and Fig. 5
show the crystallographic data and the ORTEP drawing of salt 8.
Salt 8 crystallised in the monoclinic space group P21 with two
sets of molecules in a unit cell.
Desiraju introduced the concept of supramolecular synthons,22
which are the common spatial arrangements of intermolecular
interactions in crystals. In crystalline salt 8, the ammonium–
carboxylate ion pair was formed by supramolecular synthons
Table 1 X-Ray crystallographic data for salts 8 and 9
Compound
8
9
Molecular formula
Formula weight
Crystal system
Space group
Z
C22H25NO3
351.44
Monoclinic
P21
C22H25NO3
351.44
Monoclinic
P21
2
2
ꢀ
a/A
11.3857(9)
6.7698(3)
12.7237(9)
103.730(4)
952.70(11)
1.225
9.3455(7)
6.7383(4)
14.6868(12)
101.529(4)
906.21(12)
1.288
ꢀ
b/A
ꢀ
c/A
b/ꢁ
ꢀ
V/A
3
Dcalculated
m/cmꢀ1
0.809
55.0
0.850
55.0
ꢁ
2qmax
/
Temperature/K
No. of reflections collected
No. of reflections unique
Rint
No. of parameters
Final R1 (I > 2q(I))a
wR2 (all data)b
123
7339
4296
0.014
336
0.0403
0.0991
1.130
ꢀ0.4(10)
123
7051
4082
0.022
336
0.0494
0.1220
1.089
ꢀ0.3(13)
GOF
Flack parameter
a
b
R1 ¼ (SkFo| ꢀ |Fck)/(S|Fo|). wR2 ¼ {[Sw(Fo ꢀ Fc )2]/[Sw(Fo2)2]}1/2
.
2
2
Fig. 5 ORTEP drawing of salt 8.
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ꢀ
Table 2 Dihedral angles, interatomic distances, and interatomic angles
of crystalline 8a
between H25 and the methoxy oxygen atom O3 [d4 ¼ 2.30(3) A]
were relatively short.26,33 The multipoint recognition of func-
tional groups is expected to improve synthon robustness.22
Similar bifurcated hydrogen bonds have been observed in crys-
talline (S)-1, (RS)-1 and (S)-3.9,11 The aromatic hydrogen atom
H13 of the naphthyl group was almost above the neighbouring
ꢀ
phenyl plane [d5 ¼ 3.15(2) A]. This distance suggests contribution
of an aromatic CH/p interaction.29,33
Kobayashi and Saigo reported that the characteristics of
aromatic CH/p interactions in bulk crystals resemble
a conventional hydrogen bond with regard to co-operativity, the
polarisation of the bond, and the shortened interaction
distance.19 Recently, Headen et al. considered the p/p inter-
actions in aromatic liquids. They found that neighbouring
aromatic rings are predominantly perpendicular when the
ꢀ
distance between their centres is large (>5 A) and that two H
atoms per molecule are directed toward the acceptor’s p orbitals
in a Y-shaped configuration.23 They further reported a prefer-
ence for parallel p/p contacts at smaller molecular separations
23
ꢀ
(<5 A).
Sakai et al. introduced the concept of a space filler.16 They
found that the diastereomeric salt formation method was most
successful when the chiral resolving agent and the racemic
substrate had the same molecular length (i.e., the same number of
bonds between the most distant carbon atom and the carboxy or
amino groups). Considering the role of the methoxy group, the
MaNP anion was five bond lengths from the MaNP plane. The
identical distance was observed in the PEA cation [Fig. 4 (A)].
For this reason, salt 8 crystallised without any space fillers such
as water or methanol.
As discussed above, the methoxy-assisted salt bridge and
aromatic CH/p interactions play an important role in the chiral
recognition of crystalline salt 8.
Crystal packing of the less-soluble diastereomeric salt 8
Dihedral angle (ꢁ)
Fig. 6 (A) shows the crystal packing of salt 8 as viewed along
the a-axis. Fig. 6 (B) displays the homoaromatic CH/p inter-
actions. The distances between H10 and H11 of the naphthyl
ꢀ
group and the neighbouring naphthyl group were 2.4 A and 3.1
ꢀ
A, respectively. Similar relationships were observed in the PEA
O1–C1–C2–O3
C4–O3–C2–C1
C3–C2–C5–C6
C16–C15–C17–C18
ꢀ27.17(19)
+177.82(14)
ꢀ0.1(2)
ꢀ66.64(19)
ꢀ
Interatomic distance (A)
H13/O1 (¼ d1)
H13/O3 (¼ d2)
H25/O1 (¼ d3)
H25/O3 (¼ d4)
H13/p (¼ d5)
2.875(19)
2.43(3)
2.02(3)
2.30(3)
3.15(2)
anions in which the distance between H21 of the phenyl group
ꢀ
and the neighbouring phenyl group was 3.3 A [Fig. 6 (C)].
Tsuzuki et al. reported that the major source of attraction in
benzene dimers is long-range interactions.25 However, the
distances observed here suggest that CH/p interactions
between phenyl groups were weaker than those between naph-
thyl groups.33
Interatomic angle (ꢁ)
C12–H13/O1
142.0(17)
116.5(16)
161(2)
C12–H13/O3
N1–H25/O1
N1–H25/O3
125.1(19)
In addition, the methoxy group of the MaNP anion, and the
methyl group of the PEA cation, helped stabilise the crystal
structure through intermolecular CH/p interactions. The
distances between H4 and H5 of the methoxy group and the
a
ꢀ
The van der Waals radii (A): C, 1.70; H, 1.20; O, 1.52; the half-thickness
of aromatic ring, 1.77.
ꢀ
neighbouring naphthyl group were 2.9 A and 2.7 A, respectively
ꢀ
[Fig. 6 (B)], while the distance between H15 of the methyl group
ꢀ
and the phenyl group of the neighbouring PEA cation was 3.0 A
consisting of a methoxy-assisted salt bridge26 (Fig. 3) and an
aromatic CH/p interaction.28,29 As shown in Table 2, the
interatomic distances between the ammonium hydrogen atom
[Fig. 6 (C)]. Note that the methoxy group allows stacking of the
MaNP anions by acting as an internal space filler.
Fig. 6 (D) shows that salt 6 forms a polar column19,32 facili-
tated by salt bridges and hydrogen bonds (i.e., NH/O–CH3)
ꢀ
H25 and the carboxylate oxygen atom O1 [d3 ¼ 2.02(3) A] and
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ꢀ
Fig. 6 The crystal packing of salt 8 as viewed along the a-axis. The assigned numbers are distances between atoms or moieties (A).
that act as supramolecular cement.26 In addition to the methoxy-
assisted salt bridge (see above), conventional salt bridges were
observed between the ammonium and carboxylato groups: both
the interatomic distances between H23/O1 and H24/O2 were 1.87
2.88(3) A and 2.85(3) A, respectively. It is probable that these
heteroaromatic CH/p interactions between the naphthyl and
phenyl groups contributed to the crystal packing of salt 8.
ꢀ
ꢀ
ꢀ
(3) A. A CH/O interaction was observed between H17, the
hydrogen atom in the methyl group of PEA cation and the
Crystal conformation of the more-soluble diastereomeric salt 9
neighbouring carboxylate oxygen atom O1 at a distance of 2.39
ꢀ
Salt 9 was prepared from (S)-1 and (R)-7 and was recrystallised
from a mixture of methanol and chloroform. Table 1 and Fig. 8
show the crystallographic data and the ORTEP drawing of salt 9,
respectively. Salt 9 crystallised in the monoclinic space group P21
with two sets of molecules in a unit cell. This is the first prepa-
ration of the more-soluble diastereomeric salt 9.
(3) A. Furthermore, a CH/p interaction was observed between
H14, the hydrogen atom attached to the chiral centre of PEA
cation and the neighbouring naphthyl group at a distance of
ꢀ
2.9 A.
A herringbone motif was again observed in the crystal packing
when viewed along the c-axis (Fig. 7). Although the aromatic
hydrogen atoms were not located closely above the aromatic
moieties, the short contacts were observed in addition to those
noted above: the distances between H12/C21 and H19/C6 were
The dihedral angles, interatomic distances, and interatomic
angles of salt 9 are shown in Table 3. The carboxylato and
methoxy groups of salt 9 were in the MaNP plane: the dihedral
angles O1–C1–C2–O3 and C4–O3–C2–C1 were +16.3(3)ꢁ and
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ꢀ
Fig. 7 Crystal packing of salt 8 as viewed along the c-axis. The assigned numbers are distances between atoms (A).
26
group was 1.81(3) A, suggesting a salt bridge. In addition,
ꢀ
a CH/O hydrogen bond was observed: the interatomic distance
d6 between the aromatic hydrogen atom H22 and O2 of the
ꢀ
carboxylato group was 2.44(3) A. Furthermore, the naphthyl and
phenyl groups were nearly parallel and slightly overlapping,
suggesting a p/p interaction: the interatomic distance d7
ꢀ
between the aromatic carbon atoms C11 and C21 was 3.327(4) A.
This distance was shorter than the sum of the half-thickness of
the phenyl groups and almost identical to the distance between
parallel base pairs in double-stranded DNA.34 However, the
partial overlap of aromatic groups suggests limited contributions
from p/p interactions.24 The parallel pairs of aromatic groups
form a motif similar to a sandwich herringbone (see below).
Desiraju and Gavezzotti reported an important predictive
mapping for the crystal structures of polynuclear aromatic
hydrocarbons based on the glide-to-stack ratio as a function of
the total molecular surface.13
Fig. 8 ORTEP drawing of salt 9.
Recently, we reported the crystal structure of a diastereomeric
amide prepared from (R)-1 and (S)-10.11 Similar to crystalline
salt 9, which was prepared from (S)-1 and (R)-7, the two naph-
thyl groups of the (Racid,Samine)-MaNP amide were almost
parallel and formed a herringbone motif. To fill the space, the
benzyl moiety of the PEA cation Y overlapped with the naphthyl
group of the MaNP cation in salt 9 [Fig. 4 (C) and Table 3]. Note
that the parallel pairs of aromatic groups formed the herringbone
motif with other aromatic groups in both the crystalline MaNP
amide and its corresponding salt.
+171.24(17)ꢁ, respectively. The methyl group was in the aromatic
plane with dihedral angle C3–C2–C5–C6 ¼ ꢀ0.5(3)ꢁ. The
aromatic hydrogen atom H13 of the naphthyl group formed
9
ꢀ
a bifurcated CH/O hydrogen bond with d1 ¼ 2.66(3) A and d2
ꢀ
¼ 2.40(3) A. In the PEA cation, the dihedral angle C16–C15–
C17–C22 was ꢀ92.2(3)ꢁ.
A methoxy-assisted salt bridge was also observed in salt 9
(Table 3). The interatomic distances d3 and d4 between H250 of
the PEA cation X and oxygen atoms O1 and O3 of the MaNP
ꢀ
ꢀ
anion were 1.87(4) A and 2.38(4) A, respectively. However, the 1-
naphthyl group and the phenyl group of PEA cation X did not
overlap [Fig. 4 (B) and Table 3].
Crystal packing of the more-soluble diastereomeric salt 9
Fig. 9 (A) shows the crystal packing of salt 9 as viewed along the a-
axis. Aromatic CH/p interactions between naphthyl groups
resulted in a motif similar to a sandwich herringbone.12 The
distance between aromatic hydrogen atoms H10 and the naphthyl
Instead, the MaNP anion formed a close ion pair with PEA
cation Y [Fig. 4 (C) and Table 3]. The interatomic distance d5
between H23 of the ammonium group and O1 of the carboxylato
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Table 3 Dihedral angles, interatomic distances, and interatomic angles
of crystalline 9a
Salt bridges and conventional hydrogen bonds (i.e., NH/O–
CH3) formed a polar layer. In addition to the interactions shown
in Table 3, a salt bridge was formed between the O2 of the
carboxylato group and H24 of the neighbouring ammonium
ꢀ
group with an interatomic distance of 1.89(4) A [Fig. 9 (D)].
As viewed along the c-axis, the methyl group of the MaNP
anion was close to the phenyl group (Fig. 10). The interatomic
distance between H1 of the methyl group and C18 of the
ꢀ
neighbouring phenyl group was 2.72(4) A. However, neither
aromatic CH/p interactions nor CH/O hydrogen bonds were
observed between the sandwich herringbone structures.
The considerable contributions of the methoxy-assisted salt
bridge and larger aromatic groups to chiral recognition imply
that diastereomeric salt formation employing (S)- or (R)-2-aryl-
2-methoxypropanoic acids will be important in the preparation
of single-enantiomer biofunctional molecules, agrochemicals,
and pharmaceuticals.
NMR analyses of MbNP amides 11 and 12
Dihedral angle (ꢁ)
Acids 1 and 3 exhibited similar analytical properties in normal-
phase HPLC separations of their diastereomeric esters and in the
1H NMR anisotropy measurements.6 However, many of the
analytical properties of acid 2 have yet to be characterised.3,30,31
To investigate these properties, (RS)-2 was condensed with
(S)-10 to yield the diastereomeric amides 11 and 12. Amide 11
was also prepared from (S)-231 and (S)-10. Therefore, the
O1–C1–C2–O3
C4–O3–C2–C1
C3–C2 –C5–C6
C16–C15–C17–C22
+16.3(3)
+171.24(17)
ꢀ0.5(3)
ꢀ92.2(3)
ꢀ
Interatomic distance (A)
H13/O1 (¼ d1)
H13/O3 (¼ d2)
H250/O1 (¼ d3)
H250/O3 (¼ d4)
H23/O1 (¼ d5)
H22/O2 (¼ d6)
C11/C21 (¼ d7)
Interatomic angle (ꢁ)
C12–H13/O1
2.66(3)
2.40(3)
1.87(4)
2.38(4)
1.81(3)
2.44(3)
3.327(4)
stereochemistry was assigned as (Sacid,Samine)-11 and (Racid
,
Samine)-12, respectively. The NMR signals of amides 11 and 12
were assigned based on the analyses of the two-dimensional
NMR spectra consisting of DQF COSY, NOESY, HMQC, and
HMBC measurements at 800 MHz in chloroform-d. This report
constitutes the second NMR analysis of the MbNP amides.
Previously, we reported the NMR data of the MbNP amides
prepared from phenylglycine methyl ester (PGME).30
134.3(19)
114.4(16)
162(3)
124(3)
167(3)
148(3)
C12–H13/O3
N10–H250/O1
N10–H250/O3
N1–H23/O1
C22–H22/O2
As discussed for the MaNP amides prepared from (S)-10,11
a
ꢀ
The van der Waals radii (A): C, 1.70; H, 1.20; O, 1.52; the half-thickness
of aromatic ring, 1.77.
a coupling constant of 8.5 Hz was observed for the amide proton
1
(d 7.25) in the H NMR spectra of amide 11 (Fig. 11). This
suggests that the amide hydrogen atom and the vicinal hydrogen
atom at the 15-position (d 5.90) adopted a trans conformation in
solution. Recently, Takahashi et al. reported that the CH/O
hydrogen bond contributes to the stabilization of the CH3/C]O
eclipsed or gauche conformation of methyl formate, N-methyl-
formamide and propanal.29 Steiner and Saenger discussed the
origin of similar five-membered circular arrangements.35
Considering the NH/O hydrogen bond between the amide NH
and methoxy group,11,30 it is probable that the carbonyl and
methoxy groups adopted an anti conformation (Fig. 2). Similar
relationships were observed for amide 12. The high-field shifts
observed for the protons at the 23- and 24-positions (d 7.16 and
d 7.78, respectively) in amide 12 suggest shielding by the 2-
naphthyl group.
ꢀ
group of the neighbouring MaNP anion was 2.5 A [Fig. 9 (B)].
Considering the distance between the phenyl groups as defined by
the distance between aromatic hydrogen atom H18 and the
ꢀ
neighbouring phenyl plane (3.9 A), aromatic CH/p interactions
between phenyl groups were not significant [Fig. 9 (C)].
As noted above, the methoxy group of the MaNP anion and
the methyl group of the PEA cation helped stabilise the crystal
structure through CH/p interactions. The distance between H6
of the methoxy group and the naphthyl group of the neigh-
ꢀ
bouring MaNP anion was 2.8 A. The distances between H15 and
H17 of the methyl group and the neighbouring phenyl group
ꢀ
ꢀ
were 3.2 A and 3.1 A, respectively. In addition, CH/O inter-
actions were observed between MaNP anions. The interatomic
distance between H6 of the methoxy group and O2 of the
The NOESY spectra of amides 11 and 12 showed major and
minor crosspeaks between the methyl group of MbNP moiety
and the aromatic hydrogen atoms at the 1- and 3-positions of the
2-naphthyl groups, respectively (Fig. 2 and 11). This result
suggests the higher rotational freedom of the 2-naphthyl group
than the 1-naphthyl group.36 Harada et al. observed the
conformer L of MbNP amide by X-ray crystallography, in which
ꢀ
neighbouring MaNP anion was 2.59(3) A [Fig. 9 (B)]. CH/O
interactions were also observed between H15 of the methyl group
of the PEA cation and O2 of the neighbouring MaNP anion at
ꢀ
a distance of 2.59(3) A [Fig. 9 (D)].
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ꢀ
Fig. 9 Crystal packing of salt 9 as viewed along the a-axis. The assigned numbers are distances between atoms or moieties (A). The partially extracted
figures (B) and (C) were rotated to clarify the intermolecular interactions.
the methyl group and the aromatic hydrogen atom at the
1-position were syn.3
1
The Dd values of the H NMR spectra suggest that the two
absorbance at 280 nm). Fig. 12 shows that the retention times of
amides 11 and 12 were 12.91 and 21.37 min, respectively. Similar
to the MaNP ester and amide, the MbNP amide 12, which
possesses a larger and more hydrophobic substituent of the
amine moiety that overlaps the aromatic group of the acyl
moiety, was more polar.10,11 The separation factor (a) and
resolution (Rs) for amides 11 and 12 were 2.25 and 18.0,
respectively. The separation efficiency of the MbNP amides was
better than those for the MaNP amides (a ¼ 2.03, Rs ¼ 17.4)
prepared from (S)- and (R)-1 with (R)-10 under identical
conditions.3,11
naphthyl groups of amide 12 were parallel and shielded each
other (Fig. 11). These data also suggest that NMR analyses of the
MbNP amides could be used for the elucidation of the relative
stereochemistry as a supplement to X-ray crystallography.
Chromatographic analysis of MbNP amides 11 and 12
The separation of amides 11 and 12 was investigated on
a normal-phase HPLC column (silica SG80, 250 ꢂ 4.6 mm I.D.;
eluent, hexane–ethyl acetate ¼ 4 : 1, 0.5 mL minꢀ1; detection, UV
Note that the retention times of the MbNP amides 11 and 12
(see above) were shorter than those of the corresponding MaNP
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ꢀ
Fig. 10 Crystal packing of salt 9 as viewed along the c-axis. The assigned number is interatomic distance between atoms (A).
Fig. 11 The 1H NMR chemical shifts and Dd values for amides 11 and 12. Dd ¼ d[(S)-MbNP amide] ꢀ d[(R)-MbNP amide] ¼ d(amide 11) ꢀ d(amide
12). Solid arrows indicate NOESY correlations, whereas dashed arrows indicate weak ones.
amides.11 The less-polar MaNP amide prepared from (S)-1 and
(S)-10 exhibited a retention time of 15.62 min, while the more-
polar MaNP amide prepared (R)-1 and (S)-10 had a retention
time of 25.37 min. The 2-naphthyl group of acid 2 is longer than
the 1-naphthyl group of acid 1. These differences in polarity and
molecular length will be important in the crystal engineering of
their derivatives.
Fig. 12 HPLC profiles for MbNP amides 11 and 12. Analyte, amides 11
and 12, each 1 mg in 2mL of ethanol; column, silica SG80 (250 mm ꢂ 4.6
mm I.D.); eluent, hexane–ethyl acetate ¼ 4 : 1, 0.5 mL minꢀ1; detection,
UV absorbance at 280 nm. Retention time, t0 (1,3,5-tri-tert-butylben-
zene) ¼ 6.16 (min), t1 ¼ 12.91, t2 ¼ 21.37; peak width, W1 ¼ 0.37 (min),
W2 ¼ 0.57; a (separation factor) ¼ 2.25; Rs (resolution) ¼ 18.0.
a ¼ (t2 ꢀ t0)/(t1 ꢀ t0); Rs ¼ 2 ꢂ (t2 ꢀ t1)/(W1 + W2).
Conclusions
The crystal structures of diastereomeric salts prepared from (R)-
and (S)-1 with (R)-7 were first elucidated by X-ray crystallog-
raphy. The conformation of the MaNP anion was similar to
those of the MaNP acid and its esters. The three oxygen atoms of
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the carboxylato and methoxy groups were nearly in the MaNP
plane, and the methyl group was syn to the aromatic hydrogen
atom at the 2-position. These crystal structures contained
a methoxy-assisted salt bridge acting as a supramolecular syn-
thon. The bifurcated structure of this synthon implies robust
structure.
(250 mm ꢂ 4.6 mm I.D.; Shiseido, Tokyo, Japan) with a line
filter (column savor; Supelco, Pennsylvania, USA).
Preparation of salt 8
A solution of (R)-1 (31.4 mg, 136 mmol) and (R)-7 (17.3 mg,
143 mmol) in methanol–chloroform (1 : 1, v/v; 6 mL) was
partially concentrated in vacuo at 45 ꢁC. The solution was kept at
room temperature for 18 h. After the removal of mother liquor
from the mixture, salt 8 (8.5 mg, 24 mmol) was obtained as
colourless crystals in 18% yield.
In the less-soluble diastereomeric salt 8, the (R)-MaNP and
(R)-PEA ions formed a close ion pair through a methoxy-assisted
salt bridge and an aromatic CH/p interaction. The molecular
length of the (R)-MaNP and (R)-PEA ions from the MaNP
plane were well matched, suggesting that the distance from the
MaNP plane is critical to crystal engineering in this class of
molecules. The salt bridges, NH/O hydrogen bond, and CH/
O hydrogen bond resulted in the formation of polar columns in
salt 8. CH/p interactions between the methoxy group and the
1-naphthyl group of the neighbouring MaNP anion assisted in
aligning the crystals. In addition, the 1-naphthyl and phenyl
groups of salt 8 formed a hydrophobic layer through aromatic
CH/p interactions.
(R)-1-Phenylethylammonium
(R)-2-methoxy-2-(1-naphthyl)-
propanoate 8. IR (diamond ATR): nmax/cmꢀ1 3200–2300, 1612,
27
1572, 1531, 1454, 1385, 1375, 1354, 1344, 1140, 1047. [a]D
ꢀ55.2 (c 0.235, methanol). Elemental analysis. Found: C, 75.27;
H, 7.27; N, 3.92. Calc. for C22H25NO3: C, 75.19; H, 7.17; N,
3.99%.
Preparation of salt 9
The methoxy-assisted salt bridge in the more-soluble diaste-
reomeric salt 9 also bound (S)-MaNP and (R)-PEA ions without
any overlap between the 1-naphthyl and phenyl groups. Instead,
the (S)-MaNP and (R)-PEA ions formed another ion pair via
a normal salt bridge, a CH/O hydrogen bond, and a p/p
interaction. This ion pair formed a motif similar to a sandwich
herringbone via aromatic CH/p interactions between the
1-naphthyl groups. The salt bridges, NH/O hydrogen bond,
and CH/O hydrogen bond created a polar layer in salt 9.
The NOESY spectra of amides 11 and 12 suggested the higher
rotational freedom of the 2-naphthyl group than the 1-naphtyl
group. Positive and negative Dd values were observed on both
sides of MbNP plane, demonstrating the applicability of 1H
NMR anisotropy to the determination of relative stereochem-
istry. HPLC profiles showed that the MbNP amides 11 and 12,
which possessed 2-naphthyl groups and were more efficiently
separated, were less polar than the MaNP amides.
A solution of (S)-1 (64.6 mg, 281 mmol) and (R)-7 (34.2 mg,
282 mmol) in methanol–chloroform ꢁ(1 : 1, v/v; 4 mL) was
partially concentrated in vacuo at 45 C. After the addition of
seed crystals, the solution was kept at room temperature for 18 h.
After the removal of mother liquor from the mixture, the crystals
were washed with cold ethanol (ca. 0.5 mL). This procedure
yielded salt 9 (32.4 mg, 92 mmol) as colourless crystals in 33%
yield.
(R)-1-Phenylethylammonium
(S)-2-methoxy-2-(1-naphthyl)-
propanoate 9. IR (diamond ATR): nmax/cmꢀ1 3200–2300, 1608,
1560, 1535, 1444, 1387, 1369, 1352, 1340, 1330, 1240, 1095, 1041.
[a]D29 + 61.7 (c 0.373, methanol). Elemental analysis. Found: C,
75.14; H, 7.16; N, 3.92. Calc. for C22H25NO3: C, 75.19; H, 7.17;
N, 3.99%.
These findings have elucidated the chiral recognition mecha-
nisms of MaNP salts, and can be used in the crystal engineering
of 2-aryl-2-methoxypropanoic acid derivatives for the develop-
ment of single-enantiomer biofunctional molecules, agrochemi-
cals, and pharmaceuticals.
X-Ray crystallography
Single crystals of salts 8 and 9 were covered by paraffin oil and
mounted on a glass fiber. All data were collected at 123 K on
a Rigaku Mercury CCD detector, with monochromatic Mo-Ka
radiation, operating at 50 kV/40 mA. Data were processed on
a PC using CrystalClear Software (Rigaku, Tokyo, Japan).
Structures were solved by direct methods and refined by full-
matrix least-squares methods on F2 (SHELXL-97). CCDC
801461 (salt 8) and CCDC 801460 (salt 9) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Experimental
Materials and methods
NMR spectra were obtained with a Bruker Avance 800 spec-
trometer (Bruker BioSpin, Rheinstetten, Germany) equipped
1
with a cryoprobe. The H NMR chemical shifts were reported
relative to trimethylsilane (TMS). 13C NMR spectra were
1
obtained with H composite pulse decoupling. IR spectra were
Preparation of amides 11 and 12
recorded with a Freexact-II spectrometer (Horiba, Kyoto,
Japan) equipped with a diamond ATR accessory, or an FTIR-
8200 spectrophotometer (Shimadzu, Kyoto, Japan) with
a potassium bromide cell. MS data were obtained with an Apex
70e ESI-FTICR MS instrument (Bruker Daltonics, Bremen,
Germany) in positive ion mode. HPLC was performed using an
LC10AT VP system (Shimadzu) and a silica SG80 column
Amide 11 (14.7 mg, 38.3 mmol, 45%) and amide 12 (14.9 mg,
38.9 mmol, 46%) were prepared from (RS)-2 (19.6 mg, 85.1 mmol)
and (S)-10 (53.6 mg, 313 mmol) with 4-dimethylaminopyridine
(DMAP, 82.1 mg, 672 mmol), 1-ethyl-3-(3-dimethylamino-
propyl)-carbodiimide hydrochloride (EDC$HCl, 85.2 mg, 444
mmol), and dichloromethane (0.5 mL). The reaction time was
18 h. See ref. 11 for details.
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(S)-2-Methoxy-2-(2-naphthyl)-N-[(S)-1-(1-naphthyl)ethyl]prop-
anamide 11.
–NH–), 7.16 (1H, ddd, J ¼ 8, 7, 1 Hz, 23-H), 5.83 (1H, dq, J ¼
8.3, 7 Hz, 15-H), 3.13 (3H, s, 14-H), 1.94 (3H, s, 13-H), 1.73 (3H,
d, J ¼ 7 Hz, 16-H). 13C NMR (201 MHz, chloroform-d): d 172.09
(C12), 137.99 (C17), 137.77 (C2), 133.79 (C26), 133.01 (C9),
132.91 (C10), 131.25 (C25), 128.48 (C21), 128.31 (C20), 128.31
(C8), 128.02 (C4), 127.41 (C5), 126.38 (C23), 126.12 (C6), 125.97
(C7), 125.79 (C1), 125.75 (C22), 125.02 (C19), 124.17 (C3),
123.63 (C24), 122.54 (C18), 81.92 (C11), 51.04 (C14), 44.32
(C15), 20.37 (C16), 20.07 (C13). IR (KBr, chloroform): nmax/cmꢀ1
29
3411, 3059, 3011, 1668, 1506, 1144, 1132. [a]D ꢀ109 (c 0.483
chloroform). MS (ESI–FTICR, positive): m/z 406.1776 ([M +
Na]+, 100%). Calc. for C26H25NO2Na: 406.1778.
Preparation of amide 11
Amide 11 (9.1 mg, 24 mmol) was prepared from (S)-2 (6.3 mg,
27 mmol) and (S)-10 (108.3 mg, 632 mmol) with DMAP (81.7 mg,
669 mmol), EDC$HCl (80.0 mg, 417 mmol), and dichloromethane
(0.5 mL) in 87% yield. The reaction time was 18 h. See ref. 11 for
details.
1H NMR (800 MHz, chloroform-d): d 8.13 (1H, br d, J ¼ 8 Hz,
24-H), 7.94 (1H, br s, 1-H), 7.88 (1H, br d, J ¼ 8 Hz, 21-H), 7.87
(1H, m, 8-H), 7.86 (1H, m, 4-H), 7.84 (1H, m, 5-H), 7.82 (1H, br
d, J ¼ 8 Hz, 20-H), 7.57 (1H, dd, J ¼ 8, 2 Hz, 3-H), 7.56 (1H, br
d, J ¼ 7 Hz, 18-H), 7.55 (1H, ddd, J ¼ 8, 7, 1 Hz, 23-H), 7.51 (1H,
ddd, J ¼ 8, 7, 1 Hz, 22-H), 7.49 (1H, m, 6-H), 7.49 (1H, m, 7-H),
7.48 (1H, m, 19-H), 7.25 (1H, m, –NH–), 5.90 (1H, dq, J ¼ 8.5, 7
Hz, 15-H), 3.10 (3H, s, 14-H), 1.85 (3H, s, 13-H), 1.61 (3H, d, J ¼
7 Hz, 16-H). 13C NMR (201 MHz, chloroform-d): d 172.26 (C12),
138.39 (C17), 138.29 (C2), 133.90 (C26), 133.10 (C9), 132.90
(C10), 131.20 (C25), 128.74 (C21), 128.31 (C8*, *assignment
interchangeable), 128.30 (C20*), 128.21 (C4), 127.50 (C5), 126.42
(C23), 126.18 (C6), 126.11 (C7), 125.84 (C22), 125.60 (C1),
125.21 (C19), 123.94 (C3), 123.56 (C24), 122.58 (C18), 81.97
(C11), 51.18 (C14), 44.29 (C15), 20.61 (C16), 20.41 (C13). IR
(KBr, chloroform): nmax/cmꢀ1 3412, 3061, 3009, 1670, 1506, 1194,
Acknowledgements
The authors are grateful to Ms. I. Maeda (NFRI), Dr T. Hatta
(JIRCAS) and Ms. S. Nemoto (JIRCAS) for the measurements
of NMR and IR spectra, respectively.
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