conformation

a) N-(4-methoxybenzoyl)leucine diethyl amide (±)-2c was crystallized at rt.

The structure was analyzed by X-ray crystallography and was found to dimerize in the solid state (space group Pbca, show in Figure 34). Two views of the complex are shown in Figure 33. There are two simultaneous interactions for each molecule which are two intermolecular hydrogen bonds between the methoxybenzoyl N-Hs and C-terminal carbonyl oxygens.

Figure 33. (a) The two simultaneous interactions involved the solid state dimer of (R)-2c and (S)-2c. Capped sticks plot of the solid state dimer (side view) showing the hydrogen bonding (shown as cyan lines) between three molecules (b) Capped sticks plot of the solid state dimer (top view)

a b

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Figure 34. Unit cell of the crystals formed from (±)-2c

b) N-(4-bromobenzoyl)leucine diethyl amide (±)-2d was crystallized at rt.

The structure was analyzed by X-ray crystallography and was found to dimerize in the solid state (space group Pbca, show in Figure 36). Two views of the complex are shown in Figure 35. There are two simultaneous interactions for each molecule which are two intermolecular hydrogen bonds between the methoxybenzoyl N-Hs and C-terminal carbonyl oxygens.

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Figure 35. (a) The two simultaneous interactions involved the solid state dimer of (R)-2d and (S)-2d. Capped sticks plot of the solid state dimer (side view) showing the hydrogen bonding (shown as cyan lines) between three molecules. (b) Capped sticks plot of the solid state dimer (top view).

Figure 36. Unit cell of the crystals formed from (±)-2o

c) N-(4-chlorobenzoyl)leucine diethyl anmide (±)-2f was crystallized form hexane/ dichloromethane (ratio= 4:1) at rt. The structure was analyzed by X-ray crystallography and was found to dimerize in the solid state (space group Pbca, show in Figure 38). Two views of the complex are shown in Figure 37. There are two simultaneous interactions for each molecule which are two intermolecular hydrogen bonds between the methoxybenzoyl N-Hs and C-terminal carbonyl oxygens.

a b

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Figure 37. (a) The two simultaneous interactions involved the solid state dimer of (R)-2f and (S)-2f. Capped sticks plot of the solid state dimer (side view) showing the hydrogen bonding (shown as cyan lines) between three molecules. (b) Capped sticks plot of the solid state dimer (top view).

Figure 38. Unit cell of the crystals formed from (±)-2f.

a b

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In these three conformations, the X-ray structures and crystallographic analysis are show in Table 1. Prominently, as show in Figure 23 and entry 9, homochirl dimerization is not observed in unsubstituted benzene ring. In addition, there is no homochiral dimerization when the aromatic group is changed to a cyclohexyl group (show in Figure 25 and entry 19). We can observe the homochiral self-assembly dimer only for 3-substituted (entry 1-5), 3,5-substituted (entry 6-8) and few 4-substituted (entry 10 and 14) compounds in the solid state. In all the 2-substituted, compounds, we cannot observe self-assemble in to homochiral dimers (entry 16-18). The aromatic ring is significantly out of the plane with the adjacent carbonyl group, presumably to minimize steric interactions. Hence, the π-π interaction cannot be form into the 2-substituted compounds.

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Table 1. X-ray crystallographic analysis of 2-substituted, 3-substituted, 3,5-substituted, and 4-substituted benzoyl leucine diethyl amides

Compound

aThe angle (θ) is defined by the ring to ring centroid to the plane of benzyl ring (see below).

bVertical displacement (R) of ring centroid to plane defined by opposite ring (see below).

cHorizontal displacement (I) between two ring centroids (see below).

dDegree (α) out of plane (see below).

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The small scheme of Table 1 display the various parameters used to define the orientation of the rings with respect to each other. The vertical displacement (R) and the horizontal displacement (I) are measures of the amount of offset of the interacting rings. For all the derivatives of benzoylleucine diethyl amide, the horizontal displacement (I) values range from 1.13 Å for 2a (4-NO₂) to 3.21 Å for 1d (3-Br) dimer. Significantly, the horizontal displacement (I) values are controlled by the electron capacity of the substituents. For instance, the I values of strong electron-withdrawing or donating substituents are small than the other substituents. However, there is no correlation between in the degree of offset and the electron capacity of the substituent. For instance, the horizontal displacements (I) values of 1a (3-NO₂), 1c (3-OMe), and 1g (3,5-OMe) are similar. The halogen-substituted and methyl-substituted dimers have the largest parallel displacements values due to the week withdrawing and donating substituents of the ring.

The value range of the vertical displacement (R) from 3.20 Å for 1d (3-Br) to 3.21 Å for 2a (4-NO₂) dimer is not that much difference among the different substituents of the benzene ring. There is an interacting relationship of two stacking ring between in the vertical displacements (R) and the horizontal displacements (I). For instance, the largest values of vertical

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displacements (R) are 3.58 Å, 3.52 Å, and 3.61 Å for compound 1a (3-NO₂), 1c (3-OMe), and 2a (4-NO₂) respectively. Additionally, these three compounds gives the shortest horizontal displacements (1.68 Å, 1.56 Å , and 1.13 Å respectively). Also, methyl and halogen groups of benzene ring are represented this phenomenon too. This phenomenon suggests that the relationship of two stacking ring between in the vertical displacements (R) and horizontal displacements (I) is reversed. The possible explanation for this relationship is that the offset values (means I values) are more significant, the repulsive forces are more small. Therefore, the dimer will show a great overlap of the ring moieties in the vertical direction.

Figure 39. Various perspectives of the partial structures of N-(3-nitrobenzoyl)leucine diethyl amide 1a. The dotted lines show potential local dipole interactions between the interacting aromatic rings of the respective dimers.

To zoom in the crystal structures of the aromatic part of the 1a (3-NO₂), 1f (3,5-NO₂) , and 1g (3,5-OMe) dimers show the local interactions may

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influence the energetics and the orientations of the aromatic rings in the respective dimers. Several different type of view for the aromatic part of 1a (3-NO₂), 1f (3,5-NO₂), and 1g (3,5-OMe) are shown in Figure 39-41 respectively. First, for the 1a (3-NO₂) dimer, an oxygen on the nitro group is close and roughly parallel to a hydrogen atom on the other aromatic ring (shortest distance is 3.60 Å, show in Figure 39).

Figure 40. Various perspectives of the partial structures of N-(3,5-dinitrobenzoyl)leucine diethyl amide 1f. The dotted lines show potential local dipole interactions between the interacting aromatic rings of the respective dimers

Second, for the 1f (3,5-NO₂) dimer, there are similarly interaction between the oxygen on the nitro group to the hydrogen atom of other aromatic ring (shortest distance is 3.75 Å, show in Figure 40) and the last one is the 1g (3,5-OMe) dimer. The oxygen of the methoxy group is close to the hydrogen atom of the opposing aromatic ring, but this interaction is not strong as the nitro substituents (shortest distance is 4.05 Å, show in Figure

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40). These observations maybe suggest that some interactions stabilize the ring stack with each other in the dimer by the hydrogen of one ring and the oxygens of nitro and merhoxy groups.

Figure 41. Various perspectives of the partial structures of N-(3,5-dimethoxybenzoyl)leucine diethyl amide 1g. The dotted lines show potential local dipole interactions between the interacting aromatic rings of the respective dimers.

In Table 2, we choose three most import dihedral angles form the molecules which form homochiral self-assembly dimers are shown. Figure 42 shows the atoms number model for the dihedral angle. The values the dihedral angles of (S,S)-dimers and (R,R)-dimers are opposite (here only shows the angles of (R,R)-dimers). There are some interesting differences between the dihedral angles of the various homochiral dimer. In the stacking compounds, there are five compounds which show different dihedral angles for each molecule in a dimer. For example, dihedral angle N1-C3-C2-C1 (or N2-C8-C7-C6) means the deviation from the two position carbon of ring

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with respect to the amide part. The range of N1-C3-C2-C1 (or N2-C8-C7-C6) is 160.4° to 174.0° ( or 155.4° to 172.4°)

Figure 42. Numbering molecular atom model for dihedral angle

The dissimilarities are observed in the other four dihedral angles show in Table 2. These ranges of dihedral angles are dependent on the substituents on the ring. For entry1, 6, 7, 10, and 11, the dihedral angles of molecule 1 is different with molecule 2, but for entry 2-5 and 8, the dihedral angles of molecule 1 or molecule 2 are the same with each other. This result suggests that the dimers of entry 1, 6, 7, 10 and 11 are more flexible than other compounds.

Assuming that a strong dipole moment is display on the aromatic ring, the respective molecules include each dimer are supporting each other so as to maximize the favorable local interactions and minimize the repulsive local interactions. The different dihedral angles show in the same position of two molecules of dimer which suggest that these compounds are more

C1

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flexible than the other compounds show the same dihedral angles. The molecules of these five compounds orientate themselves to make maximize direct interaction to stabilize the π-π interaction of dimers.

Table 2. Dihedral angles for (R,R)-dimers of individual molecules comprising the homochiral dimers crystallized in the present study. The orange colors represent compounds with nonequivalent dihedral angles in the individual molecules of the dimer.

Accordingly, if the ring stacking affects the local interactions between dipole, the molecules may assume conformations so as to optimize these interactions.

Molecule 1 Molecule 2 entry Compounds

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