Polymorphism in a Symmetrical Dipeptidyl Urea with Z′ > 1 - Crystal

Mar 29, 2010 - CCLRC, Daresbury Laboratory, Warrington, Cheshire WA4 4AD, ... on the molecular interactions and facilitate a network of hydrogen bonds...
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DOI: 10.1021/cg9015564

Polymorphism in a Symmetrical Dipeptidyl Urea with Z 0 > 1 Basab Chattopadhyay,† H. P. Hemantha,‡ N. Narendra,‡ Vommina. V. Sureshbabu,‡ John E Warren,^ Madeleine Helliwell,§ Alok K. Mukherjee,# and Monika Mukherjee*,†

2010, Vol. 10 2239–2246

†

Department of Solid State Physics, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India, ‡Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Bangalore 560 001, India, ^CCLRC, Daresbury Laboratory, Warrington, Cheshire WA4 4AD, United Kingdom, §Department of Chemistry, University of Manchester, Manchester, M13 9PL, United Kingdom, and #Department of Physics, Jadavpur University, Kolkata 700032, India Received December 11, 2009; Revised Manuscript Received March 16, 2010

ABSTRACT: Two polymorphic forms of a symmetrical Aib containing urea derivative, DIPUR(R) and DIPUR( β), have been structurally characterized using synchrotron/X-ray diffraction data with a detailed analysis of Hirshfeld surfaces and fingerprint plots facilitating a comparison of the type and nature of intermolecular interactions in the supramolecular architectures. Structural study of DIPUR(R) crystallizing in a Sohnke space group P21 reveals four crystallographically independent molecules (A, B, C, and D) in the asymmetric unit with the pairs of molecules A, B and C, D interlinked via N-H 3 3 3 O hydrogen bonds forming antiparallel one-dimensional chains having a C22(8)R21(6)R21(6) sequence. The combination of intermolecular N-H 3 3 3 O and C-H 3 3 3 O hydrogen bonds generates a three-dimensional framework in DIPUR(R). In the polymorph DIPUR( β) with space group P212121 and Z0 = 2, the N-H 3 3 3 O-bonded R22(11) rings propagate along the [001] direction through C22(8) chains to form a one-dimensional molecular assembly. The Aib residues in DIPUR(R) and DIPUR( β) induce constraints on the molecular interactions and facilitate a network of hydrogen bonds in both polymorphs.

Introduction The peptidyl urea compounds containing R-aminoisobutyryl (Aib) residues form an important class of pseudopeptides with increasing applications in peptidomimetics.1 These ureido linked pseudopeptides exhibit increased metabolic stability and improved pharmacokinetic properties such as absorption, transport characteristics, and lower toxicity over the native peptides.2 The insertion of a urea moiety as a replacement for the amide bond in peptides facilitates selfassembly of molecules via hydrogen bonding through the two NH protons and the lone pairs of the CdO group.3 The good complementarity between the two groups results in supramolecular architecture with robust one-dimensional R-networks, which in turn are often linked to form two-dimensional β- sheets.4,5 The peptidyl urea compounds with β-sheets comprising urea molecular scaffolds and peptide strands have been reported in the literature.6,7 Structural studies of these model peptide systems are of key importance for a better understanding of conformational properties and interactions in polypeptide sequences in proteins. In recent years, there has been growing interest in crystal structures that contain multiple molecules in the asymmetric unit (Z0 > 1).8-11 Although about 8.9% of structures in the Cambridge Structural Database (version 5.30, November CSD 2008 release)12 crystallize with Z0 > 1, the underlying causes for occurrence of high Z0 structures are not fully understood. One hypothesis is that high Z0 structures possibly represent kinetically metastable situations, which have not relaxed to their thermodynamically more stable polymorphs and the molecules organize themselves into stable clusters prior to reaching the highest symmetry arrangements.13 Other

reasons, such as better interactions, packing efficiency, modulation, pseudosymmetry, equienergetic conformations, etc., have also been proposed for structures adopting Z0 > 1,14-17 but no consensus has been reached. Steed and co-workers18 have shown that deliberate incorporation of features within a molecule that can frustrate or place constraints on supramolecular assembly formation facilitates polar or chiral packing arrangements. The occurrence of structures with Z0 > 1 is known to be higher in Sohnke and chiral space groups and a CSD12 search shows that 14.6% of structures in the Sohnke and chiral space groups have Z0 > 1 compared to 8.9% for the database overall.19 In the course of our ongoing program of synthesis and structural characterization of pseudopeptides,20,21 we came across an interesting polymorphic dipeptidyl urea compound, dimethyl 2,20 - carbonylbis(azanediyl)-bis-2-methylpropanaote (DIPUR). The phenomenon of polymorphism is of fundamental importance in our understanding of crystal nucleation and growth through synthon evolution, and structure-property correlation. The identification and characterization of different polymorphic forms of a drug material is now an essential element in pharmaceutical research and development.22-24 Crystallographic study of two polymorphs of DIPUR(R and β), both having Z0 > 1, is discussed here together with the Hirshfeld surface analysis25 to visualize and discriminate the features of molecular interactions in the two polymorphic forms. Experimental Section

*Corresponding author. Tel.: þ91 33 2473 4971, ext 312. Fax: þ91 33 2473 2805. E-mail: [email protected].

Synthesis (Scheme 1). A solution of amino isobutyric acid methyl ester hydrochloride salt, 1 (0.76 g, 5 mmol), in a mixture of CH2Cl2 (40 mL) and saturated aqueous NaHCO3 (40 mL) was cooled to 0 C in an ice bath and stirred vigorously for 10 min. The stirring was stopped and the biphasic mixture was allowed to separate. A solution of triphosgene in CH2Cl2 (3.4 mmol, 1.1 g in 10 mL) was

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Scheme 1. Synthesis of the Dipeptidyl Urea: (1) Amino Isobutyric Acid Methyl Ester Hydrochloride Salt; (2) Methyl 2-Isocyanato-2Methylpropanoate; (3) DIPUR

Table 1. Crystal Data and Structure Refinement Parameters for DIPUR(R) and DIPUR(β) DIPUR(r) empirical formula formula weight T (K) wavelength (A˚) cryst syst space group a (A˚) b (A˚) c (A˚) β (deg) V (A˚3) Z D(calculated) (Mg/m3) absorp coeff (mm-1) F(000) cryst size (mm3) cryst color cryst size θ range (deg) no. of reflns collected no. of independent reflns data completeness (%) data/restraints/params GOF on F2 final R indices [I > 2σ(I)] largest diff. peak and hole(e A˚-3)

C11H20N2O5 260.29 150(2) 0.68840 monoclinic P21 9.113(4) 16.870(7) 18.204(7) 90.363(5) 2799.0(2) 8 1.236 0.097 1120 0.6  0.04  0.04 colorless needle 1.59-24.19 15985 4949 [R(int) = 0.0454] 96.5 4949/1/675 1.110 R1 = 0.0364 wR2 = 0.0906 0.145 and -0.147

DIPUR(β) C11H20N2O5 260.29 150(2) 0.71073 orthorhombic P212121 8.976(1) 16.868(2) 18.528(2) 2805.3(5) 8 1.233 0.097 1120 0.25  0.15  0.05 colorless plate 1.10-18.46. 16657 1216 [R(int) = 0.0564] 99.8 1216/0/339 1.069 R1 = 0.0283 wR2 = 0.0711 0.103 and -0.112

directly added to the organic phase using a syringe followed by stirring for another 15 min at 0 C. The aqueous layer separated was extracted with CH2Cl2 (15 mL  2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain methyl 2-isocyanato-2-methylpropanoate (2). In the next step, the isocyanate, 2 (0.690 g, 4.8 mmol), was added to the stirred solution of 1 in CH2Cl2 (0.840 g, 5.5 mmol, previously neutralized with triethylamine). The reaction mixture was stirred at room temperature for 2 h, diluted with CH2Cl2 (20 mL), washed with water (10 mL x 2), brine (15 mL) and finally dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the crude product was purified by MPLC (Medium Pressure Liquid Chromatography) using 50% hexane:ethyl acetate to obtain Dimethyl 2, 20 - carbonylbis(azanediyl)-bis-2-methylpropanaote (DIPUR), 3, as a crystalline powder in good yield. Slow evaporation of a solution of 3 in a mixture of chloroform and pet-ether (3:1) yielded needle shaped (R-form) and rectangular plate (β-form) single crystals of DIPUR (see Figure S1 in the Supporting Information). Anal. Calcd for C11H20N2O5: C, 50.56; H, 7.74; N, 10.76; O, 30.73%. Found: C, 50.61; H, 7.64.; N, 10.83; O, 30.92%., 1H NMR (300 MHz, DMSOd6) δ: 1.63 (s, 12H), 3.77 (s, 6H), 6.3 (s, 2H). 13C NMR (300 MHz, DMSO-d6) δ: 24.2, 51.7, 60.2, 158.8, 172.5. X-ray Powder Diffraction. X-ray powder diffraction data of crystalline powder sample of 3 were collected on a Bruker D8 Advance powder diffractometer using CuKR radiation (λ = 1.5418 A˚). The diffraction pattern was recorded with a step size of 0.02(2θ) and counting time 20 s/step over an angular range of 4.0-100.0 (2θ) using the Bragg - Brentano geometry.

Single-Crystal X-ray Diffraction. Because the single crystals of DIPUR(R) were too thin and weakly diffracting, synchrotron radiation (λ= 0.68840 A˚) from Station 9.8 at the SRS Daresbury Laboratory was used for data collection. For DIPUR(β), data collection was carried out with a Bruker APEX CCD diffractometer using Mo KR radiation (λ = 0.71073 A˚). The crystal structures were solved by direct methods using SIR200426 and refined by fullmatrix least-squares methods based on F2 using SHELXL97.27 The displacement parameters of all non-H-atoms were treated anisotropically. H-atoms were placed at calculated positions using suitable riding model with fixed isotropic thermal parameters [Uiso(H)=1.2Ueqv(N) for NH groups and Uiso(H)= 1.5Ueqv(C) for CH3]. Crystal data for both DIPUR(R) and DIPUR(β) are summarized in Table 1. Energy Calculations. The atomic coordinates from the final X-ray refinement cycle were used as input for energy calculations via DFT approach. Solid state DFT calculations were carried out using the Dmol3 code28 in the framework of the Perdew-Wang generalizedgradient approximation (PW91)29 with the numeric DNP basis set. For better accuracy, the octupole expansion scheme is adopted for resolving the charge density and Coulombic potential. Symmetry restrictions were also applied during the energy calculation. Hirshfeld Surface Analysis. Hirshfeld Surfaces and the associated fingerprint plots were calculated using CrystalExplorer,30 which accepts a structure input file in the CIF format. Bond lengths to hydrogen atoms were set to typical neutron values (C-H = 1.083 A˚, O-H = 0.983 A˚).

Results and Discussion A comparison of observed powder diffraction pattern of 3 with that of the simulated powder data (Figure 1) of DIPUR(R) and DIPUR(β) showed that the compound 3 synthesized as a polycrystalline material was a mixture of phases; a fact which could rationalize our inability to index the X-ray powder diffraction pattern of 3. The appearance of peaks in the observed X-ray powder pattern of 3 at 2θ ∼ 16.5, 18.7, and 21.5, which were absent in the simulated patterns of both DIPUR(R) and DIPUR(β), possibly indicates presence of a third polymorph of DIPUR. Single-crystal X-ray analysis indicated that the asymmetric unit of DIPUR(R) crystallizing in the monoclinic space group P21 consists of four molecules, A, B, C, and D (Figure 2a), and that of DIPUR(β) crystallizing in the orthorhombic space group P212121 comprises two molecules, A and B (Figure 3a). From the similarity of unitcell parameters of two polymorphs (Table 1) and the β angle of DIPUR(R) being close to 90, it can be proposed that a minor adjustment would easily transform the monoclinic unit cell of DIPUR(R) into the orthorhombic cell in DIPUR(β) with a nearly identical unit-cell volume. A search of the November 2008 release of CSD revealed that out of 112 acyclic symmetrical urea derivatives (the search was restricted to singlecomponent molecular structures without any solvent) 42 structures had Z0 = 0.5, whereas the corresponding number with Z0 = 2 was only 7, and there was no report for Z0 = 4. The only structure of a symmetrical urea derivative with Z0 = 4 reported in the literature31 is 1,3-Bis-(2-benzanilidephenyl)urea, which contained acetonitrile as a solvent of crystallization.

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A further CSD search for structures containing Aib-ureido fragment returned with 259 hits. Of these, 50 structures exhibited Z0 > 1, 33 (66%) of them belonged to Sohnke space groups, and only one had a chiral space group. Incidentally, both polymorphs of 3, DIPUR(R) and DIPUR(β), crystallize in Sohnke space groups, P21 and P212121. This is consistent

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with the report by Anderson et al.19 that occurrence of structures with Z0 > 1 is higher in the Sohnke and chiral space groups. The bond lengths and bond angles in independent molecules of two polymorphs, DIPUR(R) and DIPUR(β), are statistically similar to one another, and are in agreement with similar structures containing Aib-residues.32-34 The overlay of molecules (Figure 2b, 3b) and the selection of torsion angles (Table 2) suggest that different molecules in the asymmetric unit of DIPUR(R) and DIPUR(β) adopt virtually the same conformation. Each molecule in the asymmetric unit of DIPUR(R) exhibits nearly C2 symmetry about the C6-O3 bond, whereas in DIPUR(β), half of both molecules A and B is related to the other half by an approximate Cs symmetry. The magnitudes of j (C6-N1-C3-C2, C6-N2-C7-C10) and ψ (N1-C3-C2-O1, N2-C7-C10-O5) torsion angles (Table 2), clustering in the region j ≈ -50, ψ ≈ 140 and Table 2. Selected Torsion Angles (deg) of Different Molecules in the Asymmetric Unit for DIPUR(R) and DIPUR(β)a

Figure 1. Observed X-ray powder pattern of 3 and the simulated patterns of DIPUR(R) and DIPUR(β).

polymorph

molecule

Φ1/Ψ1

Φ2/Ψ2

R β R β R R

A A B B C D

-52.2(5)/142.5(3) 54.3(6)/-152.4(7) 52.2(5)/-139.3(3) -55.6(6)/152.4(4) -50.2(5)/141.8(3) 57.2(5)/-139.0(3)

-54.7(5)/134.6(3) -57.0(6)/143.5(4) 55.1(5)/-141.7(3) 52.4(6)/-144.0(0) -49.7(4)/137.7(3) 52.8(4)/-135.9(3)

a Φ1 = C6-N1-C3-C2; Ψ1 = N1-C3-C2-O1; Φ2 = C6-N2C7-C10; Ψ2 = N2-C7-C10-O5.

Figure 2. (a) Perspective view of the asymmetric unit of DIPUR(R). (b) Overlay of four molecules in the asymmetric unit of DIPUR(R).

Figure 3. (a) Perspective view of the asymmetric unit of DIPUR(β). (b) Overlay of two molecules in the asymmetric unit of DIPUR(β).

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Figure 4. Antiparallel N-H 3 3 3 O bonded chains in DIPUR(R) propagating along the [100] direction.

j ≈ 50, ψ ≈ -140, indicate that the Aib residues in both structures assume a semiextended polyproline II conformation.35 The opposite signs of j, ψ set in the molecules A and B as well as C and D in the two polymorphs suggest a reversing of screw sense in the peptide chain. The semiextended polyproline II conformation of Aib residue, although unusual in both natural and synthetic acyclic (linear) peptide sequences, has been observed previously in dipeptides and tripeptides.32,35-38 It is to be noted that such a conformation leads to a cisoid arrangement of the terminal C1-O1 and C11-O5 bonds with respect to the urea carbonyl group (C6dO3). As a consequence the intramolecular distances between O2-O3 and O4-O3 are in the range 2.991(4)-3.207(5)A˚ [in DIPUR(R)] and 2.951(4)-3.112(5)A˚ [in DIPUR(β)].

In general, structures with high Z0 often display pseudosymmetry.13,39 The four independent molecules in DIPUR(R) can be divided into two sets, viz. A, B and C, D; the two molecules of each sets are almost orthogonal to each other with a relative shift of 0.5 along the a-axis. The dihedral angles between the planes through N1/C6/N2/O3 atoms of molecules A, B and C, D are 87.2(1) and 85.7(1), respectively, which indicate a pseudo 42-axis about C6-O3 bond. The corresponding dihedral angle in DIPUR(β) between the two molecules having a relative shift of 0.5 along the c-axis is 79.8(2). The two molecules in DIPUR(β), i.e., A and B are related by a pseudoglide symmetry along the crystallographic a -axis. Similar to other N,N0 -disubstituted urea derivatives, the molecular assembly in DIPUR(R) and DIPUR(β) generates a

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Figure 5. Packing in DIPUR (R) formed by a combination of N-H 3 3 3 O and C-H 3 3 3 O hydrogen bonds. H-bonds forming R33(15) rings are shown in red.

R-network of p211 rod symmetry.40 The two hydrogen atoms of the urea motif chelate the oxygen atom of its neighbor. The self-assembly of molecules A and B as well as C and D in DIPUR(R) is established via bifurcated urea tape N-H 3 3 3 O synthon to form one-dimensional antiparallel chains propagating along the [100] direction (Figure 4). The separation between adjacent parallel chains is 9.45 A˚. This hydrogenbonded motif can be described using the graph set notation as C22(8)R21(6)R21(6).41 There is a twisting of neighboring urea molecules within each tape and also of Aib residue with respect to the urea moiety to achieve close packing. The parallel one-dimensional N-H 3 3 3 O-bonded ABAB 3 3 3 and CDCD 3 3 3 chains in DIPUR (R) are interlinked through C-H 3 3 3 O hydrogen bonds (see Table S1 in the Supporting Information) to generate β-networks. Intermolecular hydrogen bonds [C5A 3 3 3 O2C 3.421(5) A˚, H(C5A) 3 3 3 O2C 2.53 A˚, C5A-H(C5A) 3 3 3 O2C 155.1; C4C 3 3 3 O4B 3.393(6) A˚, H(C4C) 3 3 3 O4B 2.46 A˚, C4C-H(C4C) 3 3 3 O4B 164.8;

C9B 3 3 3 O2A 3.295(5)A˚, H(C9B) 3 3 3 O2A 2.43 A˚, C9B-H(C9B) 3 3 3 O2A 149.2] combine A, B, and C types of molecules forming an R33(15) ring, whose propagation along the [010] direction is facilitated by the urea tape N-H 3 3 3 O synthon and C1C-H(C1C)...O4A hydrogen bond [C1C 3 3 3 O4A 3.418(5) A˚, H(C1C) 3 3 3 O4A 2.52 A˚, C1C-H(C1C) 3 3 3 O4A 156.7]. Adjacent chains of R33(15) rings thus formed are further connected through C9A-H(C9A) 3 3 3 O4C hydrogen bonds [C9A 3 3 3 O4C 3.422(5)A˚, H(C9A) 3 3 3 O4C 2.54 A˚, C9A-H(C9A) 3 3 3 O4C 153.6(3)] to generate a three-dimensional network in DIPUR(R) (Figure 5). In DIPUR(β), the two N-H groups of Aib residues in molecule B act as a donors to carbonyl O atoms in molecule A to form a N-H 3 3 3 O-bonded R22(11) ring. The ureido O3 atom in DIPUR(β), in marked contrast with DIPUR(R), does not act as a double acceptor in generating the characteristic R21(6) synthon. Linking of adjacent R22(11) rings are achieved through N1(A)-H1(A) 3 3 3 O3(B) hydrogen bond, so forming

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antiparallel one-dimensional ABAB 3 3 3 chains (Figure 6) along the [001] direction. The parallel chains separated by 9.36 A˚ can be represented using the graph set notation as C22(8)[R22(11)] (Figure 6). The propagation of N-H 3 3 3 O bonded chains in DIPUR(β) thus generates a helical packing arrangement (Figure 6) with a pitch of 18.53 A˚ (crystallographic c axis). The Hirshfeld surface analysis,25,42,43 which is a relatively new approach for quantification of intermolecular interactions

Figure 6. Antiparallel N-H 3 3 3 O bonded chains in DIPUR(β) propagating along the [001] direction.

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in molecular crystals, has been applied to elucidate the similarities and differences between the crystal packing of two polymorphs, DIPUR(R) and DIPUR(β). Because Hirshfeld surfaces are directly related to a given molecular environment, their use can enable a rapid and easy visual comparison of the role of independent molecules in the asymmetric unit of structures with Z0 > 1. The Hirshfeld surfaces of DIPUR(R) and DIPUR(β) are illustrated in Figure 7, showing surfaces that have been mapped over a de range of 0.85-2.30 A˚. The color codes from red for short de ranges to blue for long ranges were employed in the mapping. The surfaces for four independent molecules in DIPUR(R) display two strong N-H 3 3 3 O hydrogen bonds as red spots (marked as 1a and 1b in Figure 7) and few orange and yellow spots due to C-H 3 3 3 O and H 3 3 3 H interactions. The surfaces for the DIPUR(β) polymorph clearly reveal different molecular environment for molecules A and B. The two red spots for molecule A, marked as 2a and 2b in Figure 7, indicate two N-H 3 3 3 O hydrogen bonds with the O atoms of the ureido group and Aib residue acting as the acceptors. The surface corresponding to molecule B, however, shows a single red spot (Figure 7) due to lone N-H 3 3 3 O hydrogen bond (see Table S1 in the Supporting Information). The 2D fingerprint plots44,45 of DIPUR(R) and DIPUR(β) are shown in Figure 8. A careful analysis reveals some significant differences between the molecular interactions in two polymorphs as well as among the crystallographically independent molecules in the asymmetric unit of each polymorph. A prominent pair of spikes around de = 0.80 A˚ to di = 1.15 A˚ and de = 1.15 A˚ to di = 0.80 A˚ of almost equal lengths with diffuse regions of points in between is apparent in the plots for all four molecules of DIPUR(R). This feature is a characteristic of nearly equal N 3 3 3 O donor-acceptor distances (2.84 ( 0.03 A˚) and the cyclic hydrogen-bonding motif R21(6). The asymmetry in the lengths of two spikes (marked as 1a and 1b in Figure 8) for DIPUR(β) can be attributed to the large variation of N-H 3 3 3 O hydrogen bond distances [2.849(5)-3.046(5)A˚] and also the fact that only the N1 atom of molecule A participates in forming N-H 3 3 3 O bonded polymeric chain (Figure 8). The wings in the region of de = 1.62 A˚ to di = 1.14 A˚ and di = 1.62 A˚ to de = 1.14 A˚ (marked as 2 in Figure 8) in the fingerprint plots for molecules of DIPUR(β) correspond to C 3 3 3 H interactions. There is

Figure 7. Hirshfeld surfaces for different molecules in the asymmetric unit of DIPUR(R) and DIPUR(β).

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Figure 8. 2D fingerprint plots of DIPUR(R) and DIPUR(β).

distinct difference between the two polymorphic forms, DIPUR(R) and DIPUR(β) in terms of H 3 3 3 H interactions. This is reflected in the distribution of scattered points in high di, de region in the plots (Figure 8) and appearance of small wings around di = 2.32 A˚ to de = 1.87 A˚ and de = 2.43 A˚ to di = 1.86 A˚ for molecules B and D in particular (marked as circle in Figure 8). The relative contributions of H 3 3 3 H, O 3 3 3 H, and other interactions to the Hirshfeld surface area

are depicted in Figure S2 in the Supporting Information for all molecules in the two polymorphs. The quantitative analysis clearly shows that the molecular interactions in both polymorphs are predominantly of H 3 3 3 H and O 3 3 3 H types, which can account for 96-98% of the Hirshfeld surface area. The variation in O 3 3 3 H interaction contributions from 33% for molecule A to 26% for molecule D confirms different packing environments of molecules in DIPUR(R).

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Although the calculated densities of two polymorphs are nearly equal (Table 1), the packing of molecules in DIPUR(R) seems to be more efficient due to extensive N-H 3 3 3 O and C-H 3 3 3 O hydrogen bonds and the formation of R21(6) synthon, a characteristic of dipeptidyl urea derivatives.4,46 A distance-angle scatter plot (see Figure S3 in the Supporting Information) showing more numerous short N-H 3 3 3 O and C-H 3 3 3 O interactions in high Z0 polymorph [DIPUR(R)] compared with the low Z0 one [DIPUR(β)] also supplement this. These observations are consistent with the lattice energy calculations, which show that the polymorph DIPUR(R) is energetically more favorable than DIPUR(β) by 18 KJ/mol. Conclusions The two polymorphic forms of a N,N0 - dipeptidyl urea compound, DIPUR(R) and DIPUR(β), represent an interesting example, in which both polymorphs crystallize with multiple molecules in the asymmetric unit. The present structural studies clearly demonstrates that deliberate incorporation of Aib residues in the title compound can impose constraints on supramolecular aggregation and lead to chiral packing arrangement. The packing of molecules in DIPUR(R) with Z0 = 4 seemed to be more efficient than that in DIPUR(β) with Z0 = 2 due to numerous intermolecular N-H 3 3 3 O and C-H 3 3 3 O hydrogen bonds in the polymorph with higher Z0 . The Hirshfeld surfaces and fingerprint plots prove to be particularly suited for comparing the molecular environments in structures with Z0 > 1, which often exhibit complex interplay between the crystallographically independent molecules. Synthesis and structural characterization of other Aib containing pseudopeptides is underway to establish any correlation between supramolecular aggregation and Z0 > 1. This kind of approach can be useful in crystal engineering for quantitative analysis of intermolecular interactions and designing of novel organic materials, which are intrinsically linked to polymorphism. Supporting Information Available: Two crystallographic files (CIF); hydrogen-bonding interactions, figures of the two crystals, figure for relative contributions to the Hirshfeld surface areas for the various intermolecular contacts, and a distance-angle scatter plot (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.

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