S S symmetry

Article X-ray Crystal Structure and Hirshfeld Analysis of Gem-Aminals-Based Morpholine, Pyrrolidine, and Moieties

Abdullah Mohammed Al-Majid 1, Matti Haukka 2 , Saied M. Soliman 3, Abdullah Saleh Alamary 1, Saeed Alshahrani 1, M. Ali 1, Mohammad Shahidul Islam 1 and Assem Barakat 1,3,*

1 Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia; [email protected] (A.M.A.-M.); [email protected] (A.S.A.); [email protected] (S.A.); [email protected] (M.A.); [email protected] (M.S.I.) 2 Department of Chemistry, University of Jyväskylä, P.O. Box 35, FI-40014 Jyväskylä, Finland; matti.o.haukka@jyu.fi 3 Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt; [email protected] * Correspondence: [email protected]; Tel.: +966-11467-5901; Fax: +966-11467-5992

Abstract: The gem-aminals of 1,2-dimorpholinoethane (1) and 1-morpholino-3-morpholinium bro- mide propane (2) were synthesized by reaction of two molar ratio of morpholine with the halo-

genating agents in the presence of basic condition (K2CO3) in acetone at room (RT) overnight. The structures of the centro-symmetric compound 1 and the morpholinium derivative 2 were assigned unambiguous by single crystal X-ray diffraction analysis and compared with the 1,2- di(pyrrolidin-1-yl)ethane 3 and 1,2-di(piperidin-1-yl)ethane 4. The 1,2-dimorpholinoethane molecule has a center of symmetry at the midpoint of the C-C bond of the ethyl moiety leading to two equiva-   lent halves. It crystallized in monoclinic crystal system and P21/n space group, while the unit cell parameters are determined to be a = 6.0430(3), b = 8.0805(3), c = 11.1700(4) Å, and β = 97.475(2)◦ with Citation: Al-Majid, A.M.; Haukka, M.; unit cell volume of 540.80(4) Å3 and Z = 2 at 170(2) K. The less symmetric analogue 2 crystallized in Soliman, S.M.; Alamary,A.S.; Alshahrani, the lower space group P21 with unit cell parameters of a = 6.37450(10), b = 11.1378(2), c = 9.6549(2) Å, S.; Ali, M.; Islam, M.S.; Barakat, A. and β = 93.358(2)◦, while the unit cell volume is 684.30(2)Å3 at 120(2) K. Using Hirshfeld analysis, X-ray Crystal Structure and Hirshfeld the molecules of 1 are mainly packed by weak N ... H (4.2%), O ... H (16.8%), and H ... H (79.0%) Analysis of Gem-Aminals-Based interactions. In contrast, the molecules of 2 are packed by significantly short O ... H (14.4%) and Br Morpholine, Pyrrolidine, and Piperidine Moieties. Symmetry 2021, 13, 20. ... H (11.6%) interactions in addition to the relatively long H ... H (73.3%) interactions. DFT cal- https://dx.doi.org/10.3390/sym130 culations predicted the molecular geometry of the studied compounds showing a good agreement 10020 with the experimental X-ray structures. Due to symmetry considerations, compounds 1, 3, and 4 are nonpolar with zero dipole moment, while the less symmetric molecule 2 has a dipole moment Received: 12 November 2020 of 6.914 Debye. Their electronic aspects, such as natural population charges, HOMO, and LUMO Accepted: 23 December 2020 energies as well as the corresponding reactivity descriptors, were also calculated and discussed. Published: 24 December 2020 Keywords: aminals; morpholine; pyrrolidine; piperidine; X-ray; Hirshfeld analysis; DFT Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional claims in published maps and institutional affiliations. 1. Introduction Aminals (gem-dimaines) linked with a spacer were studied extensively in a wide area of chemistry aspects. Aminals were employed as building blocks for the synthesis of gemini Copyright: © 2020 by the authors. Li- basic ionic liquids. This type of ionic liquids was recently investigated as environmental censee MDPI, Basel, Switzerland. This benign catalysts in due to high chemical and thermal stability with low article is an open access article distributed vapor and low viscosities [1–6]. under the terms and conditions of the Indeed, the diamines worked as N-donor ligands and chiral auxiliaries with many of Creative Commons Attribution (CC BY) metal ions such as Ca [7], Fe [8], Ag [9], Ni [10], Pd [11], and Rh [12], indeed, it explored license (https://creativecommons.org/ in various catalyzed protocols and were successively employed as efficient catalysts for licenses/by/4.0/).

Symmetry 2021, 13, 20. https://dx.doi.org/10.3390/sym13010020 https://www.mdpi.com/journal/symmetry Symmetry 2021, 13, 20 2 of 13

many transformations in organic synthesis. In this aspect, the aminals (gem-diamines) have been considered as promising electrophiles in metal-catalyzed nucleophilic addition reactions [13]. Nevertheless, gem-diamines are widely used in medicinal products, because the Symmetry 2021, 13, x FOR PEER REVIEW 4 of 14 existence of a lone pair on the atom will increase and improve the lipophilicity and the solubility of the pharmaceutical targets [14–16]. Given to the prevalence of diamines, there is a need for doing structure elucidation and also studying their chemical insights [17]. 3.2. X-ray Structure Description of 1 and 2 The symmetric as well as asymmetric catalysis, in particular in pharmaceutical industry, The X-ray structures of 1 and 2 with atom numbering and thermal ellipsoids drawn atare 50% continually probability level seeking are shown for rapid in Figure synthetic 2. The aminal routes 1 toas an novel example heterocyclic for gem-dia- structures for early- minestage is drug crystallized discovery, in the asmonoclinic well as crystal safe, robustsystem and and centro-symmetric environmentally P21/n friendly space routes for large groupscale with production. Z = 2. The Generalasymmetric tactics unit comprised for the half structure molecule elucidations due to the presence of the of aminals based on inversionmorpholine, center pyrrolidinelocated at the midpoint and piperidine of the C-C as of examplesthe ethane moiety. for gem-diamines The molecules are discussed in of 1 in the crystal are packed mainly by weak C5-H5A...O1 interactions leading to the hydrogenthis text bonding (Figure network1). shown in Figure 3.

Figure 1. 1.Gem-diaminesGem-diamines used in used this study. in this study.

2. Materials and Methods “The topology analyses were performed using Crystal Explorer 17.5 program [18]. All DFT calculations were performed using Gaussian 09 software package [19,20] utiliz- ing1 B3LYP/6-31G(d,p) method. Natural charge populations were calculated using NBO 3.1 program as implemented in the Gaussian 09W package [21]”.

2.1. Synthesis of 1,2-Dimorpholinoethane 1 and 1-Morpholino-3-Morpholinium Bromide Propane 2

The appropriate morpholine (10 mmol, 870 mg) and K2CO 3 (11 mmol, 1.520 gm) were stirred in acetone (10 mL) for 1 h, then 1,2-dibromoethane (5 mmol, 935 mg) or 1,3- dibromopropane (5 mmol,1005 mg) was added followed by continuous stirring overnight. K2CO3 in the reaction mixture was removed by simple filtration, and the product was washed with acetone. The was removed under vacuum, and the crystalline com- pounds were obtained upon standing at room temperature after three and five days for compounds2 1 and 2, respectively.

2.2. X-ray Structure Determinations of 1 and 2 The crystals of 1,2-dimorpholinoethane 1 or 1-morpholino-3-morpholinium bromide propane 2 were immersed in cryo-oil, mounted in a loop and measured at a temperature of

170 K in case of 1 and at 120 K for 2. The X-ray diffraction data were collected on a Bruker FigureKappa 2. X-ray Apex structure II and showing Rigaku atom Oxford numbering Diffraction and thermal ellipsoids Supernova at 50% diffractometers probability level for the aminals for compounds 1 (upper) and 2 (lower). 1 and 2, respectively. The Denzo-Scalepack [22] or CrysAlisPro [23] software packages were used for cell refinements and data reductions for 1 and 2, respectively. A multi- scan or Gaussian absorption correction based on equivalent reflections (SADABS [24]

(1) or CrysAlisPro [23](2) was applied to all data. The structures were solved by intrinsic phasing method using the SHELXT [25] software. Structural refinements were carried Symmetry 2021, 13, 20 3 of 13

out using SHELXL [25] software. In 2, the NH atom was located from the difference Fourier map and refined isotropically. Other hydrogen atoms were positioned geometrically and constrained to ride on their parent atoms, with C-H = 0.99 Å and Uiso = 1.2 Ueq (parent atom). The structure of 2 was solved in Sohncke space group P21. The Flack parameter was determined to be −0.039(9), indicating the presence of just one enantiomer. The crystallographic details are summarized in Table1.

Table 1. Crystal data of 1,2-dimorpholinoethane 1 and 1-morpholino-3-morpholinium bromide propane 2. Symmetry 2021, 13, x FOR PEER REVIEW 3 of 14

1 2

Table 1. Crystalempirical data of formula 1,2-dimorpholinoethane 1 and C 1-morpholino-3-morpholinium10H20N2O2 bromideC11 H23BrN2O2 propane 2. fw 200.28 295.22 temp (K) 170(2) 120(2) 1 2 λ (Å) 0.71073 1.54184 empirical formula C10H20N2O2 C11H23BrN2O2 cryst syst Monoclinic Monoclinic fw 200.28 295.22 space group P2 /n P2 temp (K) 170(2) 1 120(2) 1 a 6.0430(3) 6.37450(10) λ (Å) 0.71073 1.54184 crystb (Å) syst Monoclinic8.0805(3) Monoclinic 11.1378(2) spacec (Å) group P21/n11.1700(4) P21 9.6549(2) βa(deg) (Å) 6.0430(3) 97.475(2) 6.37450(10) 93.358(2) 3 Vb (Å(Å) ) 8.0805(3)540.80(4) 11.1378(2) 684.30(2) c (Å)Z 11.1700(4) 29.6549(2) 2 3 ρcalcβ (Mg/m(deg) ) 97.475(2) 1.230 93.358(2) 1.433 − µ (MoV K α(Å)3 (mm) 1) 540.80(4)0.086 684.30(2) 4.021 No. reflns.Z 2 124612 14253 Uniqueρcalc (Mg/m reflns.3) 1.230 15921.433 2811 μ (MoGOOF Kα) (mm (F2) −1) 0.086 1.074 4.021 1.054 No.R reflns.int 12461 0.0310 14253 0.0266 UniqueR1 a (I ≥reflns.2σ) 1592 0.0419 2811 0.0195 wR2GOOFb (I (F≥2)2 σ) 1.074 0.10961.054 0.0491 CCDCRint 0.0310 2,022,360 0.0266 2,039,255 a a R1 (I ≥ 2σ) b 0.04192 2 2 2 2 1/20.0195 R1 = Σ||Fo| − |Fc||/Σ|Fo|. wR2 = [Σ[w(Fo − Fc ) ]/Σ[w(Fo ) ]] . wR2 b (I ≥ 2σ) 0.1096 0.0491 CCDC 2022360 2039255 3.a R1 Results = Σ||Fo| − |Fc||/Σ|Fo|. b wR2 = [Σ[w(Fo2 − Fc2)2]/Σ[w(Fo2)2]]1/2.

3.1.3. Results Chemistry 3.1. ChemistryThe aminals compounds 1,2-dimorpholinoethane 1 and 1-morpholino-3-morpholinium bromideThe aminals propane compounds2 were 1,2-dimorpholinoethane synthesized according 1 and to Scheme1-morpholino-3-morpholin-1[ 26–28]. The target compounds provedium bromide to be propane synthesized 2 were synthesized in high chemicalaccording to yield Scheme (83 1 [26–28]. and 87% The fortarget1 and com-2, respectively) at roompounds temperatureproved to be synthesized (25 ◦C). in Their high chemical yield features (83 and were87% for elucidated 1 and 2, respec- based on the single tively) at room temperature (25 °C). Their chemical features were elucidated based on the crystalsingle crystal X-ray X-ray diffraction diffraction analysis.analysis.

Scheme 1. Synthesis 1. Synthesis of 1,2-dimorpholinoethane of 1,2-dimorpholinoethane 1 and 1-morpholino-3-morpholinium1 and 1-morpholino-3-morpholinium bromide bromide propane 2. propane 2.

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3.2. X-ray Structure Description of 1 and 2 The X-ray structures of 1 and 2 with atom numbering and thermal ellipsoids drawn at 50% probability level are shown in Figure 2. The aminal 1 as an example for gem-dia- mine is crystallized in the monoclinic crystal system and centro-symmetric P21/n space group with Z = 2. The asymmetric unit comprised half molecule due to the presence of inversion center located at the midpoint of the C-C of the ethane moiety. The molecules of 1 in the crystal are packed mainly by weak C5-H5A...O1 interactions leading to the hydrogen bonding network shown in Figure 3.

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3.2. X-ray Structure Description of 1 and 2 The X-ray structures of 1 and 2 with atom numbering and thermal ellipsoids drawn at 50% probability level are shown in Figure2. The aminal 1 as an example for gem-diamine is crystallized in the monoclinic crystal system and centro-symmetric P21/n space group with Z = 2. The asymmetric unit comprised half molecule due to the presence of inversion center located at the midpoint of the C-C of the ethane moiety. The molecules of 1 in

the crystal are packed mainly by weak C5-H5A...O1 interactions leading to the hydrogen Figure 1. Gem-diamines used in this study. bonding network shown in Figure3.

1

2

Symmetry 2021, 13, x FOR PEER REVIEWFigure 2. X-ray structure showing atom numbering and thermal ellipsoids at 50% probability5 of 14 level Figure 2. X-ray structure showing atom numbering and thermal ellipsoids at 50% probability level forfor compounds compounds 1 (upper)1 (upper) and 2 (lower). and 2 (lower).

FigureFigure 3. Packing 3. Packing of the of the molecular molecular units units in in1 1via viaweak weak C5-H5A...O1 {C5-H5A: {C5-H5A: 0.990 0.990 Å, H5A...O1: Å, H5A...O1: 2.683 2.683 Å, C5...O1: Å, C5...O1: 3.577(1) 3.577(1) Å, and C5-H5A...O1:150.2 Å; Symm. code: 1/2-x,-1/2+y,1/2-z}. Å, and C5-H5A...O1:150.2 Å; Symm. code: 1/2 − x, −1/2 + y,1/2 − z}.

Similarly, 2 crystallized in the monoclinic crystal system and the less symmetric P21 space group with Z = 2 and n-propyl moiety connecting the morpholine fragments where one of the morpholine moieties comprised a protonated nitrogen site. As a result, the com- pound is crystallized as 1-morpholino-3-morpholinium bromide propane. In this com- pound, there is no inversion center at the aliphatic n-propyl moiety. The molecular units in the crystal are packed by relatively short N-H...Br hydrogen bonding interactions as well as longer C-H...O and C-H...Br interactions. The details of the hydrogen bond param- eters are listed in Table 2. The hydrogen bonding network showing these interactions is shown in Figure 4.

Table 2. Hydrogen bond (Å, º) details in 2 a.

Atoms D-H H…A D…A D-H…A N2-H2...Br1 0.92(3) 2.29(3) 3.205(2) 178(2) C5-H5B…O1 0.99 2.52 3.457(3) 158 C11-H11B...Br1 0.99 2.75 3.580(3) 142 a D: hydrogen bond donor and A: hydrogen bond acceptor.

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Similarly, 2 crystallized in the monoclinic crystal system and the less symmetric P21 space group with Z = 2 and n-propyl moiety connecting the morpholine fragments where one of the morpholine moieties comprised a protonated nitrogen site. As a result, the compound is crystallized as 1-morpholino-3-morpholinium bromide propane. In this compound, there is no inversion center at the aliphatic n-propyl moiety. The molecular units in the crystal are packed by relatively short N-H...Br hydrogen bonding interactions as well as longer C-H...O and C-H...Br interactions. The details of the hydrogen bond parameters are listed in Table2. The hydrogen bonding network showing these interactions is shown in Figure4.

Table 2. Hydrogen bond (Å, ◦) details in 2 a.

Atoms D-H H ... AD ... A D-H ... A N2-H2...Br1 0.92(3) 2.29(3) 3.205(2) 178(2) C5-H5B . . . O1 0.99 2.52 3.457(3) 158

Symmetry 2021, 13, x FOR PEER REVIEW C11-H11B...Br1 0.99 2.75 3.580(3) 142 6 of 14

a D: hydrogen bond donor and A: hydrogen bond acceptor.

Figure 4. PackingFigure of the 4. molecular Packing of units the inmolecular2. units in 2.

3.3. Analysis of Molecular Packing 3.3. Analysis of Molecular Packing The Hirshfeld surfaces of 1 are shown in Figure 5. The molecules are mainly packed The Hirshfeld surfaces of 1 are shown in Figure5. The molecules are mainly packed by by weak N…H (4.2%), O…H (16.8%), and H…H (79.0%) interactions. The decomposed weak N ... H (4.2%), O ... H (16.8%), and H ... H (79.0%) interactions. The decomposed dnorm maps and fingerprint plots indicated that all these interactions are weak (Figure 6). dnorm maps and fingerprint plots indicated that all these interactions are weak (Figure6). All appeared as white or blue regions in the corresponding dnorm maps, indicating equal All appeared as white or blue regions in the corresponding dnorm maps, indicating equal oror longer longer distances distances than than the the vdW vdW radii sum ofof thethe interactinginteracting atoms, atoms, respectively. respectively.

dnorm

Shape index

Curvedness

Figure 5. Hirshfeld surfaces of 1.

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Figure 4. Packing of the molecular units in 2.

3.3. Analysis of Molecular Packing The Hirshfeld surfaces of 1 are shown in Figure 5. The molecules are mainly packed by weak N…H (4.2%), O…H (16.8%), and H…H (79.0%) interactions. The decomposed dnorm maps and fingerprint plots indicated that all these interactions are weak (Figure 6). Symmetry 2021, 13, 20 6 of 13 All appeared as white or blue regions in the corresponding dnorm maps, indicating equal or longer distances than the vdW radii sum of the interacting atoms, respectively.

dnorm

Shape index

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FigureFigure 5. Hirshfeld 5. Hirshfeld surfaces surfaces of 1. of 1.

Figure 6. Fingerprint plots (upper) and d surfaces (lower) of the N...H, O...H and H ... H contacts in 1 (d and d in Å). Figure 6. Fingerprint plots (upper) and dnormnorm surfaces (lower) of the N...H, O...H and H…H contacts in 1 (di andi de ein Å). Structure CCDC search returned with two structurally related compounds, which are Structure CCDC search returned with two structurally related compounds, which the 1,2-di(pyrrolidin-1-yl)ethane 3 [29] and 1,2-di(piperidin-1-yl)ethane 4 (CCDC: 840298). are the 1,2-di(pyrrolidin-1-yl)ethane 3 [29] and 1,2-di(piperidin-1-yl)ethane 4 (CCDC: Their Hirshfeld analyses are presented in Figure7. Additionally, the molecular packing of 840298). Their Hirshfeld analyses are presented in Figure 7. Additionally, the molecular 3 is mainly controlled by weak N ... H (4.7%) and H ... H (95.3%) interactions (Figure packing of 3 is mainly controlled by weak N…H (4.7%) and H…H (95.3%) interactions 8). Similarly, the packing in case of 4 is dominated by N ... H (3.5%) and H ... H (96.5%) (Figure 8). Similarly, the packing in case of 4 is dominated by N…H (3.5%) and H…H interactions. (96.5%) interactions.

3 4

dnorm

Shape index

Curvedness

Figure 7. Hirshfeld surfaces of 1,2-di(pyrrolidin-1-yl)ethane 3 and 1,2-di(piperidin-1-yl)ethane 4.

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Figure 6. Fingerprint plots (upper) and dnorm surfaces (lower) of the N...H, O...H and H…H contacts in 1 (di and de in Å).

Structure CCDC search returned with two structurally related compounds, which are the 1,2-di(pyrrolidin-1-yl)ethane 3 [29] and 1,2-di(piperidin-1-yl)ethane 4 (CCDC: 840298). Their Hirshfeld analyses are presented in Figure 7. Additionally, the molecular packing of 3 is mainly controlled by weak N…H (4.7%) and H…H (95.3%) interactions Symmetry 2021, 13, 20 7 of 13 (Figure 8). Similarly, the packing in case of 4 is dominated by N…H (3.5%) and H…H (96.5%) interactions.

3 4

dnorm

Shape index

Symmetry 2021, 13, x FOR PEER REVIEW 8 of 14 Curvedness

FigureFigure 7. 7. HirshfeldHirshfeld surfaces surfaces of of 1, 1,2-di(pyrrolidin-1-yl)ethane2-di(pyrrolidin-1-yl)ethane 33 andand 1,2-di(piperidin-1-yl)ethane 1,2-di(piperidin-1-yl)ethane 4..

3 4

FigureFigure 8.8. FingerprintFingerprint plotsplots (upper)(upper) and and d normdnorm surfacessurfaces (lower)(lower) ofof the the N...H, N...H, and and H H…H... H contacts in 1,2-di(pyrrolidin-1-1,2-di(pyrrolidin-1- yl)ethaneyl)ethane 33 andand 1,2-di(piperidin-1-yl)ethane1,2-di(piperidin-1-yl)ethane4 4(d (di i andand ddee inin Å).Å).

On the other other hand, hand, Hi Hirshfeldrshfeld surfaces surfaces of of 2 2areare shown shown in inFigure Figure 9. 9In. contrast In contrast to 1 to, 3, 1and, 3, 4and, the4 ,molecules the molecules of 2 ofare2 packedare packed by significantly by significantly short short O…H O (14.4%)... H (14.4%) and Br…H and Br(11.6%) . . . H interactions(11.6%) interactions in addition in addition to the relatively to the relatively long H…H long (73.3%) H ... H interactions. (73.3%) interactions. The de- Thecomposed decomposed dnorm maps dnorm showedmaps showed intense intense red spots red corres spots correspondingponding to these to theseinteractions interactions (Fig- (Figureure 9). 9Additionally,). Additionally, the the fingerprint fingerprint plot plot has has one one sharp sharp spike spike for for the the Br...H Br...H contacts contacts due due to tothe the interaction interaction between between the the N-H N-H proton proton inside inside the the surface surface and and the the bromide bromide anion outsideoutside thethe surfacesurface withwith H...BrH...Br distancedistance ofof 2.1972.197 ÅÅ (Br1...H2).(Br1...H2). OnOn thethe otherother hand,hand, thethe O...HO...H contactscontacts appeared as twotwo relativelyrelatively sharpsharp spikes,spikes, indicatingindicating thatthat thethe surfacesurface actingacting asas hydrogenhydrogen bond donor asas well as hydrogen bondbond acceptoracceptor (Figure(Figure 1010).). TheThe shortestshortest O...HO...H contactscontacts areare O1...H5B (2.431(2.431 Å)Å) andand O1...H10BO1...H10B (2.539(2.539 Å),Å), while the shortest H...HH...H contact isis H1A...H9A (2.281(2.281 Å).Å). AllAll thesethese interactionsinteractions stabilizedstabilized thethe crystalcrystal structurestructure ofof thethe studiedstudied molecules,molecules, wherewhere 22 hashas aa higherhigher meltingmelting pointpoint thanthan 11 as a consequence of the stronger intermolecular interactionsinteractions inin thethe formerformer comparedcompared toto thethe latterlatter compound.compound.

dnorm

Shape index

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3 4

Figure 8. Fingerprint plots (upper) and dnorm surfaces (lower) of the N...H, and H…H contacts in 1,2-di(pyrrolidin-1- yl)ethane 3 and 1,2-di(piperidin-1-yl)ethane 4 (di and de in Å).

On the other hand, Hirshfeld surfaces of 2 are shown in Figure 9. In contrast to 1, 3, and 4, the molecules of 2 are packed by significantly short O…H (14.4%) and Br…H (11.6%) interactions in addition to the relatively long H…H (73.3%) interactions. The de- composed dnorm maps showed intense red spots corresponding to these interactions (Fig- ure 9). Additionally, the fingerprint plot has one sharp spike for the Br...H contacts due to the interaction between the N-H proton inside the surface and the bromide anion outside the surface with H...Br distance of 2.197 Å (Br1...H2). On the other hand, the O...H contacts appeared as two relatively sharp spikes, indicating that the surface acting as hydrogen bond donor as well as hydrogen bond acceptor (Figure 10). The shortest O...H contacts are O1...H5B (2.431 Å) and O1...H10B (2.539 Å), while the shortest H...H contact is H1A...H9A Symmetry 2021, 13, 20 (2.281 Å). All these interactions stabilized the crystal structure of the studied molecules, 8 of 13 where 2 has a higher than 1 as a consequence of the stronger intermolecular interactions in the former compared to the latter compound.

dnorm

Symmetry 2021, 13, x FOR PEER REVIEW 9 of 14 Symmetry 2021, 13, x FOR PEER REVIEW 9 of 14

Shape index

Curvedness Curvedness FigureFigure 9. 9.Hirshfeld Hirshfeld surfaces of of 2.2 . Figure 9. Hirshfeld surfaces of 2.

Figure 10. Fingerprint plots (upper) and dnorm surfaces (lower) of the Br...H, O...H, and H…H contacts in 2 (di and de in Å).

3.4. DFT Studies The optimized geometries of the studied molecules are presented in Figure 11. Struc- FigureFigure 10. 10.Fingerprint Fingerprint plots plots (upper) (upper) and and d dnorm surfaces (lower) of the Br...H Br...H,, O...H, and HH…H... H contacts contacts inin 2 (d2 (di andand de din Å).in ture matchingnorm between the computed molecular geometries with the experimentali onese Å). 3.4.indicated DFT Studies very well the agreement between them (Table S1, Supplementary Materials). The maximum deviations in the bond distances do not exceed 0.013 Ǻ, while for angles, theThe maximum optimized deviation geometries is 3.2º for of 1the. In studiedthe case ofmo thelecules 1,2-di(pyrrolidin-1-yl)ethane are presented in Figure 3, the11. Struc- turecorresponding matching between values are the 0.098 computed Ǻ and 1.5º, molecular respectively, geometries while they with are the0.019 experimental Ǻ and 2.46º ones indicatedfor 2 and very 0.014 well Ǻ and the 2.9º agreement in 4, respectively. between Generally, them (Table the root S1, mean Supplementary square deviations Materials). The(RMSD) maximum for bond deviations distances in are the 0.008, bond 0.008, distances 0.027, and do 0.007not exceed Å in case 0.013 of compounds Ǻ, while for1–4 ,angles, therespectively. maximum Duedeviation to symmetry is 3.2º considerations,for 1. In the case compounds of the 1,2-di(pyrrolidin-1-yl)ethane 1, 3, and 4 are nonpolar with 3, the correspondingzero dipole moment, values while are 0.098 the less Ǻ andsymmetric 1.5º, respectively, 2 is polar and while has a netthey dipole are 0.019 moment Ǻ and of 2.46º for6.914 2 and Debye. 0.014 Ǻ and 2.9º in 4, respectively. Generally, the root mean square deviations (RMSD) for bond distances are 0.008, 0.008, 0.027, and 0.007 Å in case of compounds 1–4,

respectively. Due to symmetry considerations, compounds 1, 3, and 4 are nonpolar with zero dipole moment, while the less symmetric 2 is polar and has a net dipole moment of 6.914 Debye.

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3.4. DFT Studies The optimized geometries of the studied molecules are presented in Figure 11. Struc- ture matching between the computed molecular geometries with the experimental ones indicated very well the agreement between them (Table S1, Supplementary Materials). The maximum deviations in the bond distances do not exceed 0.013 Å, while for angles, the maximum deviation is 3.2◦ for 1. In the case of the 1,2-di(pyrrolidin-1-yl)ethane 3, the corresponding values are 0.098 Åand 1.5◦, respectively, while they are 0.019 Åand 2.46◦ for 2 and 0.014 Åand 2.9◦ in 4, respectively. Generally, the root mean square deviations (RMSD) for bond distances are 0.008, 0.008, 0.027, and 0.007 Å in case of compounds 1–4, Symmetry 2021, 13, x FOR PEER REVIEWrespectively. Due to symmetry considerations, compounds 1, 3, and 4 are nonpolar10 withof 14 zero dipole moment, while the less symmetric 2 is polar and has a net dipole moment of 6.914 Debye.

1

2

3

4

Figure 11. TheThe optimized optimized geometries geometries (left (left) and) and overlay overlay of the of theoptimized optimized with with experimental experimental structures structures (right (right) for the) for stud- the studiedied molecules. molecules.

The partial atomic charges using the NBO method revealed the high electronegative nature ofof nitrogennitrogen andand oxygen atoms atoms where where the the partial partial charges charges are are−0.520 −0.520 and and−0.577 −0.577 e, re-e, respectively,spectively, for for1. All1. All hydrogen hydrogen atoms atoms have have positive positive partial partial charges charges while while carbon atoms atoms have havenegative negative partial partial charges charges (Figure (Figure 12). Similar 12). Similar results results were obtainedwere obtained for the forbis the-pyrrolidino bis-pyrrol-3 idinoand bis- 3 piperidinoand bis-piperidino4 analogues, 4 analogues, where the where partial the charges partial at charges the pyrrolidine at the pyrrolidine and piperidine and piperidineN-atoms are N-atoms−0.511 andare −0.5110.518 and e, respectively. −0.518 e, respectively. The map of molecularThe map electrostaticof molecular potential electro- static potential over electron density revealed these results very well (Figure 13; MESP). On the other hand, the bromide anion has a partial charge of −0.703 e in 2, indicating some charge transfer from the bromide anion to the organic fragment. The amount of charge transference is 0.297 e. In this case, the red region of MESP is located over the bromide anion, while the most intense blue region is located over the protonated morpholine moi- ety.

Symmetry 2021, 13, 20 10 of 13

over electron density revealed these results very well (Figure 13; MESP). On the other hand, the bromide anion has a partial charge of −0.703 e in 2, indicating some charge transfer from the bromide anion to the organic fragment. The amount of charge transference is Symmetry 2021, 13, x FOR PEER REVIEW 11 of 14 0.297 e. In this case, the red region of MESP is located over the bromide anion, while the most intense blue region is located over the protonated morpholine moiety.

1

2

3

4

FigureFigure 12. 12.Partial Partial atomic atomic charges charges in in thethe studied molecular molecular systems. systems.

Symmetry 2021, 13, 20 11 of 13 Symmetry 2021, 13, x FOR PEER REVIEW 12 of 14

FigureFigure 13. The 13. MESP,The MESP, HOMO, HOMO, and and LUMO LUMO of of the the studied studied molecularmolecular systems. systems. Compounds Compounds 1, 2,1 3,,2 and, 3, and4 from4 fromup to updown, to down, respectively.respectively.

InIn addition, addition, the the HOMOHOMO and LUMO LUMO frontier frontier molecular molecular orbitals orbitals shown shown in Figure in Figure 12 12 areare important important for for the the moleculemolecule reactivity reactivity [3 [0–36].30–36 Their]. Their energies energies in case in caseof compound of compound 1 1 were calculated to be −5.889 and 2.323 eV, respectively. The relatively high HOMO– were calculated to be −5.889 and 2.323 eV, respectively. The relatively high HOMO–LUMO LUMO energy gap suggests a low tendency for the system to undergo intramolecular energy gap suggests a low tendency for the system to undergo intramolecular charge charge transfer (8.212 eV). The corresponding values in case of the bis-pyrrolidino-ana- transferlogue 3 (8.212 are −5.660, eV). 2.305, The correspondingand 7.872 eV, respectively. values in In case this ofregard, the bisthe-pyrrolidino-analogue ionization potential 3 are(I)− and5.660, electron 2.305, affinity and 7.872 (A) for eV, 1 are respectively. 5.889 and −2.323 In this eV, regard,respectively, the while ionization the hardness potential (I) and(η electron), electrophilicity affinity index (A) for (ω),1 andare chemical 5.889 and potential−2.323 (μ eV,) are respectively, 8.212, 0.194, whileand −1.783 the hardnesseV, (η),respectively electrophilicity (Table index 3). The (ω corresponding), and chemical values potential in the (µbis)-pyrrolidino-analogue are 8.212, 0.194, and 3− are1.783 eV, respectively5.660, −2.305, (Table 7.872,3). 0.169, The and corresponding −1.630 eV, respectively. values in Simila the bisr results-pyrrolidino-analogue were obtained for 3 are 5.660,compound−2.305, 4 7.872,. The high 0.169, stability and − of1.630 the eV,system respectively. towards intramolecular Similar results charge were transfer obtained for compoundcould be attributed4. The high to the stability absence of of delocalized the system π-system, towards where intramolecular 1 is slightly more charge stable transfer couldthan be the attributed bis-pyrrolidino-analogue to the absence of3. On delocalized the other πhand,-system, the HOMO where 1 (−is5.422 slightly eV) of more 2 is stable thanlocated the bis over-pyrrolidino-analogue the bromide ion, while3 the. On LUMO the other (1.361 hand, eV) is located the HOMO over the (− 5.422protonated eV) of 2 is locatedmorpholine over the moiety bromide indicating ion, whilean intramolecular the LUMO charge (1.361 transfer eV) is located from the over former the protonatedto the latter. The energy of this transition is 6.783 eV. The other reactivity descriptors for 2 are morpholine moiety indicating an intramolecular charge transfer from the former to the listed in the same table. latter. The energy of this transition is 6.783 eV. The other reactivity descriptors for 2 are listedTable in 3. the Reactivity same table.descriptors (eV) of the studied molecular systems.

Table 3. ReactivityParameter descriptors (eV)1 of the studied molecular2 systems.3 4 I 5.889 5.422 5.566 5.594 ParameterA 1−2.323 − 21.361 −2.305 3 −2.337 4 Iη 5.889 8.212 5.4226.783 7.872 5.566 7.931 5.594 A μ −2.323−1.783 −1.361−2.031 −−1.6302.305 −1.629− 2.337 ω 0.194 0.304 0.169 0.167 η 8.212 6.783 7.872 7.931 µ −1.783 −2.031 −1.630 −1.629 ω 0.194 0.304 0.169 0.167 Symmetry 2021, 13, 20 12 of 13

4. Conclusions Compounds 1 and 2 were successfully synthesized, and their structural features were assigned based on single crystal X-ray diffraction technique, while 3 and 4 were retrieved from literature for comparison with the structurally related 1. The supramolecular struc- tures of the studied compounds were analyzed using Hirshfeld calculations. The reactivity descriptors based on the HOMO and LUMO energies were also calculated. The calculated structures are found in good agreement with the experimentally observed X-ray structures. The molecular packing aspects and electronic properties of 1 are compared with the bis- pyrrolidino 3 and bis-piperidino 4 analogues. For 2, there is some intramolecular charge transfer from the bromide anion as electron donor fragment to the protonated morpholine moiety as electron acceptor one. The energy of this charge transfer is 6.783 eV, and the amount of electron density transferred is 0.297 e.

Supplementary Materials: The following are available online at https://www.mdpi.com/2073-899 4/13/1/20/s1. Software for X-ray determination (Tables for X-ray data); tables for computational studies; along with copies of NMR spectrum of the synthesized compounds. Author Contributions: Conceptualization, A.B.; data curation, S.M.S. and M.H.; formal analysis, M.H. and M.A.; funding acquisition, A.B.; investigation, M.S.I.; A.S.A.; S.A.; methodology, M.S.I. and M.A.; software, S.M.S. and M.H.; validation, A.M.A.-M.; Visualization, A.M.A.-M.; writing—original draft, A.B. and S.M.S.; writing—review and editing, A.B. and S.M.S. All authors have read and agreed to the published version of the manuscript. Funding: Deanship of Scientific Research at King Saud University for providing funding to this Research group NO (RGP-257). Acknowledgments: The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for providing funding to this Research group NO (RGP-257). The authors thank the Deanship of Scientific Research and RSSU at King Saud University for their technical support. Conflicts of Interest: The authors declare no conflict of interest.

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