Journal of Molecular Structure 1001 (2011) 68–77

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Journal of Molecular Structure

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Experimental and theoretical structural study of (3E,5E)-3,5-bis-(benzylidene)-4-oxopiperidinium mono- and (3E,5E)-3,5-bis-(4-N,N-dialkylammonio)benzylidene)-4-oxopiperidinium trications

Alexandr Fonari a, Evgeniya S. Leonova a,b, Michail V. Makarov b, Ivan S. Bushmarinov b, Irina L. Odinets b,Marina S. Fonari a,c, Mikhail Yu. Antipin a,b, Tatiana V. Timofeeva a,⇑a Department of Biology & Chemistry, New Mexico Highlands University, Las Vegas, NM 87701, USAb A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilova Str. 28, 119991 Moscow, Russiac Institute of Applied Physics, Academy of Sciences of Moldova, Academy Str. 5, MD2028, Chisinau, Republic of Moldova

a r t i c l e i n f o

Article history:Received 28 April 2011Received in revised form 17 June 2011Accepted 17 June 2011Available online 25 June 2011

Keywords:3,5-Bis(benzylidene)-piperid-4-one3,5-Bis[(4-dialkylamino)benzylidene]-piperid-4-one3,5-Bis(benzylidene)-4-oxopiperidiniumsaltsX-ray structureDFT calculations

0022-2860/$ - see front matter � 2011 Elsevier B.V. Adoi:10.1016/j.molstruc.2011.06.020

⇑ Corresponding author. Tel.: +1 505 454 3362.E-mail address: tvtimofeeva@nmhu.edu (T.V. Timo

a b s t r a c t

(3E,5E)-3,5-Bis(benzylidene)-4-oxopiperidinium tetrafluoroborate [C19H18NO][BF4] (1), (3E,5E)-3,5-bis[4-(dimethylammonio)benzylidene]-4-oxopiperidinium bearing mixed tetrafluoroborate and bis(hexa-fluoro(l-hydroxo)diborate) anions [C23H30N3O][B2F6OH]n[BF4]m�xH2O (2), and (3E,5E)-3,5-bis[4-(diethyl-ammonio)benzylidene]-4-oxopiperidinium tris(tetrafluoroborate) monohydrate [C27H38N3O][BF4]3�H2O(3) were obtained via mediated by the boron trifluoride etherate aldol-crotonic condensation of the cor-responding aldehyde and piperidin-4-one hydrochloride monohydrate. Their structures were studied byIR and multinuclear NMR spectroscopy, and single crystal X-ray diffraction. The X-ray analysis revealedthe presence of monoprotonated piperidinium cation in 1 and triprotonated cations in 2 and 3. The hexa-fluoro(l-hydroxo)diborate anion was found in the mixed-anionic salts 2A and 2B which differ by theratio of the anions. The extended hydrogen-bonded system is registered in all compounds. Static firstorder hyperpolarizabilities for the neutral (3E,5E)-3,5-bis[4-(dimethylamino)benzylidene]-piperidin-4-one and its positively charged derivatives along with their molecular geometries and binding energy of1 were calculated using DFT approach.

� 2011 Elsevier B.V. All rights reserved.

1. Introduction

Symmetrical 3,5-bis(arylidene)-4-cyclohexanones (ACHs), -cyclopentanones (ACPs), and 3,5-bis(arylidene)piperid-4-ones(APs) (Scheme 1) are around for many years. They attract a partic-ular interest due to their remarkable physical properties as well asbioactivity. Physical and chemical nature allowed them to be uti-lized as antiviral, antitumor, and antimutagen agents [1]. The un-ique biological properties of the ACHs, ACPs, and APs have beenexplained by the presence of the conjugated 1,5-diaryl-3-oxo-1,4-pentadienyl (dienone) pharmacophore moiety, which canselectivity interact with cell thiols, without touching the hydroxyland amino groups, which are present in DNA and RNA, thereby thegenotoxyc side effects may be excluded [2]. Moreover, APs demon-strated high antimycobacterial properties [3], and the activity ofACHs and APs as potent reverters of multidrug resistance was alsoobserved [4].

In addition, compounds with the D–p–A–p–D structure pre-sented in Scheme 1 are good candidates for non-linear optical

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feeva).

(NLO) organic materials with two-photon absorption (TPA) andfluorescence properties [5] as well as the structural units forphoto-crosslinkable [6] and coordination polymers [7]. The combi-nation of their bioactivity and physical properties suggests thatsuch materials have potential as the agents for the localized treat-ment of cancers via photodynamic therapy [8]. Note that both bio-logical and physical properties can be diversified by alteration ofthe substituents at the phenyl rings or by introduction of thegroups at the piperidone nitrogen atom [9,10]. Thus, the presenceof strong electron-withdrawing substituents in aryl moieties aswell as introduction of N-acyl, N-alkyl or N-phosphoryl moietiesusually results in significant increase of the antitumor propertiesof 3,5-bis(arylidene)piperid-4-ones, while the electron-donorgroups contribute significantly to fluorescence and TPA.

Traditionally, the ACHs, ACPs and APs are prepared by the aldol-crotonic condensation of the cyclic ketone or N-substituted piperid-4-ones with two equivalents of the corresponding aldehyde [11], thereaction proceeds under the action of strong bases (NaOH/EtOH) orprotic acids (gaseous HCl/AcOH). In time, the synthetic procedure forpreparation of ACHs and ACPs was significantly improved by appli-cation of Lewis acid or base catalysts, including also the concurrentuse of microwave or ultrasonic irradiation and ionic liquids [12].

Scheme 1. General structure for ACH, ACP, and AP.

A. Fonari et al. / Journal of Molecular Structure 1001 (2011) 68–77 69

More recently, a range of Lewis acids and bases was tested for the al-dol-crotonic condensation of piperid-4-ones [13]. This comparativestudy has revealed three effective catalytic systems, namely lithiumperchlorate and magnesium bromide (both in the presence of ter-tiary amine), and boron trifluoride etherate allowing the highyielding synthesis of 3,5-bis[(hetero)arylidene]-piperid-4-ones,including those bearing acid or basic labile groups. The usage of bor-on trifluoride etherate was especially advantageous as it providedsimultaneous condensation and deprotection of O-protected pipe-rid-4-ones along with an easy isolation procedure of the final prod-ucts as tetrafluoroborate salts [13].

Therefore, using the improved procedure, we have performedthe synthesis of a number of 3,5-bis(arylidene)-4-piperidones inthe presence of boron trifluoride etherate, and carried out thestructural characterization of the final salt products. The reportedso far crystalline E,E-3,5-bis(4-benzylidene)-4-piperidones fall intotwo groups: neutral bases with substituents either at piperidoneN-atom or at the two phenyl rings, or at all three rings [9,10,14–23], and their salts, where pharmacophore molecule exists as amonocation bearing a positive charge at the piperidone N-atom[17,21,24–28]. As it was noted previously [29], under physiologicalconditions the pharmacophore molecule such as E,E-3,5-bis(4-ben-zylidene)-4-piperidone, which has a basic center, exists as an equi-librium mixture of the ionized species and free base. The authors[29] suggested that the charged molecules may be unable to pen-etrate cell membrane, however N-alkyl- and N,N-dialkyl-3,5-bis(arylidene)piperidone hydrohalides demonstrated the cytotoxicproperties towards human carcinoma cell lines in micromolarrange [24]. Hence it was interesting to compare structural andelectronic characteristics of neutral AP molecules studied before,and mono- and tri-cations obtained in the form of fluoroboratesalts and characterized in present publication. To the best of ourknowledge, the tri-cations of piperidones have not been structur-ally studied so far.

Here we report the synthesis, spectroscopic, and X-ray investi-gation, as well as DFT characterization for (3E,5E)-3,5-bis(benzyli-dene)-4-oxopiperidinium tetrafluoroborate [C19H18NO][BF4](1), (3E,5E)-3,5-bis[4-(dimethylammonio)benzylidene]-4-oxopipe-ridinium tetrafluoroborate–bis(hexafluoro(l-hydroxo)diborate)[C23H30N3O][B2F6OH]n[BF4]m�xH2O (2A and 2B), and (3E,5E)-3,5-

Scheme 2. Schematic representation for 1–3.

bis[4-(diethylammonio)benzylidene]-4-oxopiperidinium tris(tetra-fluoroborate) monohydrate [C27H38N3O][BF4]3�H2O (3) (Scheme 2)obtained via the aldol-crotonic condensation in the presence ofboron trifluoride etherate. We also compared the neutral mole-cules and cationic forms based on results from DFT computationand X-ray data stored at CSD [30].

2. Experimental and calculation details

2.1. Materials and general methods

Unless otherwise noted, all chemicals were used as receivedfrom commercial suppliers. Melting points were taken using opencapillary tubes and are uncorrected. The 1H (300 MHz), 13C(75 MHz), 19F (282 MHz) NMR spectra were recorded in solutionsin DMSO-d6 using residual proton signals (1H) and that of carbonatom (13C) of a deuterated solvent as an internal standard relativeTMS, and CFCl3 (19F) as an external standard. Chemical shifts arereported in parts per million (ppm), the coupling constants are re-ported in Hertz (Hz). Analytical TLCs were performed with SorbentTechnologies Silica G TLC plates w/UV254. Visualization wasaccomplished by UV light. IR spectra were recorded in KBr pelletson a Fourier-spectrometer ‘‘Magna-IR™’’ (Nicolet).

2.2. Synthesis

Compounds 1–3 were obtained using the procedure elaboratedby us earlier [13], namely by reacting of piperid-4-one monochlo-ride monohydrate with 2 equivalents of the corresponding alde-hyde in the presence of excess of BF3�Et2O (4 equiv.) in CH3CNunder reflux for ca. 12 h. After completion of the reaction, the mix-ture containing solid precipitate of crude product was dissolved inhot MeOH instead of EtOH used in the above original procedure.Growth of the crystals was observed in about 24 h.

2.2.1. (3E,5E)-Bis(benzylidene)-4-oxopiperidinium tetrafluoroboratemonohydrate 1

Beige crystalline solid. Mp = 220–225 �C (from MeOH). Yield 86%.1H NMR (DMSO-d6) d: 4.53 (4H, s, NCH2 (cyclic)), 7.51–7.57 (10H, m,2Ph), 7.92 (2H, s, CH@), 9.22 (2H, s, HN+H). 13C NMR (DMSO-d6) d:44.81 (NCH2 (cyclic)), 128.39 (CAr), 129.62 (CAr), 130.80 (@CH-),131.21 (CAr), 134.27 (CAr), 139.99 (NCH2C (cyclic)), 182.97 (C@O).19F NMR (DMSO-d6) d: �148.22, �148.15. IR (KBr): 3179br, 2884br(NAH), 2766br (NAH), 2713br, 2598br, 2566br, 1679w (C@O),1626s (C@C), 1622w (Ar), 1610s (Ar), 1601s (Ar), 1573w, 1479w,1446w, 1332w, 1295w, 1225w, 1193w (Ar), 1181w (Ar), 1168w,1099w, 1099w, 1087w, 1066w, 1046w, 972w, 927w, 776w, 690w,539w. Anal. Calcd. for C19H17NO�HBF4�H2O: C, 59.87; H, 5.29; N,3.67%. Found: C, 60.50; H, 4.78; N, 3.59%.

2.2.2. Bis[(3E,5E)-3,5-bis[4-(dimethylammonio)benzylidene]-4-oxopiperidinium] penta(tetrafluoroborate) bis(hexafluoro(l-hydroxo)diborate) pentahydrate 2A

Beige crystalline solid. Mp = 251–254 �C (from MeOH). Yield 81%.1H NMR (DMSO-d6) d: 3.12 (s, 12H, NMe2), 4,51 (s, 4H, NCH2 (cyclic)),

Table 1Selected crystal data, details of data collection and structure refinement for 1–3.

Compound 1 2A 2B 3

Empirical formula C19H18BF4NO C46H71.44B7F26N6O8.22 C23H34B5F16N3O4 C27H40B3F12N3O2

Composition [C19H18NO][BF4] [C23H30N3O]2[B2F3OH][BF4]5�(H2O)5.22 [C23H30N3O][B2F3OH]2[BF4]�H2O [C27H38N3O][BF4]3�H2OFw 363.15 1409.72 774.58 699.05T, K 100(2) 100(2) 100(2) 100(2)Crystal system Monoclinic Triclinic Triclinic MonoclinicSpace group Cm P-1 P-1 P21/na, Å 7.641(2) 9.9625(6) 9.9667(14) 8.1595(4)b, Å 18.838(6) 19.1062(11) 10.2557(15) 11.9256(6)c, Å 6.1654(17) 19.2366(11) 16.828(2) 33.2358(18)a, deg. 90.0 64.641(1) 105.600(3) 90.0b, deg. 111.882(5) 87.288(1) 99.157(3) 90.912(3)c, deg. 90.0 77.193(1) 90.255(3) 90.0V, Å3 823.5(4) 3221.7(3) 1633.6(4) 3233.7(3)Z 2 2 2 4dcalc, g cm�3 1.465 1.453 1.575 1.436l, mm�1 0.120 0.145 0.163 0.136F(0 0 0) 376 1448 788 1448Reflections collected/unique 1347/858 [Rint = 0.0293] 49,032/15,977 [R(int) = 0.0528] 11,527/6407 [Rint = 0.0413] 30,892/3779 [Rint = 0.1275]Data/restraints/parameters 858/2/133 15,977/406/983 6407/61/531 3779/165/531Goodness-of-fit on F2 0.966 1.255 0.995 1.020R1; wR2 (I > 2(I)) 0.0340; 0.0732 0.1443; 0.3653 0.0470; 0.0927 0.0708, 0.1555R1; wR2 (all data) 0.0440; 0.0763 0.2224; 0.4174 0.0992; 0.1100 0.1463, 0.1919

70 A. Fonari et al. / Journal of Molecular Structure 1001 (2011) 68–77

6.15 (br, 10H, H2O), 7.14 (d, 3JHH = 7.8 Hz, 4H), 7.49 (d, 3JHH = 8.5 Hz,4H), 7.84 (s, 2H, CH@), 9.25 (s, 2H, HN+H). 13C NMR (DMSO-d6) d:41.43 (NMe2), 44.41 (NCH2 (cyclic)), 114.73 (CAr), 124.24 (CAr),125.21 (NCH2C (cyclic)), 132.83 (CAr), 139.16 (@CHA), 149.18 (CAr),181.44 (C@O). 19F NMR (DMSO-d6) d: �145.43, �147.31, �147.37.IR (KBr): 3390br, 3016br (NAH), 2955br (NAH), 2628br, 2501br,1674m (conj. C@O, C@C), 1614w (Ar), 1594w (Ar), 1511w, 1469w,1450w, 1325w, 1304w, 1240w, 1186w, 1124s (Ar), 1084s (Ar),1061s (Ar), 980w, 943w, 898w, 847w. Anal. Calcd. forC23H27N3O�2.5HBF4�0.5H[(BF3)2OH]�2.5H2O: C, 39.30; H, 5.05; N,5.98%. Found: C, 39.33; H, 4.82; N, 6.02%. Along with 2A, the crystalsof bis[hexafluoro(l-hydroxo)diborate] tetrafluoroborate monohy-drate [C23H30N3O][B2F3OH]2[BF4]�H2O (2B) were also found andinvestigated by single crystal X-ray diffraction.

2.2.3. (3E,5E)-3,5-bis[4-(diethylammonio)benzylidene]-4-oxopiperidinium tris(tetrafluoroborate) dihydrate 3

Dark-beige crystalline solid. Mp > 160 �C (decomposition),(purified by precipitation from CH3CN with Et2O after crystalliza-tion from MeOH). Yield 80%. 1H NMR (DMSO-d6) d: 3.02 (12H, s,NMe2), 3.16 (0.6H, s, MeOH), 4,29 (8H, s, H2O), 4.47 (4H, s, NCH2

(cyclic)), 6.83 (4H, d, 3JHH = 8.9 Hz,), 7.37 (4H, d, 3JHH = 9.1 Hz,),7.76 (2H, s, CH@), 9.22 (2H, s, HN+H). 13C NMR (DMSO-d6) d:11.49 (N(CH2CH3)2), 44.39 (N(CH2CH3)2), 48.00 (NCH2 (cyclic)),116.84 (CAr), 125.20 (CAr), 133.07 (CAr, @CHA), 138.77 (NCH2C (cyc-lic)), 144.28 (CAr), 181.50 (C@O). 19F NMR (DMSO-d6) d: �148.08,�148.14. IR (KBr): 3518br, 3457br, 3134br (NAH), 2978br (NAH),2765br, 2674br 1691m (C@O), 1679w (C@C), 1622s (Ar), 1609w(Ar), 1560w, 1512w, 1450w, 1409w, 1315w, 1303w, 1233w,1181w, 1152w, 1082s (Ar), 1061s (Ar), 1037s, 979w, 939w,738w. Anal. Calcd. for C27H35N3O�3HBF4�2H2O:�C, 45.23; H, 5.90;N, 5.86%. Found: C, 45.30; H, 5.36; N, 5.67%.

2.3. X-ray crystallographic studies

The X-ray diffraction experiments for 1–3 were carried out witha Bruker SMART APEX II CCD diffractometer, using Mo Ka radiation(k = 0.71073 Å) at 100 K. The raw data frames were integrated withthe SAINT + program using narrow-frame algorithm [31]. Absorp-tion corrections were applied using the semiempirical method ofthe SADABS program [32]. The structures were solved by directmethods and refined using the Bruker SHELXTL programs suite

[33] by full-matrix least-squares methods on F2 with SHELXL-97in anisotropic approximation for all non-hydrogen atoms. All C-bound H atoms were placed in idealized positions and refined withconstrained C–H distances and Uiso(H) values set to 1.2Ueq or1.5Ueq (for methyl groups) of the attached C atom. The N-boundH-atoms in 1, 2B and 3 were located on difference Fourier mapsand refined in isotropic approximation. In 2A due to heavy disorderthe hydrogen atoms in water molecules were not localized, all theother H-atoms were calculated. In 2A the five [BF4]- anions disor-dered over 9 positions were refined as rigid bodies with allowedscaling (AFIX 9 in SHELX) except for B(60) one, which was refinedconstrained by DFIX instructions. As the positions of B(8), B(5)and B(7) groups could not be occupied simultaneously due to shortintermolecular contacts, the occupancies of B(8), B(80), B(5) andB(7) groups were allowed to refine with the sum of occupanciesconstrained to 2.00 to fulfill the electroneutrality of the unit cell.The two NMe2 groups were also disordered over two positionseach. The SIMU restraint was applied to fluorine atoms of each[BF4]� group and to each disordered NMe2 group. The NAC bondsin NMe2 groups were restrained to 1.502 Å using DFIX instruction.In 2B the F atoms in the [BF4]� anion are disordered over two ori-entations with the occupancy factors of 0.835(5) and 0.165(5). TheH-atoms in the water molecules were located on a difference Fou-rier map and refined using DFIX instruction for OAH and H� � �H dis-tances (0.86 and 1.46 Å, respectively). X-ray data for 3 wereobtained from the poor-diffracted crystal. The all three [BF4]� an-ions in 3 are disordered over two orientations, two anions definedby B(1) and B(2) with the equal occupancies, in the third anionthree F atoms (0.117 occupancy) are related by a pivot of approx-imately 60� about the fourth BAF bond. To hold the tetrahedralgeometry of the anions, both orientations were modeled usingSADI instruction for BAF and F� � �F distances. Water molecule in3 was refined with a half occupancy. Crystallographic data forthe structures in this paper have been deposited with the Cam-bridge Crystallographic Data Centre as supplementary publicationnos. CCDC 805229–805231 and 823348. Copies of the data can beobtained, free of charge, on application to CCDC, 12 Union Road,Cambridge CB2 1EZ, UK, (fax: +44 (0)1223 336033 or e-mail: de-posit@ccdc.cam.ac.uk). The X–ray data and details of the refine-ment for 1–3 are summarized in Table 1, the hydrogen bondinggeometry is given in Table 2, selected geometric parameters are gi-ven in Supporting information as Tables 1S-3S.

Table 2Intermolecular hydrogen bonds (Å, �) detected in 1, 2B, 3.

Compound DAH� � �A d(DAH) d(H� � �A) d(D� � �A) DHA

1 N(1)AH(1N)� � �F(2) 0.95(5) 2.13(4) 2.960(4) 146(2)N(1)AH(2N)� � �F(1)1 0.95(5) 1.86(6) 2.792(5) 159(4)C(3)AH(3B)� � �O(3)2 0.99 2.577 3.153 117

2B N(1)AH(1N1)� � �F(11) 0.98(3) 1.81(3) 2.769(3) 168(2)N(1)AH(2N1)� � �O(1)3 0.96(3) 1.87(3) 2.801(3) 161(3)N(2)AH(1N2)� � �F(6)4 0.93(3) 1.93(3) 2.836(3) 164(3)N(3)AH(1N3)� � �F(5)5 0.83(3) 2.11(3) 2.848(3) 148(2)N(3)AH(1N3)� � �F(4)5 0.83(3) 2.48(3) 3.141(3) 137(2)O(2)AH(2)� � �F(15A) 0.90(5) 1.70(5) 2.55(1) 156(4)O(2)AH(2)� � �F(13) 0.90(5) 1.76(5) 2.633(3) 163(4)O(3)AH(3)� � �O(1W) 0.87(3) 1.69(3) 2.554(3) 175(3)O(1W)AH(1W)� � �F(1) 0.86(2) 1.96(2) 2.803(3) 167(3)O(1W)AH(2W)� � �F(13A)6 0.85(2) 1.70(3) 2.457(2) 148(3)O(1W)AH(2W)� � �F(15)6 0.85(2) 2.02(2) 2.855(3) 170(3)

3 N(1)AH(1N1)� � �O(1W) 0.91(2) 1.85(3) 2.74(1) 164(6)N(1)AH(1N1)� � �F(11) 0.91(2) 2.37(6) 2.97(1) 124(5)N(1)AH(1N1)� � �F(8) 0.91(2) 2.36(6) 2.93(1) 120(5)N(1)AH(2N1)� � �F(2A)7 0.90(2) 1.85(5) 2.67(1) 149(7)N(1)AH(2N1)� � �F(2)7 0.90(2) 2.11(4) 2.98(1) 161(7)N(2)AH(1N2)� � �F(8)8 0.90(2) 2.01(3) 2.90(1) 169(6)N(2)AH(1N2)� � �O(1W)8 0.90(2) 2.44(6) 3.07(1) 127(5)N(2)AH(1N2)� � �F(6A)8 0.90(2) 2.53(5) 3.32(2) 147(6)N(3)AH(1N3)� � �F(11A)9 0.89(2) 1.90(6) 2.69(4) 148(7)N(3)AH(1N3)� � �F(12)9 0.89(2) 1.93(3) 2.800(7) 164(7)O(1W)AH(1W)� � �F(4) 0.86(2) 1.62(9) 2.26(1) 129(11)O(1W)AH(1W)� � �F(4A) 0.86(2) 1.81(4) 2.66(2) 165(14)O(1W)AH(1W)� � �F(11A) 0.86(2) 2.44(11) 3.04(4) 127(10)O(1W)AH(2W)� � �F(10A) 0.86(2) 2.15(11) 2.81(5) 133(11)O(1W)AH(2W)� � �F(6A) 0.86(2) 2.35(11) 2.83(2) 116(9)

Symmetry transformations used to generate equivalent atoms: 1 = x, y, z � 1; 2 = x, y, z + 1; 3 = 1 � x, 2 � y, 1 � z; 4 = x, y + 1, z; 5 = x � 1, y + 1, z + 1; 6 = 1 � x, 1 � y, 1 � z;7 = x � 1, y, z; 8 = 1 � x, �y, �z; 9 = 3/2 � x, y + 1/2, 1/2 � z.

A. Fonari et al. / Journal of Molecular Structure 1001 (2011) 68–77 71

2.4. Computational methodology

All calculations were carried out using the Gaussian09 program[34]. Geometry optimizations were performed for isolated mole-cules at the B3LYP/6-311G⁄⁄ level [35–37] without any symmetryrestriction. For 2 the denotation tails n, c, and c0 will be furtherused for neutral molecule, mono- and trications, respectively. Theoptimized geometry of 2c0 was modeled starting from the originalX-ray data presented herein. The starting geometry for monocation2c was obtained from VARZAP structure [28], where two methylgroups were replaced with two hydrogen atoms (charge was setto + 1); while for neutral molecule 2n – from KADNEI structure[19], where the methyl group at N-piperidone atom was replacedwith H-atom, both structures being retrieved from CSD [30]. Thefrequency calculations follow the geometry optimization in orderto verify the nature of stationary point. Mulliken charges [38] wereobtained at the B3LYP/6-311G⁄⁄ level of theory. First order statichyperpolarizabilities were calculated using the methodology de-scribed in [39]. Starting from the optimized geometry of 1 atB3LYP/6-311G⁄⁄ and B3PW91/6-311G⁄⁄ levels [35,40], binding en-ergy was calculated at B3LYP/6-311++G⁄⁄ and B3PW91/6-311++G⁄⁄

levels of theory as follows:

DE ¼ ðEð1Þ þ ZPEð1ÞÞ � ðEðcationÞ þ ZPEðcationÞÞ � ðEðanionÞþ ZPEðcationÞÞ þ EðBSSEÞ ð1Þ

where ZPE is the zero point energy correction, and E(BSSE) is a basisset superposition error energy correction, which was calculatedusing Counterpoise method [41,42].

Fig. 1. ORTEP plot for 1 with the numbering scheme. All non-H atoms are shownwith displacement ellipsoids drawn at the 50% probability level. The H atoms aredrawn as circles of arbitrary small radii.

3. Results and discussion

The crossed aldol-crotonic condensation of 4-piperidone and anaromatic aldehyde in the presence of boron trifluoride etherate

results in the formation of the desired 3,5-bis(arylidene)-piperid-4-one and two water molecules as the second reaction product.Hence, application of more than two equivalents of BF3�Et2O is nec-essary, and four molar equivalents of boron trifluoride etheratewere found to be optimal [13]. In the presence of water, BF3 grad-ually hydrolyses, and the consecutive substitution of fluorineatoms by hydroxyl groups affords the intermediate (HO)BF2 and(HO)2BF species, and probably, as final products, the boric acid(HO)3B and three molecules of HF. According to the elemental anal-ysis and X-ray powder diffraction data the traces of boric acid werefound in the crude salt products precipitated from the reactionmixtures. The side reaction of HF with BF3 being in excess, pro-vided tetrafluoroboric acid at any step of such substitution, and,as a consequence, the formation of the final product mainly asthe corresponding tetrafluoroborate salt precipitated from the

Fig. 2B. ORTEP plot for 2B with the numbering scheme. All non-H atoms are shown with displacement ellipsoids drawn at the 50% probability level. The H atoms are drawn ascircles of arbitrary small radii. For the disordered tetrafluoroborate anion only position with occupation of 0.835(5) is shown.

Fig. 2A. ORTEP plot for 2A with the numbering scheme. All non-H atoms are shown with displacement ellipsoids drawn at the 50% probability level. The H atoms are drawnas circles of arbitrary small radii. Only the most populated part is shown for the disordered fragments. C-bound H-atoms are omitted for clarity.

72 A. Fonari et al. / Journal of Molecular Structure 1001 (2011) 68–77

reaction medium. In the 19F NMR spectra for compounds 1–3 (seeSupporting Information) the tetrafluoroborate anion is character-ized by the presence of two closely located peaks at ca.�147–148 ppm in 1:4 ratio due to the isotopic shift for two boron iso-topes, 10B and 11B with the corresponding isotopic distribution of20% and 80%. At the same time, the 19F NMR spectrum of 2 con-tains, along with the signals typical for [BF4]� anion, the upfieldshifted signal at ca.�145 ppm, which in accordance with [43] couldbe assigned to the [F3B(l-OH)BF3]- anion. However, only X-raydata has demonstrated the reliable proof for the presence of[F3B(l-OH)BF3]� anion in both crystal forms of 2 (see below). Itshould be noted that the intensity ratio of the signals assigned tothe [F3B(l-OH)BF3]� and [BF4]� anions in the 19F spectra of the to-tal mass of the salt 2 was 1:2.5 that corresponded well to the

elemental analysis data and the X-ray structure of 2A, where twotrications, one bis(hexafluoro(l-hydroxo)diborate and five tetra-fluoroborate anions were found in the crystal lattice. However,some crystals have shown a different distribution of the anions,namely two bis(hexafluoro(l-hydroxo)diborate and one tetrafluo-roborate anion per one trication (form 2B). The generation of the l-hydroxo-bridged anion apparently proceeds as a transitional stepof BF3 hydrolysis comprising inter alia the reaction of the possible[HOBF3]�H+ intermediate with the second molecule of boron tri-fluoride. In this particular case, the mixed-anionic salt 2 with the[F3B(l-OH)BF3]� and [BF4]� anions evidently possesses the lowestsolubility in the CH3CN medium and precipitates from the solution.

ORTEP drawings for compounds 1–3 are presented in Figs. 1–3.A binary salt 1 with a molar ratio 1:1 crystallizes in the monoclinic

Fig. 3. ORTEP plot for 3 with the numbering scheme. All non-H atoms are shown with displacement ellipsoids drawn at the 30% probability level. The H atoms are drawn ascircles of arbitrary small radii. Only one position is shown for the disordered tetrafluoroborate anions.

Fig. 4. Schematic view of hexafluoro(l-hydroxo)diborate anion. Two tetrahedraformed by trifluoroboron groups (green), share the oxygen atom (red) vertex. The Hatom is drawn as circle of arbitrary radius. (For interpretation of the references tocolour in this figure legend, the reader is referred to the web version of this article.)

A. Fonari et al. / Journal of Molecular Structure 1001 (2011) 68–77 73

acentric Cm space group. Both cation and [BF4]� anion reside on thecrystallographic mirror plane passing through the piperidone C@Ogroup and NAH atoms, as well as B(1) and F(1) atoms. The multi-component salts 2A, 2B and 3 crystallize as hydrates in the centro-symmetric P-1 (both forms of 2) and P21/n (3) space groups, withall species occupying general positions in the unit cells.

The bond length distribution in the p-conjugated upper rim ofthe cation, referred as 1,5-diaryl-3-oxo-1,4-pentadienyl pharmaco-phore by Dimmock’s group [29], definitely shows the alternation ofsingle and double bonds (Table 3S). These values agree with thosereported in the literature [9,14–28]. The two bridging fragmentshaving sp2 carbons as their vertexes hold angle values greater than120� (128.2(2)–131.3(3)� range in 1–3). The authors [27] explainedthis fact by the existence of steric repulsion between H atoms

(a) (b)

Fig. 5. Supramolecular packing patterns in 1: hydrogen-bonded chai

attached to the C(3) and C(10) atoms and their symmetry-relatedcounter-parts (atom numbering corresponds to compound 1).

Similarly to the previously reported (3E,5E)-3,5-bis(4-benzyli-dene)-piperid-4-one compounds, the structures of the cations inthis paper are characterized by three planar fragments labeled inScheme 2, namely, the planar part of the central core (plane A),the two almost planar fragments that include phenyl ring andbridging atoms (planes B and C). In all compounds, the core adoptsan envelope conformation, N(1)-atom deviates at �0.687(6) in 1,0.736(3) in 2B, and �0.646(8) Å in 3 from the plane of five cyclicC-atoms. The dihedral angles between the planar fragments aresummarized in Table 2S, which also includes similar structures, ex-tracted from CSD [30]. In the majority of compounds includingneutral pharmacophore molecules, mono-, and trications, the dihe-dral angles between the piperidone and aryl rings do not exceed30�. Only in 3 and in 3,5-bis(4-dimethylaminobenzylidene)-1-methyl-4-piperidone methoiodide (refcode VARZAP) [28] these an-gles essentially exceed this value probably due to the cation–anionpacking interactions.

The [BF4]- anions in 1–3 have a tetrahedral geometry. The twosymmetrically independent hexafluoro(l-hydroxo)diborate anions[F3B(l-OH)BF3]� in 2B possess geometries similar to the reportedfor the same anion in 2-(1,3,4,5-tetramethylimidazolio) hexa-fluoro(l-hydroxo)diborate salt [44] (Table 1S). In each of the[F3B(l-OH)BF3]� units two tetrahedra of trifluoroboron groupsare rotated by 60o with respect to each other and share hydroxideoxygen as a common vertex (Fig. 4). Each boron atom has a regulartetrahedral environment with the BAF bond lengths lying in thetypical range 1.355(4)–1.398(4) Å, the slightly increased BAO

n (a); 3D network sustained by CH� � �F and p–p interactions (b).

(a) (b)

(c) (d)

Fig. 6. Fragments of crystal packing in 2: H-bonded self-assemble cationic motif (a); H-bonded self-assemble anionic motif (b); the interconnection of the cationic andanionic motifs (c); crystal packing (d).

74 A. Fonari et al. / Journal of Molecular Structure 1001 (2011) 68–77

distances, being 1.490(4)–1.508(4) Å, the OABAF angles equal to106.7(3)� and 110.0(2)�, and the bridging B(1)AO(2)AB(2) andB(3)AO(3)AB(4) angles equal to 129.7(3) and 129.8(2)�.

The crystal packing in 1–3 is governed by the combination ofstrong charge-assisted cation–anion NH+� � �F� hydrogen bonds,and weaker NH� � �O, CH� � �O and CH� � �F interactions (Table 2). In1, the cation–anion pair is bound by bifurcated NAH� � �F hydrogenbond, N(1)AH(1N)� � �F(2) = 2.960(4) Å, thus generating the R2

1(4)graph set [45]. Each [BF4]� anion displaying in a perching position,bridges two adjacent cations via the above mentioned H-bond, andthe second NH� � �F hydrogen bond, N(1)AH(2N)� � �F(1)(x, y,z � 1) = 2.792(5) Å, giving rise to the H-bonded ribbon runningalong the b direction (Fig. 5a). The self-association of the cationsoccurs via short contacts C(3)-H(3A)� � �O(1)(x, y, z + 1) = 3.153 Å,and N(1)AH(1 N)� � �O(1)(x, y, z + 1) = 2.934 Å that also act withinthe ribbon and contribute to its robustness. The ribbons are packed

into a pattern resembling a brick-wall, with the aromatic wings ofone ribbon hovering over the phenyl rings of the ribbon below (theinterplanar angle between the overlapping aromatic rings is13.87�, CgA� � �CgA centroid-to-centroid distance is 3.944 Å). The[BF4]� anions pillar the ribbons translated along the b directionvia CH� � �F weak contacts (H� � �F = 2.48 Å), thus generating thehigh-ordered 3D grid (Fig. 5b).

In 2B and 3 the trications bearing three positively charged bind-ing sites (one NHþ2 and two NHðAlkÞþ2 ) afford an extensive hydro-gen bonding system with all H-donor groups participating in H-bonding interactions. The crystal structure of 2B reveals an alterna-tion of hydrophobic and hydrophilic regions. The related by inver-sion center cations are segregated in dimers, stabilized by theintermolecular NH� � �O hydrogen bonding between the NHþ2 -groupand the carbonyl oxygen, N(1)AH(2N1)� � �O(1)(1 � x, 2 � y,1 � z) = 2.801(3) Å, the dimers are stacked along the b axis via

(a)

(c)

(b)

Fig. 7. Fragments of crystal packing in 3: association of three cations around three unique [BF4]� anions (a); self-assemble cationic motif sustained by H-bonding (view alongthe b direction) (b); crystal packing (c).

A. Fonari et al. / Journal of Molecular Structure 1001 (2011) 68–77 75

CH� � �O hydrogen bond C(22)-H� � �O(1)(�x, 2 � y, 1 � z) = 3.251 Å,giving rise to the H-bonded ladder (Fig. 6a). The negatively chargedinorganic species and water molecules form the centrosymmetric8-membered aggregates via OH� � �F and OH� � �O hydrogen bonds(Fig. 6b, Table 2). The conjunction between the cationic and anionicmotifs primarily occurs via hexafluoro(l-hydroxo)diborate anionswhose angular shapes facilitate the cations’ bridging (Fig. 6c). Sim-ilar to 1, numerous CH� � �F contacts also contribute to the robust 3Darchitecture (Fig. 6d).

An interesting feature of 3 is the H-bonded segregation of three[BF4]� anions around water molecule. Three cations are bound withthis anionic core via their different NH-binding sites (Fig. 7a). In theself-assembling cationic motif the related by the centers of symme-try cations are weakly bound in the corrugated ribbons,C(8)AH(8A)� � �O(1)(�x, 1 � y, �z) = 3.403 Å, C(12)AH(12A)� � �O(1)(1 � x, 1 � y,�z) = 3.333 Å (Fig. 7b). The crystal packing (Fig. 7c) rep-resents the most incommensurate case among 1–3, that is also evi-dent from the lowest crystal density value (Table 1).

It is well known that non-centrosymmetric molecules that havedonor and acceptor groups connected via p-conjugated bridge maypossess large NLO response. Marder with co-workers [46] corre-lated hyperpolarizability b to p-bond order alternation (BOA)[47] parameter of the molecule. In the case when the p-conjugatedbridge between donor and acceptor groups contains aromatic ringsit is important whether or not an electronic density can be redis-tributed in the quinoidal fashion to form BOA. As it is seen from

Scheme 3, structures 2n and 2c can have resonance forms facilitat-ing NLO response, since they contain quinoidal terminal phenylrings in contrast to 2c0, where the terminal nitrogen atoms sharetheir lone pairs with hydrogens to form trication. Indeed, the X-ray data and the optimized geometries as well as quantum chem-ical calculations of the first order static hyperpolarizabilityconfirmed this statement. The neutral molecules and the corre-sponding piperidonium mono-cations with the N-alkyl electron-donating substituents in the aromatic rings reveal their quinoidalstructure, with the reduced two central Csp2 –Csp2 bond distancesin the phenyl rings, and two terminal N–Csp2 bond distances. Onthe contrary, the trication loses the quinoidal structure as it is evi-dent from the less scattered Csp2 –Csp2 bond lengths in the aromaticrings, and elongated N–Csp2 distances (Table 3S).

The Mulliken population analysis reveals that in quinoidalstructures 2n and 2c the terminal nitrogens and four central Csp2

atoms of aromatic rings gain more electronegativity, suggestingsp2-hybridization of N atoms, and consequently donation of theirlone pairs in the system, while in 2c0 the charges on the terminalphenyl rings are distributed in a narrower range (aromatic system),and the hydrogen at nitrogen atom provides its sp3-hybridizationwith the formation of a single bond (Table 4S). The effect of the for-mation of quinoidal structure results in at least fivefold increase ofb value, from 5.28 for 2c0 to 31.89 (10�30esu) for 2n. A slightly lar-ger value for 2c (35.34 10�30esu) in comparison with 2n can beattributed to the more effective charge separation [46] due to

Table 3Calculated binding energies (DE) at different levels of theory for 1, corrected with ZPEand BSSE. Energies and BSSE corrections are in kcal/mol.

Level of Theory DE BSSE

B3LYP/6-311G⁄⁄ �96.00 7.75B3LYP/6-11++G⁄⁄ �93.06 1.63B3PW91/6-11G⁄⁄ �95.58 6.74B3PW91/6-11++G⁄⁄ �92.78 1.77

Scheme 3. Resonance forms of neutral 2n (top), monocationic 2c (middle) and triple cationic 2c0 (bottom) forms.

76 A. Fonari et al. / Journal of Molecular Structure 1001 (2011) 68–77

introduction of new positive charge in the system, when an exter-nal field is applied. The careful examination of CSD revealed that inthe family of 3,5-bis(arylidene)-piperid-4-ones the neutral mole-cules with donor substituents in para-positions in the aromaticfragments possess quinoidal aromatic rings (Table 3S), thus maybe candidates for NLO response.

The quantum chemical calculations of 1 were also performed.The geometries obtained from DFT calculations with both function-als are in good agreement with the XRD data (Table 3S). The aniondisplacement that results in the symmetry breaking in the complexcan be attributed to the absence of intermolecular interactions be-tween the charged species present in the crystal (Fig. 5a). The gap be-tween the highest occupied molecular orbital (HOMO) and thelowest unoccupied molecular orbital (LUMO) is 3.84 eV for B3LYP(B3PW91: 3.87 eV), implying that ground state of complex is stable.Dipole moment with the value of 8.5 Debye (B3PW91: 8.4 Debye) ispointing toward the cation species, indicating polarization of thecomplex. The binding energies of the cation–anion pair 1 are compa-rable with those reported for dimethylguaninium tetrafluoroborateionic pair [48] (Table 3). Comparing the performance of two differentfunctionals, it was observed that B3LYP gives slightly lower bindingenergies for both tested basis sets. When the basis set is augmentedwith diffuse functions, BSSE values are lowered by approximately4.5 kcal/mol for both functionals.

4. Conclusion

For the first time the trications (3E,5E)-3,5-bis[4-(dimethylam-monio)benzylidene]-4-oxopiperidinium and (3E,5E)-3,5-bis[4-

(diethylammonio)benzylidene]-4-oxopiperidinium were isolatedin the form of their hexafluoro(l-hydroxo)diborate/tetrafluorobo-rate (compound 2) and tris(tetrafluoroborate) (compound 3) salts.The structural evidence for the rare hexafluoro(l-hydroxo)dibo-rate anion is given. The screening of the molecular geometry forthe neutral 3,5-bis[4-(dialkylamino)benzylidene]-piperid-4-onesand their cationic forms using CSD, X-ray, and DFT approacheswas carried out and demonstrated the loss of the quinoidal geom-etry in the NH(Alk)2-substituted aromatic ring typical for the neu-tral molecule. The calculated interaction energy between thecharged species in (3E,5E)-3,5-bis(benzylidene)-piperidinium-4-one tetrafluorborate (1) suggests the formation of the tight ionicpair in gas phase. The calculated hyperpolarizabilities correlatewith quinoidal structures for neutral molecules and monocations.

Acknowledgments

This work was supported by the NSF DMR-0934121 and CHE-0820852. The authors are grateful for this support.

Appendix A. Supplementary material

19F NMR spectra for 1–3, Tables 1S–3S, summarizing the geo-metrical parameters obtained from the X-ray data, and DFT calcu-lations, Table 4S – summarizing Mulliken charges. Supplementarydata associated with this article can be found, in the online version,at doi:10.1016/j.molstruc.2011.06.020.

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