Abstract
1H as well as 13C chemical shifts of 32 compounds of C (3) substituted 2-(n-alkylamino)-3R-naphthalene-1,4-dione (where n-alkyl: methyl, to octyl, R = H, Cl, Br, and CH3) are investigated through 1H, 13C, DEPT, gDQCOSY, and gHSQCAD NMR experiments and M06-2X/6-311++G (d,p) density functional theory are discussed. Single crystal X-ray structure of Br-3, as well as 18 different derivatives of naphthalene-1,4-diones, are revealed for its inter and intra-molecular hydrogen bonding interactions.
Keywords: Naphthoquinone, Aminonaphthoquinone, Chemical shift, 2D NMR
Naphthoquinone; Aminonaphthoquinone; Chemical shift; 2D NMR.
1. Introduction
Annamycin antibiotics with aminonaphthoquione in its core include naphthomycin K, divergolides C and divergolide D, naphthomycin A [1, 2, 3, 4]. Annamycin antibiotic finds applications in treating tuberculosis, leprosy, and AIDS-related mycobacterial infections. Aminonaphthoquinones Echimamine A, Echinamine B, and Spinamine are isolated from natural resources [5, 6, 7, 8]. Aminonaphthoquinone antibiotics are synthesized in the laboratory [8]. More interestingly, naphthalene-1,4-dione is rendered with anticancer, antibacterial, antifungal activities [9, 10, 11, 12, 13, 14, 15, 16] and its derivatives Menadione, Juglone, Plumbagin, or Vitamin K3-epoxide find applications in therapeutic use. These drug molecules generate reactive oxygen species (ROS), cause cell growth inhibition and consequently, cell death [17, 18, 19]. It has been realized that the effective stabilization of the enol species in naphthalene-1,4-dione derivatives that participate in electron transfer processes is key to cell growth inhibition [20].
The insights for structural rearrangements at the molecular level are crucial for understanding the biological activity. Thus their ramifications to spectral features have been the focus of attention for quite some time. To this direction, Illos et al. studied the fluorescence switching of molecular naphthoquinone, which showed chemo-as well as electro photo-switching. Furthermore, the effect of varying redox control, spacers, and fluorophore subunits on fluorescent molecules' switching behavior has also been investigated [21]. It has been inferred that the π-conjugated electrons make naphthalene-1,4-diones a probable candidate for nonlinear optical (NOL) properties. Mande et al. have carried out a detailed study on the NOL properties of naphthalene-1,4-diones derivatives employing the density functional theory (DFT) and Z-scan technique [22]. More recently, Navarro-Gracia et al. explored the naphthalene-1,4-dione derivatives as sensors in supramolecular chemistry to recognize anions [23].
In pursuance of the above studies, it has further been shown that the spectroscopy techniques unravel structural arrangements accompanying the naphthalene-1,4-dione derivatives using the chemical shifts data obtained from the 1H and 13C NMR experiments. The substituted positions in different isomers thus can be distinguished. Ribeiro et al. investigated 1,2- and naphthalene-1,4-dione derivatives. These groups established that the end group's ortho/para position and size attached to the naphthoquinone ring [24] could be ascertained through the chemical shifts measured from the experiment. Furthermore, Bedir et al. analyzed the structure typifying B-Lapachone naphthoquinone that revealed the ortho-coupled hydrogen from the 1H NMR experiments.
Moreover, the stereochemistry of lapachone was elucidated through the NMR data [25]. Consequently, 1D and 2D NMR data on naphthoquinone derivatives isolated via chloroform extraction of Diospyros maritime BLUME (Ebenaceae) fruit were measured. Subsequently 1H and 13C NMR signals were assigned. Higa et al. studied the quinonoid protons' signals, and correlated to heteronuclear multiple bond connectivity (HMBC), thereby specified the position of dimeric linkage in the synthesized molecule [26]. To probe further into the conformer, Prezhdo et al. studied the Kerr effect and the 1H as well as 13C NMR spectra of chloroalkyl derivatives of naphthalene-1,4-dione [27].
As pursuance to the above considerations, we in the present work undertake synthesis and characterization of a series of 2-(n-alkylamino)-3-R-naphthalene-1,4-dione (the n-alkyl group being methyl to octyl) [28, 29, 30, 31, 32, 33, 34]; as shown in Scheme 1.
Scheme 1.
Synthesis of n-alkylamino derivatives of naphthalene-1,4-dione.
All aminonaphthoquinone derivatives were characterized by using various spectroscopic experiments, namely, NMR, FTIR, UV-visible, and elemental analysis. The work focuses on 1H and 13C chemical shifts and substituent effects on chemical shifts. Consequently, the 2D NMR data further demonstrate the impact of substituent electronegativity on chemical shifts along with the methyl (-CH3, M-1 to M-8), bromo (-Br, Br-1 to Br-8), chloro (-Cl, Cl-1 to Cl-8) series, which are depicted in Figure 1 along with unsubstituted (-H in H-1 to H-8).
Figure 1.
Molecular structures a) 2-(n-alkylamino)-3-methyl-naphthalene-1,4-dione, b) 2-(n-alkylamino)-3-bromo-naphthalene-1,4-dione, c) 2-(n-alkylamino)-3-chloro-naphthalene-1,4-dione and d) 2-(n-alkylamino)-naphthalene-1,4-dione.
2. Experimental section
2.1. Materials and methods
The materials used for synthesis, vitamin K3 (2-methyl-naphthalene-1,4-dione), 2,3-dichloro-naphthalene-1,4-dione, 2,3-dibromonaphthalene-1,4-dione, naphthalene-1,4-dione, ethanamine solution (70%), propan-1-amine (99%), butan-1-amine (99%), pentyl-1-amine (99%), hexan-1-amine (99%), heptan-1-amine (99%) and octan-1-amine(99%) were purchased from Sigma-Aldrich and used as received. Methylamine solution (40%), obtained from Loba chemicals; toluene and methanol obtained from Merck Chemicals. Solvents were distilled by standard methods [30,35] and dried wherever necessary.
2.2. Synthesis
All compounds were synthesized and characterized using reported procedures as described in references [27, 28, 29, 30, 31, 32, 33]. 1 g of 2-methyl-naphthalene-1,4-dione (5.80 mmol for M-1 to M-8), 2,3-dibromonaphthalene-1,4-dione (3.2 mmol for Br-1 to Br-8), 2,3-dichloro-naphthalene-1,4-dione (4.4 mmol for Cl-1 to Cl-8), naphthalene-1,4-dione (6.32 mmol for H-1 to H-8) dissolved in 25–30 ml of dichloromethane and magnetically stirred at room temperature (26 °C–28 °C). The respective n-alkylamines (methyl - octyl) in equal mmol to that of parent naphthoquinone was added directly to this solution [28,36, 37, 38]. The mixture was magnetically stirred for 24 h. The solvent was evaporated naturally. With column chromatography, the crude solid product was purified using toluene: methanol (9:1) as an eluent system. Pure solid products were finally obtained with 60 %–80%. Yield following the reduction of the pure fraction with the rotatory evaporator.
2.3. Analytical methods
Varian Mercury 500 MHz NMR spectrometer was used to record 1H, 13C, DEPT, gDQCOSY, and gHSQCAD NMR of all compounds in DMSO-d6 with TMS (tetramethylsilane) as a reference.
2.4. X-ray crystal structure
X-ray data of Br-3 was collected on D8 Venture PHOTON 100 CMOS diffractometer using graphite monochromatized Mo-Kα radiation (λ = 0.7107 Å) with exposure/frame = 10 s. The X-ray generator was operated at 50 kV and 30 mA, an initial set of cell constants and an orientation matrix calculated from 24 frames. The optimized strategy used for data collection included different sets off, and ω scans with 0.5° steps in φ/ω. Crystal to detector distance was 5.00 cm with 512 × 512 pixels/frame, Oscillation/frame -0.5°, maximum detector swing angle = -30.0°, beam centre = (260.2, 252.5), in-plane spot width = 1.24. Data integration was carried out using the Bruker SAINT program, and empirical absorption correction for intensity data using Bruker SADABS. The program is integrated into the APEX II package [39]. The data corrected for Lorentz and polarization effects. The structure was solved by direct Method using the SHELX-97 [40] with the final refinement of the structure performed by a full-matrix least-squares technique with anisotropic thermal data for non-hydrogen atoms on F2. The non-hydrogen atoms refined anisotropically, while the hydrogen atoms refined at the calculated positions as riding atoms with isotropic displacement parameters [40]. Molecular diagrams are drawn by Mercury software [41]. SHELXTL [40] and PLATON [42] was used to perform the structural calculations of Br-3 [43].
3. Result and discussion
All 32 compounds (Figure 1) were synthesized and characterized [28, 29, 30, 31, 32, 33, 34]. Molecular structures of most of the derivatives revealed from single-crystal X-ray diffraction studies. The majority of these compounds possess biological activity, for example, antibacterial [30], antifungal [28], and antiproliferative activity [31,32,34,44].
3.1. X-ray structure of Br-3
Crystal structures of 18 compounds (Table 2) of n-alkylamino-naphthalene-1,4-dione are known [28, 29, 30, 31, 32, 33, 34]. Compounds Cl-2 and Br-2 crystallize in the orthorhombic space group, whereas other compounds either crystallize in triclinic or monoclinic space groups. All solved crystal structures showed intramolecular and intermolecular N–H···O, C–H···O (except Br-2) interactions (Table 2). Besides, Cl-2, Cl-4 possess Cl···π and Br-2; Br···π interaction. The C–H···π interactions are evident in the methyl derivatives M-1, M-2, and M-6. Lastly, the H-3 and H-6 indicate the presence of C···O and N···O interactions.
Table 2.
X-ray structure data of n-alkylamino-3R-naphthalene-1,4-diones.
| Compound | Space group | CCDC | N–H···O | C–H···O | Cl···π/π···π | Bifurcated hydrogen through O(1)/O(4) |
|---|---|---|---|---|---|---|
| Cl-1 | P -1 | 907096 | √ | √ | π···π | O(1), O(4) |
| Cl-2 | Pca21 | 907097 | √ | √ | Cl···π | - |
| Cl-3 | P-1 | 907098 | √ | √ | π···π | O(1) |
| Cl-4 | P21 | 925343 | √ | √ | π···π/Cl···π | O(4) |
| Cl-6 | P21/C | 925344 | √ | √ | C–H···π | - |
| Cl-8 | P21/C | 924571 | √ | √ | π···π | - |
| Br-3 | P-1 | 949769 | √ | √ | π···π | O(4) |
| Br-2 | P c a 21 | 953429 | √ | × | Br···π | - |
| M-1 | C2/C | 640771 | √ | √ | C–H···π/π···π | O(1)/O(4) |
| M-2 | C2/C | 1446868 | √ | √ | C–H···π | O(4) |
| M-3 | P1 | 1021052 | √ | √ | π···π | O(4) |
| M-6 | P21 | 1446870 | √ | √ | C–H···π | O(4) |
| H-2 | P21/C | 975344 | √ | √ | - | O(4) |
| H-3 | P21/C | 1417468 | √ | √ | π···π | O(1)/O(4) |
| H-4 | P-1 | 1426148 | √ | √ | π···π | O(4) |
| H-6 | P-1 | 975345 | √ | √ | C···O, C···N | - |
| H-8 | P-1 | 1417469 | √ | √ | C···O | - |
ORTEP diagram of Br-3 is shown in Figure 2. The structure of Br-3 was reported at 100K, with a minor variation of cell parameters observed at 296 K (Table 1) with an increase in cell volume by 24 Å3. The molecules of Br-3 showed inter and intramolecular N–H···O hydrogen bonding, and the molecules formed a polymeric chain via intermolecular C–H···O and N–H···O interactions. The neighboring polymeric chains are connected via bifurcated C–H···O, N–H···O, and π-π interactions (Figure 3). Other analogs further evidence bifurcated hydrogen bonding through either O(1) and O(4) (cf. Table 2).
Figure 2.
ORTEP diagram Br-3. The ellipsoids are drawn with 50% probability.
Table 1.
Crystal data and structure refinement for Br-3.
| Empirical formula | C13 H12 Br N O2 | |
| Formula weight | 294.15 | |
| Temperature | 296 (2) K | |
| Wavelength | 0.71073 Å | |
| Crystal system | Triclinic | |
| Space group | P -1 | |
| Unit cell dimensions | a = 7.3470 (2) Å | α = 110.3660 (6)° |
| b = 7.9862 (2) Å | β = 91.5200 (6)° | |
| c = 10.9580 (2) Å | γ = 95.6780 (6)° | |
| Volume | 598.52 (2) Å3 | |
| Z | 2 | |
| Density (calculated) | 1.632 Mg/m3 | |
| Absorption coefficient | 3.422 mm−1 | |
| F (000) | 296 | |
| Crystal size | 0.32 × 0.26 × 0.11 mm3 | |
| Theta range for data collection | 2.759–28.474° | |
| Index ranges | -9<=h<=9, -10<=k<=10, -14<=l<=14 | |
| Reflections collected | 24055 | |
| Independent reflections | 3019 [R (int) = 0.0630] | |
| Completeness to theta = 25.242° | 99.9 % | |
| Absorption correction | Semi-empirical from equivalents | |
| Max. and min. transmission | 0.686 and 0.358 | |
| Refinement method | Full-matrix least-squares on F2 | |
| Data/restraints/parameters | 3019/0/155 | |
| Goodness-of-fit on F2 | 1.037 | |
| Final R indices [I > 2 sigma(I)] | R1 = 0.0580, wR2 = 0.1615 | |
| R indices (all data) | R1 = 0.0792, wR2 = 0.1751 | |
| Extinction coefficient | n/a | |
| Largest diff. peak and hole | 0.636 and -0.578 e.Å−3 | |
Figure 3.
Molecular packing of Br-3 down a-axis.
3.2. NMR spectroscopy
NMR spectra of all the compounds with a series of side-chain homologated derivatives of 2-(n-alkylamino)-3R-naphthalene-1,4-dione (where the n-alkyl group is methyl to octyl) and different substituent at C(3) position –CH3 (M-1 to M-8), or –Br (Br-1 to Br -8), or -Cl (Cl-1 to Cl-8), and –H(H-1 to H-8) have been analyzed from their NMR spectra, DMSO-d6 used as a solvent. We have performed the analysis with a 1D experiment like 1H, 13C, and DEPT to compare every side chain derivative's chemical shifts with different substituents at C (3). 1H, 13C NMR of all compounds represented in Fig. S1 through Fig. S32 in ESI, and their gDQCOSY and gHSQCAD spectra are presented in Fig. S33 through Fig. S80 in ESI. The experimental and calculated 1H chemical shift is shown in Table S1 through Table S8, whereas the 13C chemical shift is presented in Table S9 through Table S16 in ESI. The representative 1H chemical shifts of methyl, butyl, and octyl derivatives is shown in Tables 3, 4, and 5, respectively, and the 13C chemical shifts are presented in Tables 6, 7 and 8, 1H and 13C chemical shift of Br-1 to Br-8 respectively shown in Tables 9 and 10.
Table 3.
1H chemical shift in ppm (observed and calculated) of H-1, M-1, Br-1, Cl-1.
| Experimental |
Theoretical |
|||||||
|---|---|---|---|---|---|---|---|---|
| H-1 | M-1 | Br-1 | Cl-1 | H-1 | M-1 | Br-1 | Cl-1 | |
| H (8) | 7.94 | 7.90 | 7.95 | 7.96 | 9.96 | 10.14 | 9.51 | 9.96 |
| H (7) | 7.80 | 7.74 | 7.79 | 7.81 | 9.70 | 9.33 | 9.46 | 8.94 |
| H (6) | 7.69 | 7.64 | 7.71 | 7.72 | 9.61 | 9.46 | 9.84 | 9.21 |
| H (5) | 7.91 | 7.84 | 7.94 | 7.95 | 9.61 | 9.90 | 10.02 | 10.23 |
| R-(3) | 5.56 | 2.10 | - | - | 7.22 | 4.03 | - | - |
| NH | 7.60 | 6.83 | 7.53 | 7.55 | 6.16 | 6.05 | 6.37 | 6.37 |
| H(a) | 2.76 | 3.14 | 3.25 | 3.28 | 3.72 | 3.26 | 4.33 | 4.36 |
Table 4.
1H chemical shift in ppm (observed and theoretical) of H-4, M-4, Br-4 and Cl-4.
| Experimental |
Theoretical |
|||||||
|---|---|---|---|---|---|---|---|---|
| H-4 | M-4 | Br-4 | Cl-4 | H-4 | M-4 | Br-4 | Cl-4 | |
| H (8) | 7.90 | 7.86 | 7.97 | 7.88 | 10.05 | 10.12 | 10.08 | 10.22 |
| H (7) | 7.76 | 7.74 | 7.80 | 7.66 | 9.60 | 9.32 | 9.37 | 9.42 |
| H (6) | 7.65 | 7.65 | 7.73 | 7.53 | 9.42 | 9.57 | 9.48 | 9.56 |
| H (5) | 7.89 | 7.88 | 7.95 | 7.77 | 9.55 | 9.58 | 9.70 | 6.67 |
| R-(3) | 5.64 | 2.06 | - | 7.01 | 3.31 | |||
| NH | 7.50 | 6.49 | 7.42 | 7.80 | 6.03 | 5.83 | 6.28 | 6.25 |
| H(a) | 0.88 | 0.84 | 0.89 | 0.86 | 2.05 | 1.93 | 2.07 | 2.07 |
| H(b) | 1.33 | 1.27 | 1.33 | 1.32 | 2.28 | 2.21 | 2.37 | 2.30 |
| H(g) | 1.54 | 1.48 | 1.59 | 1.52 | 2.62 | 2.51 | 2.38 | 2.50 |
| H(h) | 3.15 | 3.45 | 3.74 | 2.79 | 3.88 | 4.25 | 4.79 | 4.82 |
Table 5.
1H chemical shift in ppm (observed and theoretical) of H-8, M-8, Br-8 and Cl-8.
| Experimental |
Theoretical |
|||||||
|---|---|---|---|---|---|---|---|---|
| H-8 | M-8 | Br-8 | Cl-8 | H-8 | M-8 | Br-8 | Cl-8 | |
| H (8) | 7.96 | 7.92 | 7.96 | 7.97 | 10.18 | 10.26 | 9.99 | 10.06 |
| H (7) | 7.81 | 7.76 | 7.79 | 7.80 | 9.67 | 9.03 | 9.15 | 9.31 |
| H (6) | 7.70 | 7.67 | 7.72 | 7.73 | 9.53 | 9.25 | 9.26 | 9.66 |
| H (5) | 7.92 | 7.86 | 7.95 | 7.95 | 9.29 | 9.52 | 10.15 | 9.88 |
| R-(3) | 5.64 | 2.05 | - | 7.04 | 3.25 | - | - | |
| NH | 7.53 | 6.60 | 7.46 | 7.43 | 6.08 | 5.96 | 6.37 | 6.08 |
| H(a) | 0.83 | 0.82 | 0.82 | 0.83 | 1.85 | 1.84 | 1.88 | 1.81 |
| H(b) | 1.24 | 1.25 | 1.24 | 1.27 | 2.09 | 2.16 | 2.11 | 2.15 |
| H(c) | 1.24 | 1.25 | 1.24 | 1.27 | 2.18 | 2.20 | 2.34 | 2.12 |
| H(d) | 1.24 | 1.25 | 1.24 | 1.27 | 2.31 | 2.29 | 2.21 | 2.29 |
| H(e) | 1.24 | 1.25 | 1.24 | 1.27 | 2.38 | 2.39 | 2.36 | 2.29 |
| H(f) | 1.24 | 1.25 | 1.24 | 1.27 | 2.39 | 2.33 | 2.50 | 2.33 |
| H(g) | 1.56 | 1.54 | 1.58 | 1.59 | 2.73 | 2.66 | 2.64 | 2.46 |
| H(h) | 3.14 | 3.51 | 3.70 | 3.72 | 3.95 | 4.52 | 4.86 | 4.67 |
Table 6.
13C chemical shift in ppm of H-1, M-1, Br-1, Cl-1.
| Experimental | H-1 | M-1 | Br-1 | Cl-1 |
|---|---|---|---|---|
| C1 | 181.44 | 181.53 | 175.00 | 175.15 |
| C2 | 149.50 | 147.56 | 148.29 | 146.07 |
| C3 | 99.18 | 109.89 | 129.96 | 108.05 |
| C4 | 181.10 | 182.22 | 179.94 | 180.15 |
| C5 | 125.35 | 134.22 | 125.96 | 125.67 |
| C6 | 132.07 | 126.23 | 133.00 | 132.46 |
| C7 | 134.77 | 134.53 | 134.75 | 134.78 |
| C8 | 125.82 | 126.89 | 126.50 | 126.34 |
| C9 | 133.28 | 130.71 | 131.82 | 129.84 |
| C10 | 130.55 | 131.96 | 131.82 | 132.06 |
| C12 | - | 10.44 | - | - |
| a | 28.57 | 32.40 | 32.79 | 32.25 |
Table 7.
13C chemical shift in ppm of H-4, M-4, Br-4, and Cl-4.
| Experimental | H-4 | M-4 | Br-4 | Cl-4 |
|---|---|---|---|---|
| C1 | 181.55 | 181.59 | 175.08 | 173.50 |
| C2 | 149.48 | 146.70 | 147.28 | 166.76 |
| C3 | 99.15 | 110.59 | 129.81 | 112.68 |
| C4 | 181.16 | 182.26 | 179.80 | 184.32 |
| C5 | 125.28 | 125.63 | 126.52 | 125.21 |
| C6 | 132.04 | 132.78 | 132.49 | 135.08 |
| C7 | 134.76 | 134.45 | 134.77 | 133.62 |
| C8 | 125.82 | 125.38 | 126.01 | 125.42 |
| C9 | 133.19 | 130.25 | 131.74 | 130.47 |
| C10 | 130.36 | 132.09 | 131.74 | 130.57 |
| C12 | - | 10.66 | - | - |
| g | 29.37 | 32.76 | 32.65 | 29.09 |
| b | 19.68 | 19.38 | 19.26 | 19.07 |
| a | 13.62 | 13.73 | 13.65 | 13.45 |
| h | 41.57 | 44.14 | 43.82 | 38.64 |
Table 8.
13C chemical shift in ppm of H-8, M-8, Br-8, and Cl-8.
| Experimental | H-8 | M-8 | Br-8 | Cl-8 |
|---|---|---|---|---|
| C1 | 181.57 | 181.56 | 175.11 | 175.14 |
| C2 | 148.48 | 146.65 | 147.30 | 164.55 |
| C3 | 99.12 | 110.59 | 129.85 | 129.91 |
| C4 | 181.13 | 182.24 | 179.86 | 179.89 |
| C5 | 125.27 | 125.59 | 126.57 | 126.59 |
| C6 | 132.05 | 132.05 | 132.52 | 132.56 |
| C7 | 134.78 | 134.78 | 134.81 | 134.83 |
| C8 | 125.82 | 125.35 | 126.03 | 126.05 |
| C9 | 133.20 | 130.26 | 131.77 | 131.79 |
| C10 | 130.37 | 132.78 | 131.77 | 131.79 |
| C12 | 10.63 | |||
| f | 28.65 | 26.10 | 25.98 | 25.99 |
| e | 28.58 | 28.67 | 28.58 | 28.56 |
| d | 27.22 | 28.62 | 28.62 | 28.63 |
| c | 26.44 | 31.20 | 31.16 | 31.18 |
| g | 31.18 | 30.58 | 30.51 | 30.53 |
| b | 22.03 | 22.08 | 22.04 | 22.06 |
| a | 13.90 | 13.93 | 13.90 | 13.93 |
| h | 41.83 | 44.41 | 44.05 | 44.07 |
Table 9.
Experimental 1H chemical shift in ppm of Br-1 to Br-8.
| Br -1 | Br -2 | Br -3 | Br -4 | Br -5 | Br -6 | Br -7 | Br -8 | |
|---|---|---|---|---|---|---|---|---|
| H (8) | 7.95 | 7.97 | 7.97 | 7.97 | 7.96 | 7.90 | 7.98 | 7.96 |
| H (7) | 7.79 | 7.80 | 7.80 | 7.80 | 7.80 | 7.77 | 7.79 | 7.79 |
| H (6) | 7.71 | 7.72 | 7.72 | 7.73 | 7.72 | 7.68 | 7.72 | 7.72 |
| H (5) | 7.94 | 7.95 | 7.95 | 7.95 | 7.95 | 7.92 | 7.96 | 7.95 |
| NH | 7.53 | 7.43 | 7.44 | 7.42 | 7.42 | 7.44 | 7.43 | 7.46 |
| H(a) | 3.25 | 1.20 | 0.88 | 0.89 | 0.86 | 0.82 | 0.84 | 0.82 |
| H(b) | - | - | - | 1.33 | 1.30 | 1.23 | 1.28 | 1.24 |
| H(c) | - | - | - | - | 1.30 | 1.23 | 1.28 | 1.24 |
| H(d) | - | - | - | - | - | 1.23 | 1.28 | 1.24 |
| H(e) | - | - | - | - | - | - | 1.28 | 1.24 |
| H(f) | - | - | - | - | - | - | - | 1.24 |
| H(g) | - | - | 1.62 | 1.59 | 1.60 | 1.56 | 1.61 | 1.58 |
| H(h) | - | 3.77 | 3.70 | 3.74 | 3.73 | 3.67 | 3.72 | 3.70 |
Table 10.
Experimental13C chemical shift in ppm of Br-1 to Br-8.
| Br -1 | Br -2 | Br -3 | Br -4 | Br -5 | Br -6 | Br -7 | Br -8 | |
|---|---|---|---|---|---|---|---|---|
| C1 | 175.00 | 175.60 | 175.13 | 175.08 | 175.09 | 175.08 | 175.12 | 175.11 |
| C2 | 148.29 | 147.87 | 147.87 | 147.28 | 147.30 | 147.37 | 147.37 | 147.30 |
| C3 | 129.96 | 130.38 | 129.87 | 129.81 | 129.85 | 129.84 | 129.85 | 129.85 |
| C4 | 179.94 | 180.35 | 179.85 | 179.80 | 179.84 | 179.83 | 179.86 | 179.86 |
| C5 | 125.96 | 126.50 | 126.04 | 126.52 | 126.03 | 126.54 | 126.02 | 126.57 |
| C6 | 133.00 | 133.00 | 132.54 | 132.49 | 132.51 | 132.51 | 132.56 | 132.52 |
| C7 | 134.75 | 135.26 | 134.80 | 134.77 | 134.81 | 134.78 | 134.80 | 134.81 |
| C8 | 126.50 | 127.04 | 126.57 | 126.01 | 126.55 | 126.01 | 126.55 | 126.03 |
| C9 | 131.82 | 132.24 | 131.76 | 131.74 | 131.76 | 131.75 | 131.77 | 131.77 |
| C10 | 131.82 | 132.24 | 131.76 | 131.74 | 131.76 | 131.75 | 131.77 | 131.77 |
| a | 32.79 | 16.78 | 10.82 | 13.65 | 13.85 | 13.79 | 13.87 | 13.90 |
| b | - | - | 23.87 | 19.26 | 21.80 | 21.95 | 21.95 | 22.04 |
| c | - | - | - | - | 28.22 | 30.26 | 25.95 | 31.16 |
| d | - | - | - | - | - | 25.65 | 28.31 | 28.62 |
| e | - | - | - | - | - | - | 31.12 | 28.58 |
| f | - | - | - | - | - | - | - | 25.98 |
| g | - | - | - | 32.65 | 30.24 | 30.47 | 30.50 | 30.51 |
| h | - | 39.61 | 45.67 | 43.82 | 44.04 | 44.08 | 44.08 | 44.05 |
Chemical shifts of all four homologated series of compounds obtained from the 1H, 13C NMR spectra have been compared.
1H chemical shift of –NH- was observed at ~ δ = 7.5 ppm for H-1 to H-8, at ~ δ = 7.4 ppm for Br-1 to Br-8 (Table 9); however, it varied in Cl-1 to Cl-8 (at ~ δ = 7.4–7.5 ppm), and it revealed upfield shift near δ = 6.5 ppm in M-1 to M-8. The X-ray crystal structures of these compounds reveal intra and intermolecular N–H···O interactions. Besides, the C(3) substitution may affect the 1H chemical shift of –NH-. The downfield 1H chemical shift was noticed for the first member of each series (H-1, M-1, Cl-1, and Br-1). The singlet was observed to C(3)-H at ~ δ = 5.60 ppm for H-1 to H-8 and C(3)-methyl in M-1 to M-8 at ~ δ = 2.10 ppm. The aromatic proton H(5) takes part intermolecular C–H···O interaction (Table 2) in most of the crystal structures of known derivatives; if such interactions exist in the solution, the chemical shift variation is expected. The 1H chemical shift was observed at ~ δ = 7.8–7.9 ppm in all compounds; this implies that the intermolecular C–H···O interaction does not directly affect its chemical shift [45]. A similar inference for the 1H chemical shift of other benzenoid ring protons H(8), H(6), and H(7) can be drawn. The chemical shift of terminal –CH3 protons of the n-alkylamino chain was observed at ~ δ = 0.8 ppm, except for the methyl or ethyl series of compounds.
The differences for the 13C chemical shift of C(1), C(2), C(3), and C(4) of the series are transparent. The chemical shift of C(1) and C(4) was observed at ~ δ = 181 ppm in H-1 to H-8, whereas for M-1 to M-8, it shows up at δ = 181 ppm and ~ δ = 182 ppm, respectively [46]. On the contrary, for the Cl-1 to Cl-8 and Br-1 to Br-8 (Table 10), the upfield shift was observed. The C (1) carbonyl carbon of the bromo (Br-1 to Br-8) and chloro (Cl-1 to Cl-8) series showed the carbon chemical shift at ~ δ = 174 ppm, whereas for proton (H-1 to H-8) and methyl (M-1 to M-8) series of compounds the shift in the chemical shift by ~ 7 ppm, i.e., at ~ δ = 181 ppm which ascertains the intramolecular hydrogen bonding between C–O–N–H is stronger in hydrogen (H-1 to H-8) and the methyl (M-1 to M-8) than in bromo (Br-1 to Br-8) and chloro (Cl-1 to Cl-8) series of compounds which can also noticed from by single-crystal X-ray diffraction studies [27, 28, 29, 30, 31, 32, 33]. 13C chemical shift of C(2) showed up near δ = 149 ppm for H-1 to H-8 which reveal upfield shift for M-1 to M-8 (δ = 146 ppm) Br-1 to Br-8 (at ~ δ = 147 ppm). and downfield for Cl-2 to Cl-6 and Cl-8 (at ~ δ = 167 ppm) was observed. A major difference was noticed in the 13C chemical shift of carbon, C(3). In the case of C(3), unsubstituted compounds H-1 to H-8 appear at ~ δ = 99 ppm, whereas the corresponding downfield shifts with δ being 110 ppm and 129 ppm, respectively, were noticed along M-1 to M-8 and Br-1 to Br-8 series. The differences observed in the carbon's chemical shift at C(2) and C(3) accounted for the electronegativity differences at these positions. The 13C chemical shift of n-alkylamino carbons of analogs compounds was found in a similar range except for the terminal methyl carbons of first two analogs of each series.
The variation in chemical shift can be correlated to hydrogen bond strength (intra & intermolecular) and the presence of electronegative substituent at C(3). After overlapping the single-crystal data of the H-2, Br-2, and Cl-2, it is transparent that there is a change in orientations of the alkyl chain due to electronegative substituent at C(3) position [29,47]. Similar were the observations in the overlay structures of Cl-6 and H-6. Thus the single-crystal X-ray diffraction studies were performed for all the synthesized derivatives to as certain the effect of structural change in variation of chemical shifts along homologated series [32].
3.3. DFT investigations
Energy-minimal optimized geometrical configurations of alkylamino derivatives with methyl, chlorine, and bromine substituted at C(3) positions within the M06-2X/6-311++G (d,p) density functional framework are depicted in Figures 4, 5, 6 and 7 [36,44]. 1H NMR chemical shifts (δH) were simulated through the SCRF-PCM theory and are reported in Tables 3, 4, and 5. As can be noticed from the table, the alkyl protons emerge with up-field δH signals. In contrast, the aromatic proton is relatively de-shielded in the calculated 1H NMR for all alkylamino derivatives. The NH proton shows a signal ~6.16 ppm in the compound molecule upon increasing the alkyl chain from methyl to octyl; it is observed that the chemical shift value decreases up to 0.08 ppm. Similar inferences are drawn for methyl, chlorine, and bromine series of compounds (see Figures 5 and 6).
Figure 4.
DFT structures of the 2-(n-alkylamino)-naphthalene-1,4-dione derivatives H-1 to H-7.
Figure 5.
DFT structures of the 2-(n-alkylamino)-3-methyl-naphthalene-1,4-dione derivatives M-1 to M-8.
Figure 6.
DFT structures of the 2-(n-alkylamino)-3-bromo-naphthalene-1,4-dione derivatives Br-1 to Br-8.
Figure 7.
DFT structures of the 2-(n-alkylamino)-3-chloro-naphthalene-1,4-dione derivatives Cl-1 to Cl-8.
4. Conclusions
Chloro, bromo, methyl, and proton derivatives of eight analogs of homologated series 2-(n-alkylamino)-3R-naphthalene-1,4-dione (where n-alkyl = methyl to octyl and R = –H, –CH3, -Br and -Cl) were analyzed by using the NMR spectroscopy. The 1H and 13C NMR chemical shifts of 32 compounds were assigned, and a comparison has been made. A considerable variation along the chloro, bromo unsubstituted and methyl derivatives was observed. The C(1), C(2), and C(3) carbons show a significant variation in the chemical shift values of 13C NMR spectra. The difference in the chemical shift observed along H-1 to H-8, M-1 to M-8, Br-1 to Br-8, and Cl-1 to the Cl-8 series of compounds. The 1H NMR chemical shift values are compared with the theoretical NMR values calculated from the DFT calculations. The experimental values show shifting towards the lower, whereas the computed values show higher values.
Declarations
Author contribution statement
Rishikesh Patil: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data.
Mahesh Jadhav: Analyzed and interpreted the data.
Sunita Salunke-Gawali: Conceived and designed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.
Dipali N. Lande: Performed the experiments; Analyzed and interpreted the data.
Shridhar P. Gejji: Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data.
Debamitra Chakravarty: Performed the experiments.
Funding statement
Sunita Salunke-Gawali was supported by the Science and Engineering Research Board, Department of Science and Technology, India (EMR/2016/007912). Shridhar Gejji was supported by the Board of Research in Nuclear Sciences, India (v37 (2)/14/11/2015-BRNS). Dipali Lande was supported by University Grants Commission, India.
Data availability statement
Data included in article/supplementary material/referenced in article.
Declaration of interests statement
The authors declare no conflict of interest.
Additional information
1H,13C, and DEPT NMR, Fig. S1 through Fig. S32. gDQCOSY and gHSQCAD spectra, Fig. S33 through Fig. S80. The experimental and calculated 1H chemical shift, Table S1 through Table S8, 13C chemical shift, Table S9 through Table S16. Cambridge Crystallographic Data Centre and may be obtained on request quoting the deposition number CCDC number 1505008 for Br-3, from the CCDC, 12 Union Road, Cambridge CB21EZ, U.K. (Fax: +44 1223 336 033; E-mail address: deposit@ccdc.cam.ac.uk).
Acknowledgements
SPG thanks the Centre for Development of Advanced Computing (C-DAC), Pune, India for computer time at the National Param Supercomputing Facility.
Appendix A. Supplementary data
The following is the supplementary data related to this article:
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