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Article

α-Halogenated Curcumins

by
Phuong-Truc T. Pham
1,* and
Mamoun M. Bader
2,*
1
Department of Chemistry, Penn State Scranton, Dunmore, PA 18512, USA
2
Department of Chemistry, College of Science, Alfaisal University, Riyadh 11533, Saudi Arabia
*
Authors to whom correspondence should be addressed.
Crystals 2024, 14(12), 1041; https://doi.org/10.3390/cryst14121041
Submission received: 25 October 2024 / Revised: 14 November 2024 / Accepted: 20 November 2024 / Published: 30 November 2024
(This article belongs to the Special Issue Analysis of Halogen and Other σ-Hole Bonds in Crystals (2nd Edition))
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Abstract

:
α- or 4-Substituted curcumin analogues are scarce. We describe herein the syntheses and crystal structures of the first α-halogenated curcumin derivatives: (1E,6E)-1,7-bis (4-hydroxy-3-methoxyphenyl)-4-bromo-5-hydroxy-1,3,6-heptatriene-3-one or (4-bromocurcumin) (1) and (1E,6E)-1,7-bis (4-hydroxy-3-methoxyphenyl)-4-chloro-5-hydroxy-1,3,6-heptatriene-3-one or (4-chlorocurcumin) (2). We note that the key step in the successful synthesis of the bromo-analog is the use of slightly acidic media to favor the diketo form of curcumin prior to carrying out the reaction. Both newly prepared compounds assume the keto–enol form in the solid state and crystallize in the monoclinic space group P21/c with four molecules in the unit cell each with slightly different dimensions. Inter- and intra- molecular hydrogen bonds were observed in the two structures. Most significant observed features were the inter-molecular O…O distances of 2.842 and 2.840 Å and intra-molecular O…O distances of 2.460 and 2.451 Å for bromo-or (1) and chloro- or (2) derivatives, respectively. No close halogen…halogen contacts were observed in either of the two structures. Both molecules are nearly planar with torsion angles of 0.54 and 1.16 °C between the planes of two terminal phenyl groups for (1) and (2), respectively. π-Stacks were observed in both structures with interplanar distances of 3.367 and 3.454 Å for the bromo- and chloro- compounds, respectively. Hirshfeld surface analysis confirms quantitively a picture of the inter- and intra-molecular interactions in both compounds compared with polymorph I (the most common form) of curcumin. UV–Vis absorption spectra are shifted to higher wavelengths with lmax of 475 and 477 nm for compounds 1 and 2, respectively, compared with 442 nm in dichloromethane solutions. The newly synthesized molecules will open the door for numerous possible synthetic modifications of the α-carbon to prepare valuable analogues of curcumin with more favorable solubility profiles.

1. Introduction

Curcumin, or (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptane-3,5-dione), is a yellow-orange polyphenolic compound found in turmeric. Curcumin has been the subject of numerous studies since the 1990s and has been shown to exhibit antioxidant [1,2] anti-inflammatory [3,4] and anticancer [5,6] activities.
Curcumin is characterized by the presence of an α, β-unsaturated β-diketone moiety. It exists predominantly in its diketo form in neutral and acidic solutions while the more stable keto–enol form exists predominantly under alkaline conditions. While both the phenols and the α, β-unsaturated diketo groups are responsible for the antioxidant properties of curcumin, the α, β-unsaturated diketo moiety is thought to be responsible for the anticancer activities of the molecule. Furthermore, the keto–enol tautomerism plays a critical role in biological activity, influencing molecular recognition, stability, and reactivity in enzyme catalysis and drug interactions [7]. Thus, simple structural modifications of curcumin at the α-carbon offer an attractive path to alter the steric, coordination sphere, and other properties of the molecule that may lead to enhanced solubility and biological activity [8]. In this work, we report the syntheses and crystal structures of two novel analogues of curcumin, where the hydrogen at the α-carbon or 4-position is replaced by either a bromine or a chlorine atom (Figure 1). The newly synthesized molecules will open the door for numerous possible synthetic modifications at the α-carbon of to prepare valuable analogues of curcumin with more favorable solubility profiles.
Several chemically modified curcumin derivatives have been synthesized mainly by substitution on the phenyl rings and by condensation/addition reactions such as semicarbazone and oxime derivatives [9,10]. Many curcumin metal complexes have also been prepared and characterized for a variety of applications including photodynamic therapy [11,12]. Reports on the α-functionalization of curcumin (or as is known the 4- position) are scarce [13,14,15]. Recently, however 4-alkylated curcumins were synthesized following a modified Pedersen procedure [16] and their keto–enol equilibrium constants were determined in various solvents using NMR spectroscopy [17]. Furthermore, two polymorphs of the 4-cyclobutylcurcumin were isolated and their single crystal structures determined [17].
To address low solubility and bioavailability of curcumin, researchers have explored structural modifications of curcumin through co-crystallization and co-amorphous systems [17]. Co-amorphous systems, as demonstrated by studies, help to stabilize curcumin in amorphous form by combining it with other molecules, enhancing solubility and stability. Additionally, co-crystals of curcumin involve the crystallization of curcumin with suitable co-formers. This technique creates new crystalline forms that improve the dissolution profile and bioavailability of curcumin. Furthermore, studies such as that by Görbitz et al., provide insights into modifying specific molecular sites on curcumin, allowing for more targeted enhancements of its chemical stability and interaction potential. Together, these approaches represent innovative pathways to optimize curcumin for therapeutic use [18,19,20,21].
Examining the Cambridge Structural Database reveals that curcumin is known to exist in three polymorphs (forms I, II, and III) with all polymorphs displaying the keto–enol forms. The most common polymorph of curcumin (form I) is where the molecule is nearly planar and crystallizes in the monoclinic space group P2/n whereas the other two uncommon forms are both orthorhombic with the space groups of Pca21 and Pbca for forms II and III, respectively [22,23,24,25,26,27,28,29]. There are also several reported crystal structures of curcumin derivatives including metal complexes [30,31,32]. Both solid state and solution NMR investigations of curcumin [33,34,35] in addition to curcumin co-crystals [36,37,38,39] were also reported. Surprisingly, the co-crystallization of curcumin with 4,4′-bipyridine N,N′-dioxide has resulted in the diketo form [17]. Furthermore, a comprehensive recent review of crystal engineering using curcumin was published [35].

2. Materials and Methods

All reagents were purchased from Sigma-Aldrich and used as received except curcumin, which was recrystallized from ethanol. The key in the successful synthesis of the bromo-analog was to carry out the reaction in slightly acidic media. Thus Amberlyst-15 was added before the bromination reaction. Chlorination of curcumin was successfully carried out using N-chlorosuccinimide in the absence of Amberlyst-15. Crystal structures were determined using a Rigaku MicroMax-007HF X-ray generator (Rigaku Corp., Tokyo Japan) in the Penn State Huck Institutes of Life Sciences. Data collection: SMART v5.625; cell refinement: SAINT V6.36A; data reduction: SAINT V6.36A; program(s) used to solve structure: SHELXS; program(s) used to refine structure: SHELXL 2018/3; molecular graphics: Olex2 1.3-ac4; software used to prepare material for publication: Olex2 1.3-ac4 [40,41,42,43,44]. Mo Kα radiation was used, λ = 0.71073 Å. The software packages used in this work were: Origin (Version 2024b (10.15); Crystal Explorer 21.5 [45,46] ChemDraw 16.0, Mercury 4.2, and Paint 2024). Spartan 16 was used to carry out the density Functional Theory calculations [47]. Hirshfeld surface analysis was performed using Crystal Explorer 21.5. Elemental analysis was carried out at Microanalysis Inc. (Wilmington, DE USA). Solubility was determined by preparing a saturated solution for each compound. We gradually added each compound to 1 mL of water at room temperature until it no longer dissolved, indicating saturation. The concentration was measured by using absorbance in UV–Vis after filtration. (See Supplementary Material).

2.1. Synthesis of (1E,6E)-1,7-Bis(4-Hydroxy-3-Methoxyphenyl) Hepta-4-Bromo-1,6-Diene-5-Hydroxy-3-One (1)

Curcumin (1.9865 g, 5.39 mmol) was dissolved in anhydrous acetyl acetate (60 mL) with heating at 40 °C for about 10 min. The solution was then briefly cooled in an ice bath and Amberlyst 15 (0.58 g) was added followed by N-bromosuccinimide (1.2182 g, 6.85 mmol). The ice bath was removed after 30 min and stirring continued at an ambient temperature overnight. The Amberlyst was removed, and the crude product crystallized in acetonitrile to yield bright orange crystals (16%). This product was then recrystallized to form an acetonitrile–hexane mixture (50:50) to obtain suitable crystals for the X-ray study. Anal. Calc’d (C21H19BrO6): C, 56.39; H, 4.28; Br, 17.86. Found: C, 56.88; H, 4.16, 17.63. Exact mass (NaC21H19BrO6): 469.026270; Found (EI, M+1): 469.0237. (See Supplementary Material).

2.2. Synthesis of (1E,6E)-1,7-Bis(4-Hydroxy-3-Methoxyphenyl) Hepta-4-Chloro-1,6-Diene-5-Hydroxy-3-One (2)

Curcumin (2.7444 g, 7.45 mmol) was dissolved in anhydrous acetonitrile with heating at 40 °C. The solution was briefly cooled in an ice bath before N-chlorosuccinimide (1.2081 g, 9.05 mmol) was added. Stirring was allowed to continue overnight at room temperature. The red crude powder was filtered and recrystallized in acetonitrile to give yellow crystals (33%). Anal. Calc’d (C21H19ClO6): C, 62.62; H, 4.75; Cl, 8.80. Found: C, 62.30; H, 4.77; Cl, 8.58. Exact mass: 402.0870. Found (EI, M+1): 403.0940.

3. Results and Discussion

The title compounds were successfully prepared by having curcumin react with N-bromosuccinimide or N-chlorosuccinimide with cooling in anhydrous solvents. While bromination requires Amberlyst 15, chlorination of curcumin can be achieved without the use of catalyst. Orange colored single crystals of α-bromocurcumin (1) were grown by slow evaporation from acetonitrile–hexane mixture (50:50) and a suitable crystal was selected for X-ray analysis. 4-Chlorocurcumin (2) was crystallized from acetonitrile as yellow needles. Table 1 shows a summary of the crystal data for 1 and 2. See Supplementary Material for elemental analysis and MS.
We first note that the two structures are isostructural with slightly different unit cell dimensions and solid-state structures. Both 4-bromocurcumin and 4-chloromocurcumin crystallize in the monoclinic space group P21/c, with four molecules in a unit cell. Unit cell dimensions for 1 bromo- and (2 chloro-) analogs are: a = 6.837, (16.7520) Å; b = 7.323, (7.27831) Å; c = 15.939, (15.9369) Å, β = 99.396, (100.0131)°, V = 1938.9, (1913.53) Å3. Both molecules assume the keto–enol form and are almost planar. The torsion between the phenyl rings of the mono brominated curcumin is 0.54°. The chloro- derivative is slightly less planar, having torsion between the phenyl rings of 1.16 °C.
Examining the two structures we first note that there are notable inter- and intra- molecular hydrogen bonds in both structures like those reported in polymorph I of the parent compound (Table 2). While the closest inter- O…O interactions involving the methoxy oxygens of two adjacent molecules for the bromo- and chloro- derivatives are 2.842 and 2.840 Å, respectively, compared with 2.666 in curcumin, both compounds exhibit short intra-O…O distances around the keto– enol center: 2.460 Å in (1) and 2.451 Å in (2) compared with 2.441; 2.498, and 2.490 in polymorphs I, II, and III of curcumin (Table 3). The bromo curcumin displayed slightly longer intra-O…O interactions, we note that both of the C-O and C=O bonds are longer compared to the chloro compound. As one might expect, with the presence of six oxygen atoms in each of these molecules, halogen…halogen interactions seem to play little or no role in solid state packing. No close halogen…halogen contacts were observed in either one of the two structures, with closest Br…Br distance of 5.772 Å and closest Cl…Cl distance of 5.926 Å. This might be plausible considering the many competing inter- and intra-molecular interactions involving other functional groups present and play a stronger role in steering the structure. This is not always the case as there are examples where halogen…halogen interactions play a significant role in solid-state structures of molecular materials even in the presence of other functional groups as shown in halogenated oligothiophenes for example [48,49,50,51,52,53].
We also note that the p-stack distance in the bromo compound (1) is slightly longer than the p-distance in the choro derivative (2), 3.367 and 3.362 Å, respectively (Table 2; Figure 2b and Figure 3b). Table 2 provides a summary of the main structural features observed in the structures of the two title compounds whereas Table 3 compares the major structural features reported herein with the three known polymorphs of curcumin with emphasis on main geometrical features around the keto–enol center. Plots of stacking distance and C-H…p distances as a function of the various torsion angles (shown in Figure 4) are provided in the Supplementary Material.
Crystals 14 01041 g002
Figure 2. (a) Packing in the unit cell of 4-bromocurcumin 1 along the b-axis; (b) p-stacks within the unit cell.
Figure 2. (a) Packing in the unit cell of 4-bromocurcumin 1 along the b-axis; (b) p-stacks within the unit cell.
Crystals 14 01041 g002
Crystals 14 01041 g003
Figure 3. (a) Packing in the unit cell of 4-chlorocurcumin 2 along the b-axis; (b) π-stacks within the unit cell; (c) unit cell of curcumin along the b-axis (shortest C-H...π distance is 4.387).
Figure 3. (a) Packing in the unit cell of 4-chlorocurcumin 2 along the b-axis; (b) π-stacks within the unit cell; (c) unit cell of curcumin along the b-axis (shortest C-H...π distance is 4.387).
Crystals 14 01041 g003
Table 2. Summary of main inter- and intra-molecular interactions compounds (1) and (2) compared with the most common polymorph of curcumin.
Table 2. Summary of main inter- and intra-molecular interactions compounds (1) and (2) compared with the most common polymorph of curcumin.
Structural Feature12Curc
Form
I		Curc
Form II		Curc
Form III
Closest O…O inter-2.8422.8402.6662.625; 2.8342.666; 2.975
Closest O…O intra-2.4602.4512.4412.498; 2.5272.490
π-stack distances3.3673.362NA3.3063.817
intra- O-H…O=C1.7141.7031.7241.616; 1.6761.724
C-H..p interactions2.8802.9842.8643.306; 3.3654.387
Closest Br…Br5.772----
Closest Cl…Cl-5.926---
Crystals 14 01041 g004
Figure 4. Structural features used in Table 3.
Figure 4. Structural features used in Table 3.
Crystals 14 01041 g004
Table 3. Comparison of the main structural features shown in (Figure 4) in 1 and 2 compared with three forms of Curcumin [25,26,27].
Table 3. Comparison of the main structural features shown in (Figure 4) in 1 and 2 compared with three forms of Curcumin [25,26,27].
12Curcumin Form I
P21/n		Curcumin Form II
Pca21		Curcumin
Form III
P b c a
O…O intra (R11)2.4602.4512.4412.4982.490
Φ10.541.1616.0116.5147.07
Φ24.634.140.855.0739.87
Φ34.714.1712.428.440.23
R11.4551.4561.4471.4621.463
R21.3151.3321.3251.3301.333
R31.4591.4591.4541.4481.455
R41.4161.4161.4321.3721.403
R51.4151.4031.3561.4151.397
R61.4561.4551.4661.4651.456
R71.3281.3341.3301.3301.339
R81.4551.4621.4571.4621.454
R91.2951.3001.3341.3121.298
R101.2831.2881.2771.2731.303
O-H…O angle a150.24150.63152.20155.04154.36
C-X1.8981.736nanana
Methoxy groups configurationsynsynsynsynanti
CCDC numbers2,258,9822,324,288807,904807,905807,906
a around the keto–enol. na; not applicable
Hirshfeld surface analysis was performed on the title compounds and compared with curcumin (form I), using Crystal Explorer 21. 5 software (Figure 5) [35]. It generates a 2D quantitative representation of different types of interactions in the unit cell. Distinct differences when comparing curcumin with the halo derivatives indicate the presence of cyclic hydrogen bonding (the areas between the sharp H bonding donor and acceptor; p-stacking the wings and green triangle in the center with sharper wings and more intense green triangles indicative of close p stacking distances) (Figure 5). The solubility of both new compounds in water was slightly lower than that of curcumin around 5 mg/mL for 1 and 2, respectively, compared to 6.6 mg/mL for curcumin [27,29]. This is further confirmed by studying the O…H/O…H interactions using Hirshfeld surface analysis (Figure 5) which revealed 21.2% for both compounds compared with 28.8% for curcumin which explains the solubility pattern observed. This is by interpreting a higher % of O…H/O…H interactions resulting in higher solubility.
The electronic spectra of curcumin and its derivatives were studied in detail. These studies demonstrated curcumin’s solvatochromic nature and sensitivity to hydrogen bonding and environmental polarity showcasing its potential for use in solvatochromic applications and molecular probes [54,55,56]. In the UV–Vis spectrum of the new compounds and compared with curcumin, three primary absorption maxima (λmax) are observed in each (Table 4). This is reflective of the molecules’ electronic structure. The highest λmax is usually attributed to the π → π* transition, which occurs at lower energy due to the extensive conjugation across the phenolic rings and the α,β-unsaturated β-diketone linker, leading to absorption in the visible region and imparting curcumin’s characteristic yellow color and the halo derivatives’ orange colors. The additional λmax values arise from n → π* transitions, involving the excitation of non-bonding electrons on oxygen atoms to anti-bonding π* orbitals. These transitions generally appear at shorter wavelengths. Absorption spectra showed bathochromic shift (red shift) of 33 and 35 nm for compounds 1 and 2, respectively, compared with the parent compound (Figure 6). This is consistent with the slight shortening in the carbon halogen bonds observed in their respective crystal structures indicating some electron-donating character of the halogen atoms.
Surprisingly, the melting point of the bromo derivative is significantly lower than its chloro-counterpart one (Table 4).
Density functional theory (DFT) calculations using the Spartan 18 suite of programs and the B3LYP/6-311+G(d,p)//B3LYP/6-31G(d) level of theory [47] (ground state gas phase) indicated slight lowering of the LUMO level of the halogenated compounds resulting in the lowering of the calculated band gaps while also lowering the calculated dipole moments for the new compounds. The main points we obtained from these calculations are: lower band gaps of the halo derivatives, consistent with the UV–Vis data, and also the lower dipole moments associated with the observed lower solubility. The summary of the results of these calculations are depicted in Table 5. The lower solubility of the new compounds is consistent with the calculated dipole moment.

4. Conclusions

We have successfully synthesized and structurally characterized the first two α-halogenated curcumins: 4-bromocurcumin and 4-chlorocurcumin. The new molecules were studied by single crystal structural analysis, UV–Vis, DFT, and Hirshfeld surface analyses. These molecules are more thermally stable, albeit less soluble, in water than the unsubstituted curcumin. Competing inter- and intra-molecular interactions were compared with known closely related structures, especially the three known forms of curcumin. It is interesting to note that the introduction of the halogens at the α-position result in more planar structures and shorter π-stacking distances than any known curcumin derivatives reported to date. We assume that these molecules will be used as precursors to prepare a wide range of curcumin derivatives with more favorable solubility and bioavailability profiles.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cryst14121041/s1, UV–Vis spectra; MS and elemental analysis of compounds 1 and 2.

Author Contributions

Conceptualization, P.-T.T.P.; formal analysis, P.-T.T.P. and M.M.B.; writing—review and editing, P.-T.T.P. and M.M.B.; supervision, project administration, funding acquisition, P.-T.T.P. and M.M.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded internally. Research and Development Grant Penn State Scranton (P.-T.T.P.) and VP for Research, Office of Research at Alfaisal University (IRG-2020 and IRG-2024) (M.M.B.).

Data Availability Statement

Data and possibly samples can be obtained from corresponding authors.

Acknowledgments

The authors acknowledge support from Penn State Scranton in the form of a Research and Development Grant and partial support from the SIG S10 of the National Institutes of Health under award number 1S10OD028589-01 and 1S10RR023439-01 and Neela Yennawar for the X-ray instrumentation. The authors also acknowledge Hemant P. Yennawar of the X-ray facility at Penn State University, University Park. We also highly appreciate J. Steed’s help in sharing his group’s manual on using the Crystal Explorer program. M. Bader acknowledges financial support from the VP for Research, Office of Research at Alfaisal University (IRG-2020 and IRG-2024). The help of undergraduate students at Alfaisal University, Samar M. Al Rifai and Sarah H. Younas, with Figure 5 and Figure 6 is highly appreciated. We thank Edreese Alsharaeh and Mohanraj Krishnan for their help with DSC measurements.

Conflicts of Interest

The authors declare no conflict of interest.

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Crystals 14 01041 g001
Figure 1. Structures of 4-bromocurcumin (1) and 4-chlorocurcumin (2).
Figure 1. Structures of 4-bromocurcumin (1) and 4-chlorocurcumin (2).
Crystals 14 01041 g001
Crystals 14 01041 g005aCrystals 14 01041 g005b
Figure 5. Two dimensional fingerprints and O…H/O…H interactions of (a) curcumin form I (b) Curc-Br and (c) Curc-Cl.
Figure 5. Two dimensional fingerprints and O…H/O…H interactions of (a) curcumin form I (b) Curc-Br and (c) Curc-Cl.
Crystals 14 01041 g005aCrystals 14 01041 g005b
Crystals 14 01041 g006
Figure 6. UV–Vis absorption spectra of title compounds compared with curcumin in dichloromethane.
Figure 6. UV–Vis absorption spectra of title compounds compared with curcumin in dichloromethane.
Crystals 14 01041 g006
Table 1. Crystal data and structure refinement for 1 and 2.
Table 1. Crystal data and structure refinement for 1 and 2.
Empirical FormulaC21H19BrO6
(1)		C21H19ClO6
(2)
Formula weight 447.27 447.27
Temperature/K 298 (2) K298 (2) K
Crystal system monoclinic monoclinic
Space group P21/cP21/c
a/Å 16.837 (5) 16.7520
b/Å 7.323 (2) 7.27831 (16)
c/Å 15.939 (5) 15.9369 (3)
α/° 90.00 90.00
β/° 99.396 (5) 90.00
γ/° 90.00 100.0131 (17)
Volume/Å31938.9 (10) 1913.53
Z 4 4
density calc g/cm3 1.532 1.398
Reflections collected 17651 5300
Goodness-of-fit on F21.070 1.051
Final R indexes [I ≥ 2σ (I)] R1 = 0.0670,
wR2 = 0.1733 		R1 = 0.0362,
wR2 = 0.1075
CCDC number2,258,9822,324,288
Table 4. DSC and spectroscopic data for curcumin and α-halo curcumins.
Table 4. DSC and spectroscopic data for curcumin and α-halo curcumins.
CompoundMelting Point (DSC)λmax (CH2Cl2)
curcumin184.89401, 421, 442
(1) Curcumin-Br162.76425, 449, 475
(2) Curcumin-Cl196.71427, 450, 477
Table 5. DFT calculated properties for 1, 2 and curcumin.
Table 5. DFT calculated properties for 1, 2 and curcumin.
CompoundE HOMO (eV)E LUMO (eV)Band Gap (eV)Dipole Moment (Debye)
Curcumin-H−5.31−1.983.334.13
Curcumin-Cl-−5.38−2.253.131.35
Curcumin-Br−5.39−2.263.131.21
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Pham, P.-T.T.; Bader, M.M. α-Halogenated Curcumins. Crystals 2024, 14, 1041. https://doi.org/10.3390/cryst14121041

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Pham P-TT, Bader MM. α-Halogenated Curcumins. Crystals. 2024; 14(12):1041. https://doi.org/10.3390/cryst14121041

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Pham, Phuong-Truc T., and Mamoun M. Bader. 2024. "α-Halogenated Curcumins" Crystals 14, no. 12: 1041. https://doi.org/10.3390/cryst14121041

APA Style

Pham, P. -T. T., & Bader, M. M. (2024). α-Halogenated Curcumins. Crystals, 14(12), 1041. https://doi.org/10.3390/cryst14121041

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