A cleaner and eco-friendly method was developed for the preparation of tetrakis(aminomethyl)calix-[4]-resorcinarene via a synthetic pathway of five steps starting from methylresorcinol. This alternative methodology is firstly based on avoiding the use of CH 2BrCl, which is a non-eco-friendly substance with high ozone depletion potential, and on replacing it by CH 2Cl 2 as a readily available reagent with much less dangerous effects. Secondly, this method engages acetone or CH 2Cl 2 as the solvent of the bromination step in the place of the very toxic CCl 4, leading to tetrakis(bromomethyl)calix-[4]-resorcinarene. The brominated intermediate has been reacted with sodium azide in acetone instead of the high-boiling solvent DMSO to produce tetrakis(azidomethyl) calix-[4]-resorcinarene without the need of tedious purification. Lastly, this work reports an efficient hydrogenation method of the versatile azido adduct employing Pt/C (5%) as the catalyst for the preparation of the amino cavitand as an alternative route with high atom economy that can replace the classical methods used currently.
Resorcinarenes constitute a very attractive class of macrocyclic compounds. Their unique three-dimensional structures offer almost unlimited derivation abilities through relatively viable procedures at their upper rim, methylene bridges and extra annular-OH groups [
The chemistry of resorcinarene attracted huge interest since few decades. Developing new synthetic procedures to realize these cavitands and calixarene oligomers continue to gain growing importance, especially green microwave- assisted syntheses and solvent-free methods to minimize hazardous effects, solvent elimination, and long purifications [
Chemicals and solvents (analytically pure) were purchased from Sigma-Aldrich and were used without further purification. Reactions were monitored by thin layer chromatography (Silica gel 60 on TLC Al foils, F254). Chromatography was performed on silica gel 60 column. NMR spectra were recorded on Bruker spectrometers (300 and 400 MHz). Chemical shifts (δ) are expressed in ppm and are measured by referring to the peak of TMS (singlet at δ = 0 ppm) and the solvent (residual CHCl3: 7.26 ppm for 1H; 77.16 ppm for 13C of CDCl3) as an internal reference; the abbreviations used are: s = singlet, d = doublet, t = triplet, q = quartet. Fourier transform infrared (FTIR) measurements were performed on Perkin Elmer Spectrum 100 instrument, wavenumber range was measured from 400 cm−1 to 4000 cm−1. ESI-MS was performed on a Flexar SQ 300 MS instrument. NMR spectra of cavitands II, III and IV, IR spectra of III and IV, and mass spectrum of cavitand IV (ESI in positive and in negative modes) are given in the supplementary material [
Scheme 1. Synthetic route of tetramethyl calix-[
1) Synthesis of cavitand I. This compound was prepared as described by Cram et al. [
2) Synthesis of cavitand II. 6.0 g of cavitand I (9.87 mmol) was dissolved in 150 mL DMF. Then, 28.8 g of K2CO3 (0.20 mol) and 50 ml of CH2Cl2 were added in several portions to the previous mixture and this was agitated for 24 hours at 70˚C. The mixture was then cooled down to room temperature and filtered over Celite. The collected solvent was evaporated using a rotary evaporator, and the solid residue was purified over silica gel column chromatography using ethyl acetate/cyclohexane (30/70) as eluent. The cavitand II was obtained as a white powder (yield 84%). Final product was characterized by comparison of its 1H NMR spectrum with the one reported in literature [
3) Synthesis of cavitand III. 3.0 g of Cavitand II (4.62 mmol) was dissolved in 200 mL of CH2Cl2. Then, 3.22 g of NBS (18.51 mmol) and a small quantity of benzoyl peroxide (15 mg, 0.06 mmol) were subsequently added to the solution. The mixture (clear orange color) was agitated and refluxed (40˚C) for 4 hours. The precipitation of succinimide was observed. The mixture was cooled to room temperature and the precipitate was eliminated by filtration over Celite. The volatiles were evaporated under vacuum giving withe solid. The crude was purified over silica gel column chromatography using ethyl acetate /cyclohexane (30/70) as eluent. The cavitand III was obtained as an off-white (cream) powder. The final product was characterized by comparison of its 1H NMR spectrum with spectrum already reported in literature [
4) Synthesis of cavitand IV. Into a flask containing 80 ml of acetone, 2.0 g of cavitand III (2.40 mmol) and 0.9 g of sodium azide NaN3 (15 mmol) were subsequently added. The mixture was agitated and refluxed for 3 h. After that, the mixture was filtered over Celite and the collected solution was evaporated using a rotary evaporator. The residue was purified over silica gel column chromatography with ethyl acetate/cyclohexane (65/35) as eluent. The cavitand IV was obtained as white powder (yield 85%). The final product was characterized by 1H NMR (400 MHz, CDCl3) δ [ppm]: 1.75 (d, 12H, J = 7.4 Hz, CHCH3), 4.3 (s, 8H, CH2N3), 4.42 (d, 4H, J = 7.0 Hz, inner OCH2O), 5.0 (q, 4H, J = 7.4 Hz, CH3CH), 6.0 (d, 4H, J = 7.0 Hz, outer OCH2O), 7.3 (s, 4H, ArH). X. 13C-NMR (CDCl3, 100 MHz), δ [ppm]: 153.326 (Ar-Cq), 139.058 (Ar-Cq), 122.19 (Ar-Cq), 120.277 (Ar-H), 99.677 (O-CH2-O), 45.078 (Ar-CH2-N3), 31.211 (Ar-CH-Ar), 16.072 (CH3). MS, ESI, in positive mode: m/z = 835 = [M + Na]+, m/z = 853 = [M + MeCN]+; in negative mode m/z = 847 = [M-H + 2H2O]+ and m/z = 874 = [M+ + 4H2O]+. FTIR: ν = 2100 cm−1 (band of N3).
5) Synthesis of cavitand V. 0.5 g of cavitand IV was dissolved in a toluene/ ethanol mixture (5 mL, 8 mL) followed by the addition of 0.3 g of Pt/C (5%). The mixture was agitated and refluxed for 24 h at 75˚C under one atmosphere of hydrogen pressure (or under 5 bars at 25˚C). The mixture was then filtered over Celite and the collected solvent was evaporated using a rotary evaporator. The cavitand V was obtained as white powder (yield 95%). The final product was characterized by comparison of its 1H NMR spectrum with literature [
The cavitand I was prepared as described by Cram et al., methylresorcinol and acetaldehyde were mixed in stoichiometric ratio in a proportional mixture of water and ethanol, in the presence of HCl as the catalyst. The resulting mixture was then refluxed for 16 h, and cavitand I was obtained with a high yield (88%) similar to that mentioned in the literature [
Cavitand I was transformed into cavitand II cone structure by introducing methylene bridges between the oxygen atoms in ortho positions to the methyl groups of the methylresorcinol. Cram’s group has described the methylene insertion at the upper rim to form the bridged cavitand II by reacting the relaxed-open cavitand I with an excess amount of bromochloromethane in basic medium in DMA. They have demonstrated that a higher yield is obtained with CH2BrCl as compared to using CH2I2 and CH2Br2 as methylene sources. Pellet Rostaing et al. [
The rigidified-bridged cavitand II was subjected to a bromination reaction using N-bromosuccinimide (NBS) as a source of bromide in dichloromethane (DCM) or in acetone to obtain cavitand III. The use of acetone as a solvent for this reaction has been described by Bourgeois and Evans for the bromination on aromatic of resorcinarene derived from resorcinol [
The bromination takes place through a free radical mechanism in the presence of traces of benzoyl peroxide as initiator. The most electron-rich methyl groups on the upper rim between two donor alkoxy functions are the most reactive sites towards the radical reaction since the generated radicals are stabilized by the neighboring electron donating groups. The obtained yield (80%) was better than the one attained in the literature (60%) [
Alkyl halides are usually very reactive toward nucleophilic substitution. Bromide is a very good leaving group, and N 3 − is a strong nucleophile. Thus, a substitution reaction on cavitand III occurs easily.
To achieve the synthesis of cavitand IV, we used sodium azide NaN3. This substitution needs a solvent with a high dielectric constant in order to dissociate NaN3. We have recently realized in our laboratory the azide substitution of chlorinated products using NaN3 in acetone. Therefore, we have adopted this method for the preparation of cavitand IV. These conditions proved to be successful for this bromide substitution reaction establishing the desired azido cavitand with no side products or impurities. A simple filtration over Celite followed by evaporation of the solvent affords the product with a very good yield (85%) and purity. Hence, the purification of this step is avoided in this synthetic route. It is important to note the versatility of the azido cavitand IV for further functionalization via click chemistry highlighting the importance of straightforward synthesis for this type of cavitands. For instance, Hooley’s group has published the synthesis of a compound similar to cavitand IV as precursor to advanced cavitands substituted with tri-azole groups which have been used as iron-coordinate water-soluble catalysts for C-H Oxidation [
The traditional routes to introduce amino groups into the aromatic scaffolds of calixarene chemistry are i) nitration of cavitands followed by reduction of the nitro group with common reducing agents [
A new approach to synthesize the tetrakis(aminomethyl)calix-[
We gratefully acknowledge the financial support for this project by the Lebanese University, CEDRE program, CNRSL (the National Council for Scientific Research, Lebanon).
Moussaoui, S.A., Damaj, Z., Wehbie, M., Pellet Rostaing, S. and Karamé, I. (2017) Alternative and Eco- Friendly Synthesis of Tetrakis(Aminomethyl) Calix-[