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Bis(2-hydroxyethyl) 2-phenylsuccinate

1
Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, Piazza Rinascimento 6, 61029 Urbino, PU, Italy
2
Department of Industrial Chemistry “T. Montanari”, University of Bologna, Viale Risorgimento 4, 40136 Bologna, BO, Italy
*
Author to whom correspondence should be addressed.
Molbank 2022, 2022(4), M1456; https://doi.org/10.3390/M1456
Received: 6 September 2022 / Revised: 21 September 2022 / Accepted: 22 September 2022 / Published: 26 September 2022
(This article belongs to the Topic Catalysis: Homogeneous and Heterogeneous)

Abstract

:
Succinic acid esters are important compounds that find many applications in various industrial fields. One of the most promising and easy ways of producing these molecules is represented by the bis-alkoxycarbonylation reaction of olefins. In particular, a recently developed catalytic system, consisting of an aryl α-diimine/palladium(II) catalyst and p-benzoquinone as an oxidant, has allowed succinates to be obtained in high yields. A similar methodology was applied here for the unprecedented synthesis of the bis(2-hydroxyethyl) 2-phenylsuccinate in 78% isolated yield, starting from the cheap and commercially available compounds styrene and ethylene glycol. To our knowledge, no other examples of bis-alkoxycarbonylations of olefins involving diols have been reported thus far. The obtained product was fully characterized by NMR and ESI-MS analyses.

1. Introduction

As is known, 1,4-dicarbonyl compounds are useful reagents, especially as precursors for the synthesis of diverse bioactive molecules and (hetero)cyclic compounds. Among these, succinic acid and its derivatives are very attractive products for their wide range of uses [1,2]. In particular, succinic esters find applications in various industrial fields. For example, they are widely used as components of creams and perfumes in cosmetics [3], are used as a green plasticizer to replace phthalates [4,5,6], can be found in the main structure of polymers [7,8] and dendrimers [9], and are also employed in agrochemistry and in the food industry [2]. Even if it is possible to obtain succinic acid by fermentation [10], and the respective succinate by subsequent esterification reaction, with this methodology, only minor modifications can be made on the structure, unless long synthetic routes are employed. A very efficient way for achieving one-pot variously substituted succinic acid esters consists in the bis-alkoxycarbonylation of olefins [11,12], in which a cheap functionalized alkene can be easily converted into the desired product in the presence of CO and an alcohol. This kind of reaction is usually metal-catalyzed and requires an oxidizing agent in order to regenerate the active species. Over the past years, we have developed an efficient method for the bis-alkoxycarbonylation of terminal, internal, and electron-deficient olefins and allyl compounds, which utilized aryl α-diimine/palladium(II) complexes as a catalyst and p-benzoquinone as an oxidant [13,14,15,16]. By applying an analogous methodology, we have realized the synthesis of the bis(2-hydroxyethyl) 2-phenylsuccinate 3, bearing a phenyl group on the succinic scaffold and two terminal hydroxyl groups on the ester chain, potentially useful for successive post-functionalization reactions.

2. Results and Discussion

A successful bis-alkoxycarbonylation of styrene derivatives was previously developed [13,14] utilizing palladium trifluoroacetate and the ligand 1 (N2,N3-di(anthracen-9-yl)butane-2,3-diimine), in the presence of 1.5 equiv of p-benzoquinone as an oxidant and a catalytic amount of p-toluenesulfonic acid. The reaction proceeded under mild conditions, such as room temperature and only 4 bar of CO pressure, and a mixture of alcohol and THF in a 7:1 ratio was used as the solvent. Unfortunately, when applying these conditions to the bis-alkoxycarbonylation of styrene with ethylene glycol as an alcohol, the high amount of the glycol with respect to the olefin and its high boiling point made the purification of the product difficult and resulted in a low yield eventually being obtained. Therefore, we reduced the amount of glycol, using an ethylene glycol/THF ratio of 3:1, as reported in Scheme 1. The reaction was followed through 1H-NMR, monitoring the disappearance of the signals of the olefinic double bond of the styrene. The pure product 3 was isolated in 78% yield by column chromatography. To the best of our knowledge, this represents the first example of bis-alkoxycarbonylation of olefins utilizing a diol as an alcohol. A proposed catalytic cycle is reported in Scheme S1 of the Supporting Information.
As expected, the diester 3 displaces two different C=O signals (173.4 ppm and 172.1 ppm) on the 13C-NMR spectrum. Other analyses, which confirm the structure, such as 1H-NMR, COSY, HMBC, HSQC, and the ESI-MS spectrum, can be found in the Supporting Information.
The DFT-calculated free Gibbs energy associated with the process was −43.8 kcal/mol, indicating that the whole process is highly exergonic (see Supporting Information).

3. Materials and Methods

Chemicals and instruments. The reaction was carried out in a nitrogen atmosphere with dry solvent under anhydrous conditions, in a stainless steel autoclave, by using the Schlenk technique. The reaction was monitored by 1H-NMR, taking a direct sample of the crude mixture. 1H-NMR and 13C-NMR were recorded on a Bruker Avance 400 spectrometer (1H: 400 MHz, 13C: 101 MHz), using CDCl3 as a solvent. Chemical shifts are reported in the δ scale relative to residual CHCl3 (7.26 ppm) for 1H-NMR and to the central line of CDCl3 (77.16 ppm) for 13C-NMR. 13C-NMR was recorded with 1H broadband decoupling. The following abbreviations have been used for the multiplicities: s = singlet, br = broad, d = doublet, dd = doublet of doublets, ddd = doublet of doublets of doublets, m = multiplet. Coupling constants (J) are reported in Hertz (Hz). An ESI-MS spectrum was recorded on Waters Micromass ZQ 4000, using electrospray ionization techniques, with the sample dissolved in MeOH. Carbon monoxide (Cp grade 99.99%) was supplied by Air Liquide (carbon monoxide is a toxic gas with potentially lethal action, so adequate precautions must be observed). The p-benzoquinone was purchased by Alfa Aesar and was filtered off a plug of silica gel washing with CH2Cl2, obtaining a yellow solid after drying the solution under vacuum. The pure compound 3 was isolated through flash column chromatography on silica gel 60 (40–60 μm, 230–400 mesh). Styrene 2 was purchased from Merck Sigma-Aldrich and, before use, was filtered off a plug of neutral Al2O3 without further purification. Anhydrous THF was distilled from sodium-benzophenone. Ethyl glycol was dried over molecular sieves (Alfa Aesar, 4 Å, 1–2 mm, beads). Pd(TFA)2 was purchased by Flurochem; all the other chemicals were purchased from Merck Sigma-Aldrich and used without further purification. The ligand 1 was synthesized according to the literature [17]. All solid reagents were weighted in an analytical balance without excluding moisture and air.
Computational Details. All DFT calculations have been performed using the ORCA 4.2.1 suite of quantum chemistry programs [18,19]. Geometries were optimized in vacuum using the Becke–Perdew (BP) functional [20,21] and the def2-TZVP basis [22]. Vibrational frequencies were calculated at the optimized geometries to check the stability of the stationary points and to evaluate the vibrational contribution to free energies at 298 K. Final single-point energy calculations at the optimized geometries were performed with the large def2-QZVPP basis [22] and the M06 functional [23], with the inclusion of solvation effects (with THF as a solvent) through the SMD model [24] and of dispersion interactions [25]. The final free energy of each structure, used to evaluate the reaction free energy, was built by summing the difference between the def2-TZVP electronic and free energies to the def2-QZVPP single-point electronic energy.
Synthesis of bis(2-hydroxyethyl) 2-phenylsuccinate. In a nitrogen-flushed Schlenk tube, equipped with a magnetic stirring bar, styrene 2 (2 mmol), ethylene glycol (3 mL), and THF (0.5 mL) were added in sequence. The mixture was left under stirring for 10 min. In another nitrogen-flushed Schlenk tube, equipped with a magnetic stirring bar, the Pd(TFA)2 (3.3 mg, 0.01 mmol) and THF (0.5 mL) were added in sequence. After the mixture came to show a red/brown color (20 min), ligand 1 (4.8 mg, 0.011 mmol) was added. The mixture was left under stirring for 15 min, turning to a dark orange-brown color with a precipitate. The olefin solution and the formed catalyst were injected in sequence in a nitrogen-flushed autoclave, equipped with a magnetic stirring bar, containing p-benzoquinone (325 mg, 3 mmol) and p-TSA·H2O (7.6 mg, 0.04 mmol). After 5 min of stirring, the autoclave was flushed three times with CO and pressurized with 4 bar of carbon monoxide. The reaction was vigorously stirred at room temperature (20 °C) for 67 h. The autoclave was vented off and flushed with nitrogen, and the crude was dried under reduced pressure and filtered off a plug of silica gel, washing with CH2Cl2/Et2O = 2:3. The solution was dried up in a vacuum and H2O (30 mL) was added. The solution was extracted with EtOAc (4 × 30 mL). The organic layers were combined, dried over Na2SO4, and evaporated under reduced pressure. Product 3 was eventually obtained after column chromatography on silica gel (EtOAc/CH2Cl2 = 40:60). Yield: 78% (440 mg), pale yellow oil.
Rf = 0.14 (EtOAc/CH2Cl2 = 40:60). 1H-NMR (400 MHz, CDCl3) δ 7.35–7.24 (m, 5H, CHAr), 4.31 (ddd, J = 11.8, 5.8, 3.7 Hz, 1H, COOCH2), 4.23 (ddd, J = 11.8, 5.2, 4.1 Hz, 1H, COOCH2), 4.18 (ddd, J = 11.8, 5.1, 4.2 Hz, 1H, COOCH2), 4.12 (dd, J = 11.0, 4.7 Hz, 1H, CH-CO), 4.10 (ddd, J = 11.9, 5.2, 3.6 Hz, 1H, COOCH2), 3.81–3.75 (m, 2H, CH2OH), 3.75–3.69 (m, 2H, CH2OH), 3.26 (dd, J = 16.9, 11.0 Hz, 1H, CH2-CO), 2.77 (br s, 2H, OH), 2.71 (dd, J = 16.9, 4.7 Hz, 1H, CH2-CO). 13C-NMR (101 MHz, CDCl3) δ 173.4 (C=O), 172.1 (C=O), 137.3 (Cq,Ar), 129.1 (Cortho,Ar), 128.0 (Cpara,Ar), 127.8 (Cmeta,Ar), 66.8 (COOCH2), 66.5 (COOCH2), 60.82 (CH2OH), 60.80 (CH2OH), 47.4 (CH-CO), 38.1 (CH2-CO). ESI-MS: m/z = 283 [M + H]+; m/z = 300 [M + NH4]+; m/z = 305 [M + Na]+.

4. Conclusions

Starting from cheap and commercially available compounds, the one-pot synthesis of the new succinic acid ester bis(2-hydroxyethyl) 2-phenylsuccinate, bearing hydroxy groups on the ester moieties, has been obtained in high yield through a bis-alkoxycarbonylation reaction. A low catalyst loading (i.e., 0.5 mol%) of the aryl α-diimine/palladium(II) catalyst and mild reaction conditions (i.e., 4 bar of CO at 20 °C) can be utilized. Moreover, to the best of our knowledge, this is the first time that a bis-alkoxycarbonylation reaction has been applied to diols. The final compound has been characterized by NMR and ESI-MS, and ΔrG of the reaction has been calculated by DFT calculations.

Supplementary Materials

Scheme S1: Proposed catalytic cycle; Figure S1: 1H-NMR spectrum; Figure S2: Zoom of the 1H-NMR spectrum (from 5.0 ppm to 2.2 ppm); Figure S3: 13C-NMR spectrum; Figure S4: DEPT 135 (CH and CH3 positive, CH2 negative); Figure S5: COSY spectrum; Figure S6: Zoom of the COSY spectrum (from 5.0 ppm to 2.2 ppm); Figure S7: HSQC spectrum; Figure S8: HMBC spectrum; Figure S9: ESI-MS (ESI+) spectrum of compound 3.

Author Contributions

Conceptualization, D.O. and C.C.; methodology, D.O.; software, R.T.; investigation, D.O.; data curation, D.O.; writing—original draft preparation, D.O.; writing—review and editing, C.C., D.O. and R.T.; funding acquisition, C.C. and R.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data obtained in this project are contained within this article and are available upon request from the authors.

Acknowledgments

This work was supported by the University of Bologna and the University of Urbino “Carlo Bo”. C.C. and R.T. thank UNI.RIMINI S.p.A. for funding.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 3 are available from the authors.

References

  1. Nghiem, N.P.; Kleff, S.; Schwegmann, S. Succinic Acid: Technology Development and Commercialization. Fermentation 2017, 3, 26. [Google Scholar] [CrossRef]
  2. Saxena, R.K.; Saran, S.; Isar, J.; Kaushik, R. Production and Applications of Succinic Acid. In Current Developments in Biotechnology and Bioengineering. Production, Isolation and Purification of Industrial Products; Pandey, A., Negi, S., Soccol, C.R., Eds.; Elsevier: Amsterdam, The Netherlands, 2017; pp. 601–630. [Google Scholar]
  3. Heng, K.Y.; Kei, T.Y.; Kochhar, J.S.; Li, H.; Poh, A.-L.; Kang, L. Handbook of Cosmeceutical Excipients and Their Safeties; Elsevier: Amsterdam, The Netherlands, 2015. [Google Scholar] [CrossRef]
  4. Erythropel, H.C.; Dodd, P.; Leask, R.; Maric, M.; Cooper, D.G. Designing green plasticizers: Influence of alkyl chain length on biodegradation and plasticization properties of succinate based plasticizers. Chemosphere 2013, 91, 358–365. [Google Scholar] [CrossRef] [PubMed]
  5. Jamarani, R.; Erythropel, H.C.; Burkat, D.; Nicell, J.A.; Leask, R.L.; Maric, M. Rheology of Green Plasticizer/Poly(vinyl chloride) Blends via Time–Temperature Superposition. Processes 2017, 5, 43. [Google Scholar] [CrossRef]
  6. Stuart, A.; LeCaptain, D.J.; Lee, C.Y.; Mohanty, D.K. Poly(vinyl chloride) plasticized with mixtures of succinate di-esters—synthesis and characterization. Eur. Polym. J. 2013, 49, 2785–2791. [Google Scholar] [CrossRef]
  7. Hevus, I.; Pikh, Z. Novel Surface-Active Succinate Monomers and Initiators for Obtaining Reactive Polymers. Macromol. Symp. 2007, 254, 103–108. [Google Scholar] [CrossRef]
  8. Jiang, Y.; Woortman, A.J.J.; van Ekenstein, G.O.R.A.; Loos, K. Enzyme-Catalyzed Synthesis of Unsaturated Aliphatic Polyesters Based on Green Monomers from Renewable Resources. Biomolecules 2013, 3, 461–480. [Google Scholar] [CrossRef]
  9. Carnahan, M.A.; Grinstaff, M.W. Synthesis and Characterization of Poly(glycerol-succinic acid) Dendrimers. Macromolecules 2001, 34, 7648–7655. [Google Scholar] [CrossRef]
  10. Cukalovic, A.; Stevens, C.V. Feasibility of production methods for succinic acid derivatives: A marriage of renewable resources and chemical technology. Biofuels Bioprod. Bioref. 2008, 2, 505–529. [Google Scholar] [CrossRef]
  11. Godard, C.; Muñoz, B.K.; Ruiz, A.; Claver, C. Pd-catalysed asymmetric mono- and bis-alkoxycarbonylation of vinylarenes. Dalton Trans. 2008, 853–860. [Google Scholar] [CrossRef]
  12. Wu, X.-F.; Neumann, H.; Beller, M. Palladium-Catalyzed Oxidative Carbonylation Reactions. ChemSusChem 2013, 6, 229–241. [Google Scholar] [CrossRef]
  13. Fini, F.; Beltrani, M.; Mancuso, R.; Gabriele, B.; Carfagna, C. Selective Aryl a-Diimine/Palladium-Catalyzed Bis-Alkoxycarbonylation of Olefins for the Synthesis of Substituted Succinic Diesters. Adv. Synth. Catal. 2015, 357, 177–184. [Google Scholar] [CrossRef]
  14. Olivieri, D.; Fini, F.; Mazzoni, R.; Zacchini, S.; Della Ca’, N.; Spadoni, G.; Gabriele, B.; Mancuso, R.; Zanotti, V.; Carfagna, C. Diastereospecific Bis-Alkoxycarbonylation of 1,2-disubstituted Olefins Catalyzed by Aryl α-Diimine Palladium(II) Catalysts. Adv. Synth. Catal. 2018, 360, 3507–3517. [Google Scholar] [CrossRef]
  15. Olivieri, D.; Tarroni, R.; Della Ca’, N.; Mancuso, R.; Gabriele, B.; Spadoni, G.; Carfagna, C. Bis-Alkoxycarbonylation of Acrylic Esters and Amides for the Synthesis of 2-Alkoxycarbonyl or 2-Carbamoyl Succinates. Adv. Synth. Catal. 2020, 362, 533–544. [Google Scholar] [CrossRef]
  16. Olivieri, D.; Tarroni, R.; Della Ca’, N.; Mancuso, R.; Gabriele, B.; Spadoni, G.; Carfagna, C. Combined Effect of Palladium Catalyst and the Alcohol to Promote the Uncommon Bis-Alkoxycarbonylation of Allylic Substrates. ChemCatChem 2022, 14, e202101923. [Google Scholar] [CrossRef]
  17. Carfagna, C.; Gatti, G.; Paoli, P.; Binotti, B.; Fini, F.; Passeri, A.; Rossi, P.; Gabriele, B. New Aryl α-Diimine Palladium(II) Catalysts in Stereocontrolled CO/Vinyl Arene Copolymerization. Organometallics 2014, 33, 129–144. [Google Scholar] [CrossRef]
  18. Neese, F. The ORCA program system. WIREs Comput. Mol. Sci. 2012, 2, 73–78. [Google Scholar] [CrossRef]
  19. Neese, F. Software update: The ORCA program system, version 4.0. WIREs. Comput. Mol. Sci. 2018, 8, e1327. [Google Scholar] [CrossRef]
  20. Perdew, J.P. Density-functional approximation for the correlation energy of the inhomogeneous electron gas. Phys. Rev. B 1986, 33, 8822–8824. [Google Scholar] [CrossRef]
  21. Becke, A.D. Density-functional exchange-energy approximation with correct asymptotic behavior. Phys. Rev. A 1988, 38, 3098–3100. [Google Scholar] [CrossRef]
  22. Weigend, F.; Ahlrichs, R. Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: Design and assessment of accuracy. Phys. Chem. Chem. Phys. 2005, 7, 3297–3305. [Google Scholar] [CrossRef] [PubMed]
  23. Zhao, Y.; Truhlar, D.G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: Two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor. Chem. Accounts 2008, 120, 215–241. [Google Scholar] [CrossRef]
  24. Marenich, A.V.; Cramer, C.J.; Truhlar, D.G. Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J. Phys. Chem. B 2009, 113, 6378–6396. [Google Scholar] [CrossRef] [PubMed]
  25. Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 2010, 132, 154104. [Google Scholar] [CrossRef] [PubMed]
Scheme 1. Pd-catalyzed bis-alkoxycarbonylation of styrene using 1,2-ethanediol.
Scheme 1. Pd-catalyzed bis-alkoxycarbonylation of styrene using 1,2-ethanediol.
Molbank 2022 m1456 sch001
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Olivieri, D.; Tarroni, R.; Carfagna, C. Bis(2-hydroxyethyl) 2-phenylsuccinate. Molbank 2022, 2022, M1456. https://doi.org/10.3390/M1456

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Olivieri D, Tarroni R, Carfagna C. Bis(2-hydroxyethyl) 2-phenylsuccinate. Molbank. 2022; 2022(4):M1456. https://doi.org/10.3390/M1456

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Olivieri, Diego, Riccardo Tarroni, and Carla Carfagna. 2022. "Bis(2-hydroxyethyl) 2-phenylsuccinate" Molbank 2022, no. 4: M1456. https://doi.org/10.3390/M1456

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