Cocrystal engineering for efficient separation of 4-bromo-3-methylphenol: Design of experiments, characterization, crystal structure and calculation

Wang Chunxiao; Wang Shuai; Zhang Hongsen; Li Chao; Qiao Renzhong

doi:null

Your Location：

Home >

Browse articles >

Cocrystal engineering for efficient separation of 4-bromo-3-methylphenol: Design of experiments, characterization, crystal structure and calculation

Updated：2026-03-13

- Cocrystal engineering for efficient separation of 4-bromo-3-methylphenol: Design of experiments, characterization, crystal structure and calculation
- Chinese Journal of Chemical Engineering Vol. 89, Issue 1, Pages: 83-92(2026)
- Affiliations：
  
  State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing 100029, China
- Author bio：
  
  Corresponding authors. E-mail addresses: lichao@mail.buct.edu.cn(C. Li)
  qiaorz@mail.buct.edu.cn(R. Qiao).
- Funds：
- DOI：
  CLC：
- Received：25 June 2025，
  
  Revised：2025-08-11，
  
  Accepted：12 August 2025，
  
  Online First：24 October 2025，
  
  Published：2026-01
- Accepted：
Scan QR Code
Wang Chunxiao, Wang Shuai, Zhang Hongsen, et al. Cocrystal engineering for efficient separation of 4-bromo-3-methylphenol: Design of experiments, characterization, crystal structure and calculation[J]. Chinese Journal of Chemical Engineering, 2026, 89(1): 83-92.
DOI：

Wang Chunxiao, Wang Shuai, Zhang Hongsen, et al. Cocrystal engineering for efficient separation of 4-bromo-3-methylphenol: Design of experiments, characterization, crystal structure and calculation[J]. Chinese Journal of Chemical Engineering, 2026, 89(1): 83-92. DOI：

摘要

Abstract

4-Bromo-3-methylphenol (BMP) is an important chemical intermediate with wide applications in the fields of medicine and pesticides. The synthesis of BMP from

-cresol

via

bromination is easy to c

arry out on an industrial scale. However

due to the formation of regioisomeric impurities during bromination and the low melting point of BMP

the separation process is prone to the formation of oily substances

resulting in low yield and purity. In this work

a new cocrystallization engineering approach was proposed to separate and purify BMP. Through design of experiments

the cocrystallization process of BMP and triethylenediamine (DABCO) was optimized using a minimum-run resolution IV screening design combined with response surface methodology. In addition

the obtained 2BMP-DABCO powder was characterized by thermal analysis

powder X-ray diffraction

infrared spectroscopy

and scanning electron microscopy. Single crystals of 2BMP-DABCO were grown from acetone by slow evaporation

and detailed structural information was obtained through single-crystal X-ray diffraction. The self-assembly mechanism was further clarified by density functional theory calculations. This study provides a simple

robust

and scalable method for the production of BMP and offers a reference for the separation and purification of phenolic substances.

关键词

Keywords

references

S.J. Baker, V. Sanders, T. Akama, C. Bellinger-Kawahara, Y. Freund, K.R. Maples, J.J. Plattner, Y.K. Zhang, H. Zhou, V.S. Hernandez, Boron-containing small molecules as anti-inflammatory agents, WO Pat. 2007/095638A, (2007).

Z. Pang, S. Ye, Y. Liu, W. Huang, L. Zhou, Y. Feng, Method for preparing crisaborole from m -cresol, CN Pat. 112174989A (2021).

A. Cortez, Y.K. Li, A.T. Miller, X.Y. Zhang, K. Yue, J. Maginnis, J. Hampton, D.S. Hall, M. Shapiro, B. Nayak, U. D'Oro, C. Li, D. Skibinski, M.L. Mbow, M. Singh, D.T. O'Hagan, M.P. Cooke, N.M. Valiante, T.Y. Wu, Incorporation of phosphonate into benzonaphthyridine toll-like receptor 7 agonists for adsorption to aluminum hydroxide, J. Med. Chem. 59 (12) (2016) 5868—5878.

M.L. Martini, J. Liu, C. Ray, X.F. Yu, X.P. Huang, A. Urs, N. Urs, J.D. McCorvy, M. G. Caron, B.L. Roth, J. Jin, Defining structure-functional selectivity relationships (SFSR) for a class of non-catechol dopamine D1 receptor agonists, J. Med. Chem. 62 (7) (2019) 3753—3772.

L.M. Zhao, S. Wang, C. Pannecouque, E. De Clercq, H.R. Piao, F.E. Chen, Discovery of novel biphenyl-substituted pyridone derivatives as potent nonnucleos ide reverse transcriptase inhibitors with promising oral bioavailability, Eur. J. Med. Chem. 240 (2022) 114581.

P. Magnaghi, R. D'Alessio, B. Valsasina, N. Avanzi, S. Rizzi, D. Asa, F. Gasparri, L. Cozzi, U. Cucchi, C. Orrenius, P. Polucci, D. Ballinari, C. Perrera, A. Leone, G. Cervi, E. Casale, Y. Xiao, C. Wong, D.J. Anderson, A. Galvani, D. Donati, T. O'Brien, P.K. Jackson, A. Isacchi, Covalent and allosteric inhibitors of the ATPase VCP/p97 induce cancer cell death, Nat. Chem. Biol. 9 (9) (2013) 548—556.

R.H. Mitchell, Y.H. Lai, R.V. Williams, N -Bromosuccinimide-dimethylformamide: a mild, selective nuclear monobromination reagent for reactive aromatic compounds, J. Org. Chem. 44 (25) (1979) 4733—4735.

R. Hosseinzadeh, M. Tajbakhsh, M. Mohadjerani, Z. Lasemi, Efficient and regioselective bromination of aromatic compounds with ethylenebis( N methylimidazolium) ditribromide (EBMIDTB), Synth. Commun. 40 (6) (2010) 868—876.

D.Z. Yang, H.J. Wang, Q.W. Liu, P.H. Yuan, T. Chen, L. Zhang, S.Y. Yang, Z.Z. Zhou, Y. Lu, G.H. Du, Structural landscape on a series of rhein: berberine cocrystal salt solvates: the formation, dissolution elucidation from experimental and theoretical investigations, Chin. Chem. Lett. 33 (6) (2022) 3207—3211.

X.X. Liang, Y.R. Wu, Y.H. Deng, X.Y. Zeng, S.F. Shan, Y.B. Jiang, H.Y. Yang, Supramolecular self-assembly strategy for the enhanced solubility/dissolution rate and anti-cancer efficacy of osimertinib: insights from multicomponent crystals to drug chemistry, Chem. Eng. Sci. 299 (2024) 120520.

D.D. Hu, Y.L. Wang, C. Xiao, Y.F. Hu, Z.Y. Zhou, Z.Q. Ren, Studies on ammonium dinitramide and 3, 4-diaminofurazan cocrystal for tuning the hygroscopicity, Chin. J. Chem. Eng. 61 (2023) 157—164.

S. Zheng, Y.L. Wang, D.D. Hu, Z.Y. Zhou, C. Xiao, S.C. Tian, Z.Q. Ren, Cocrystallisation of high-energy oxidant ammonium dinitramide with triaminoguanidine nitrate for reduced hygroscopicity, Chin. J. Chem. Eng. 74 (2024) 249—258.

L.X. Yu, G. Amidon, M.A. Khan, S.W. Hoag, J. Polli, G.K. Raju, J. Woodcock, Understanding pharmaceutical quality by design, AAPS J. 16 (4) (2014) 771—783.

S. N Politis, P. Colombo, G. Colombo, D. M Rekkas, Design of experiments (DoE) in pharmaceutical development, Drug Dev. Ind. Pharm. 43 (6) (2017) 889—901.

D.C. Montgomery, Design and Analysis of Experiments, John Wiley & Sons, New York (2017).

M.J. Anderson, P.J. Whitcomb, RSM Simplified: Optimizing Processes Using Response Surface Methods for Design of Experiments, second ed., Productivity Press, New York (2016).

J.Y. Liu, Z.X. Li, Y.H. Bian, G.L. Zhang, J. Li, G. Wang, C.S. Li, Promotional effect of Ti on catalytic performance of Cs/Ti—SiO 2 for conversion of methyl propionate and formaldehyde to methyl methacrylate, Chem. Eng. Sci. 283 (2024) 119441.

O.V. Dolomanov, L.J. Bourhis, R.J. Gildea, J.A.K. Howard, H. Puschmann, OLEX2: a complete structure solution, refinement and analysis program, J. Appl. Crystallogr. 42 (2)(2009)339—341.

P.R. Spackman, M.J. Turner, J.J. McKinnon, S.K. Wolff, D.J. Grimwood, D. Jayatilaka, M.A. Spackman, CrystalExplorer: a program for Hirshfeld surface analysis, visualization and quantitative analysis of molecular crystals, J. Appl. Cryst. 54(2021)1006—1011.

F. Weigend, R. Ahlrichs, 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. 7 (18) (2005) 3297—3305.

Y. Zhao, D.G. Truhlar, 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. Acc. 120(1)(2008)215—241.

W. Humphrey, A. Dalke, K. Schulten, VMD: visual molecular dynamics, J. Mol. Graph. 14 (1)(1996)33—38, 27—28.

T. Lu, F.W. Chen, Multiwfn: a multifunctional wavefunction analyzer, J. Comput. Chem. 33(5)(2012)580—592.

T. Lu, A comprehensive electron wavefunction analysis toolbox for chemists, Multiwfn, J. Chem. Phys. 161(8) (2024)082503.

T. Lu, Q.X. Chen, Interaction region indicator: a simple real space function clearly revealing both chemical bonds and weak interactions, Chem. Mater. 1 (5)(2021)231—239.

J.H. Lo ehlin, M.C. Etter, C. Gendreau, E. Cervasio, Hydrogen-bond patterns in several 2:1 amine-phenol cocrystals, Chem. Mater. 6(8)(1994)1218—1221.

K.S. Huang, D. Britton, M.C. Etter, S.R. Byrn, A novel class of phenol—pyridine co-crystals for second harmonic generation, J. Mater. Chem. 7 (5) (1997) 713—720.

W.L. Xiao, B.G. Huang, X. Ma, Z.M. Yi, H.A. Luo, S. Yang, Analysis and optimization of a novel coupling process for industrial cresol separation, Ind. Eng. Chem. Res. 61 (47) (2022) 17342—17350.

F.M. Amombo Noa, G. Mehlana, Co-crystals and salts of vanillic acid and vanillin with amines, CrystEngComm 20(7)(2018)896—905.

S.S. Jin, R. Sanii, B.Q. Song, M.J. Zaworotko, Crystal engineering of ionic cocrystals sustained by the phenol—phenolate supramolecular heterosynthon, Cryst. Growth Des. 22 (7) (2022) 4582—4591.

C. Ferdeghini, L. Guazzelli, C.S. Pomelli, A. Ciccioli, B. Brunetti, A. Mezzetta, S. Vecchio Ciprioti, Synthesis, thermal behavior and kinetic study of N -morpholinium dicationic ionic liquids by thermogravimetry, J. Mol. Liq. 332 (2021) 115662.

M.A. Elbagerma, H.G.M. Edwards, T. Munshi, M.D. Hargreaves, P. Matousek, I. J. Scowen, Characterization of new cocrystals by Raman spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and transmission Raman spectroscopy, Cryst. Growth Des. 10(5)(2010)2360—2371.

J. Prashanth, K.V. Drozd, G.L. Perlovich, S. Balasubramanian , A. Surov, Cocrystal and coamorphous solid forms of enzalutamide with saccharin: structural characterization and dissolution studies, Cryst. Growth Des. 22 (11) (2022) 6703—6716.

A. Ponnuvel, S. Nivithaa, K.L. A, G.R. Ramkumaar, K.S. Nagaraja, C. Karnan, Structural and spectral studies of bis (1, 3, 5-triazinane-2, 4, 6-trione) 1, 4-diazabicyclo [2·2·2 ] octane (TTDO), J. Chem. Crystallogr. 53 (4) (2023) 507—514.

M.T. Messina, P. Metrangolo, W. Navarrini, S. Radice, G. Resnati, G. Zerbi, Infrared and Raman analyses of the halogen-bonded non-covalent adducts formed by α , ω-diiodoperfluoroalkanes with DABCO and other electron donors, J. Mol. Struct. 524 (1—3) (2000) 87—94.

G. Balakrishnan, T. Keszthelyi, R. Wilbrandt, J.M. Zwier, A.M. Brouwer, W.J. Buma, The radical cation and lowest Rydberg states of 1, 4-diaza [2.2.2 ] bicyclooctane(DABCO), J. Phys. Chem. A 104(9)(2000) 1834—1841.

M. Nishio, The CH/π hydrogen bond: implication in chemistry, J. Mol. Struct. 1018(2012)2—7.

W.J. Kuang, S.C. Ji, X.F. Wang, J.Y. Zhang, P. Lan, Relationship between crystal structures and physicochemical properties of lamotrigine cocrystal, Powder Technol. 380(2021)18—25.

S. Wang, J. Zhao, M. Li, R.Z. Qiao, C. Li, Pharmaceutical tazobactam sodium single crystal structure determination, polymorphism and crystallization process, Chem. Eng. Sci. 270(2023)118526.

Z.P. Wang, S. Li, Y. Tao, R.F. Zheng, S.Y. Yang, D.Z . Yang, S.B. Wang, L. Zhang, J. G. Xing, G.H. Du, Y. Lu, The novel cocrystals of acacetin with 4, 4'-bipyridine and 2, 2'-bipyridine: crystal structures analysis, stability and dissolution evaluation, J. Mol. Struct. 1318(2024)139270.

C.F. MacKenzie, P.R. Spackman, D. Jayatilaka, M.A. Spackman, CrystalExplorer model energies and energy frameworks: extension to metal coordination compounds, organic salts, solvates and open-shell systems, IUCrJ 4 (Pt 5) (2017)575—587.

J.S. Murray, P. Politzer, The electrostatic potential: an overview, Wires Comput. Mol. Sci. 1 (2) (2011) 153—163.

J.S. Murray, P. Politzer, Molecular electrostatic potentials and noncovalent interactions, Wires Comput. Mol. Sci. 7(6)(2017)e1326.

Y.Y. Li, Z.B. Ke, Y.Y. Di, Comparative study of calcium lactate with calcium succinate complexes in terms of crystal structure, Hirshfeld surface, FMOs, IRI analysis and thermal stability, J. Mol. Struct. 1322 (2025) 140441.

Views

Downloads

CSCD

Alert me when the article has been cited

Submit

Tools

Publicity Resources

High extraction efficiency of N,N,N′,N′-tetracyclohexyldiglycolamide for Sr(II): An experimental and crystal structure study

Crystal structure and thermal decomposition kinetics of 1-(pyridinium-1-yl)propane-(1-methylpiperidinium) bi[bis(trifluoromethanesulfonyl)imide], [PyC3Pi][NTf2]2

Crystal Growth,Structure and Morphology of Rifapentine Methanol Solvate

Synthesis of chemiluminescent carbonized polymer dots under atmospheric conditions for multimode luminescence anti-counterfeiting

Dual-site engineering of Ga-modified HZSM-5 towards efficient propane aromatization

Related Author

Xiujing Peng

Guoxin Sun

Xuchuan Jiang

Yu Cui

Miaomiao Zhang

Jianhui Su

Riming Hu

Haiyin Yu

Related Institution

Institute for Smart Materials & Engineering, University of Jinan

School of Chemistry and Chemical Engineering, University of Jinan

Henan Provincial Key Laboratory of Surface & Interface Science, Zhengzhou University of Light Industry

College of Materials and Chemical Engineering & Chemistry, Chengdu University of Technology

College of Chemical Engineering, Sichuan University

⁰