Skip to main content
SpringerLink
Log in

Modeling the alkylation of amines with alkyl bromides: explaining the low selectivity due to multiple alkylation

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

Context

Nucleophilic substitution reactions of aliphatic amines with alkyl halides represent a simple and direct mechanism for obtaining higher-order aliphatic amines. However, it is well known that these reactions suffer from low selectivity due to multiple alkylations, which is attributed to the higher reactivity of the newly formed amine. In order to provide a detailed explanation for this kind of system, we have investigated the reactivity of primary and secondary amines with 1-bromopropane and 2-bromopropane. The free energy profile in acetonitrile solution was obtained and a detailed microkinetic analysis was needed to analyze this complex reaction system. We have found that the product of the first alkylation is an ion pair corresponding to the protonated secondary amine and the bromide ion, which can transfer the proton to the reactant primary amine. Then, the newly formed secondary amine can also react, leading to a second alkylation to produce a tertiary protonated amine. Our modeling points out that both the proton transfer equilibria and the similar reactivity of the primary and secondary amines produce reduced selectivity. The proton transfer equilibria also contribute to slowing down the kinetics of the first alkylation.

Methods

The exploration of the mechanism was done by geometry optimization using the CPCM/X3LYP/ma-def2-SVP method, followed by harmonic frequency calculation at this same level of theory. A composite approach was used to obtain the free energy profile, using the more accurate ωB97X-D3/ma-def2-TZVPP level of theory for electronic energy and the SMD model for the solvation free energy. These calculations were performed with the ORCA 4 program. The detailed microkinetic analysis was done using the Kintecus program.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

Data will be made available on request.

References

  1. Patil MD, Grogan G, Bommarius A, Yun H (2018) Oxidoreductase-catalyzed synthesis of chiral amines. ACS Catal 8:10985–11015

    CAS  Google Scholar 

  2. Wang J-W, Li Y, Nie W, Chang Z, Yu Z-A, Zhao Y-F, Lu X, Fu Y (2021) Catalytic asymmetric reductive hydroalkylation of enamides and enecarbamates to chiral aliphatic amines. Nat Commun 12:1313

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Saramago L, Gomes H, Aguilera E, Cerecetto H, González M, Cabrera M, Alzugaray MF, da Silva Vaz Junior I, Nunes da Fonseca R, Aguirre-López B, Cabrera N, Perez-Montfort R, Merlino A, Moraes J, Alvarez G (2018) Novel and selective rhipicephalus microplus triosephosphate isomerase inhibitors with acaricidal activity. Vet Sci 5:74

  4. Seayad A, Ahmed M, Klein H, Jackstell R, Gross T, Beller M (2002) Internal olefins to linear amines. Science 297:1676–1678

    CAS  PubMed  Google Scholar 

  5. Wu L, Burgess K (2008) Synthesis and spectroscopic properties of rosamines with cyclic amine substituents. J Org Chem 73:8711–8718

    CAS  PubMed  Google Scholar 

  6. Shimizu K-i, Imaiida N, Kon K, Hakim Siddiki SMA, Satsuma A (2013) Heterogeneous Ni catalysts for N-alkylation of amines with alcohols. ACS Catal 3:998–1005

    CAS  Google Scholar 

  7. Liu Y, Ge H (2017) Site-selective C-H arylation of primary aliphatic amines enabled by a catalytic transient directing group. Nat Chem 9:26–32

    Google Scholar 

  8. Bhattacharyya S, Pathak U, Mathur S, Vishnoi S, Jain R (2014) Selective N-alkylation of primary amines with R-NH2·HBr and alkyl bromides using a competitive deprotonation/protonation strategy. RSC Adv 4:18229–18233

    CAS  Google Scholar 

  9. De Vylder A, Lauwaert J, Sabbe MK, Reyniers M-F, De Clercq J, Van Der Voort P, Thybaut JW (2019) Rational design of nucleophilic amine sites via computational probing of steric and electronic effects. Catal Today 334:96–103

    Google Scholar 

  10. Rufino VC, Pliego JR (2021) Bifunctional primary amino-thiourea asymmetric catalysis: the imine-iminium ion mechanism in the Michael addition of nitromethane to enone. Asian J Org Chem 10:1472–1485

    CAS  Google Scholar 

  11. Nielsen M, Worgull D, Zweifel T, Gschwend B, Bertelsen S, Jorgensen KA (2011) Mechanisms in aminocatalysis. Chem Commun 47:632–649

    CAS  Google Scholar 

  12. Melchiorre P, Marigo M, Carlone A, Bartoli G (2008) Asymmetric aminocatalysis—gold rush in organic chemistry. Angew Chem Int Ed 47:6138–6171

    CAS  Google Scholar 

  13. MacMillan DWC (2008) The advent and development of organocatalysis. Nature 455:304–308

    CAS  PubMed  Google Scholar 

  14. Mukherjee S, Yang JW, Hoffmann S, List B (2007) Asymmetric enamine catalysis. Chem Rev 107:5471–5569

    CAS  PubMed  Google Scholar 

  15. Pliego JR (2020) Theoretical free energy profile and benchmarking of functionals for amino-thiourea organocatalyzed nitro-Michael addition reaction. Phys Chem Chem Phys 22:11529–11536

    CAS  PubMed  Google Scholar 

  16. Trowbridge A, Walton SM, Gaunt MJ (2020) New strategies for the transition-metal catalyzed synthesis of aliphatic amines. Chem Rev 120:2613–2692

    CAS  PubMed  Google Scholar 

  17. Kroutil W, Fischereder E-M, Fuchs CS, Lechner H, Mutti FG, Pressnitz D, Rajagopalan A, Sattler JH, Simon RC, Siirola E (2013) Asymmetric preparation of prim-, sec-, and tert-amines employing selected biocatalysts. Org Process Res Dev 17:751–759

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Reed-Berendt BG, Polidano K, Morrill LC (2019) Recent advances in homogeneous borrowing hydrogen catalysis using earth-abundant first row transition metals. Org Biomol Chem 17:1595–1607

    CAS  PubMed  Google Scholar 

  19. Podyacheva E, Afanasyev OI, Tsygankov AA, Makarova M, Chusov D (2019) Hitchhiker’s guide to reductive amination. Synthesis 51:2667–2677

    CAS  Google Scholar 

  20. Salvatore RN, Yoon CH, Jung KW (2001) Synthesis of secondary amines. Tetrahedron 57:7785–7811

    CAS  Google Scholar 

  21. Pliego JR (2021) The role of intermolecular forces in ionic reactions: the solvent effect, ion-pairing, aggregates and structured environment. Org Biomol Chem 19:1900–1914

    CAS  PubMed  Google Scholar 

  22. Reichardt C, Welton T (2011) Solvents and solvent effects in organic chemistry, Fourth edn. WILEY-VCH, Weinheim, Germany

    Google Scholar 

  23. Lisboa FM, Pliego JR (2022) SN2 versus E2 reactions in a complex microsolvated environment: theoretical analysis of the equilibrium and activation steps of a nucleophilic fluorination. J Mol Model 28:159

    CAS  PubMed  Google Scholar 

  24. Schindl A, Hawker RR, Schaffarczyk McHale KS, Liu KTC, Morris DC, Hsieh AY, Gilbert A, Prescott SW, Haines RS, Croft AK, Harper JB, Jäger CM (2020) Controlling the outcome of SN2 reactions in ionic liquids: from rational data set design to predictive linear regression models. Phys Chem Chem Phys 22:23009–23018

    CAS  PubMed  Google Scholar 

  25. Parker AJ (1969) Protic-dipolar aprotic solvent effects on rates of bimolecular reactions. Chem Rev 69:1

    CAS  Google Scholar 

  26. Dang TT, Ramalingam B, Shan SP, Seayad AM (2013) An efficient palladium-catalyzed N-alkylation of amines using primary and secondary alcohols. ACS Catal 3:2536–2540

    CAS  Google Scholar 

  27. Jiménez MV, Fernández-Tornos J, González-Lainez M, Sánchez-Page B, Modrego FJ, Oro LA, Pérez-Torrente JJ (2018) Mechanistic studies on the N-alkylation of amines with alcohols catalysed by iridium(i) complexes with functionalised N-heterocyclic carbene ligands. Catal Sci Technol 8:2381–2393

    Google Scholar 

  28. Hall HK, Bates RB (2012) Correlation of alkylamine nucleophilicities with their basicities. Tetrahedron Lett 53:1830–1832

    CAS  Google Scholar 

  29. Sommer HZ, Lipp HI, Jackson LL (1971) Alkylation of amines. General exhaustive alkylation method for the synthesis of quaternary ammonium compounds. J Org Chem 36:824–828

    CAS  Google Scholar 

  30. Chattaraj PK, Sarkar U, Parthasarathi R, Subramanian V (2005) DFT study of some aliphatic amines using generalized philicity concept. Int J Quantum Chem 101:690–702

    CAS  Google Scholar 

  31. Xu X, Zhang Q, Muller RP, Goddard WA III (2005) An extended hybrid density functional (X3LYP) with improved descriptions of nonbond interactions and thermodynamic properties of molecular systems. J Chem Phys 122:014105–014114

    Google Scholar 

  32. Weigend F, Ahlrichs R (2005) 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 7:3297–3305

    CAS  PubMed  Google Scholar 

  33. Cossi M, Rega N, Scalmani G, Barone V (2003) Energies, structures, and electronic properties of molecules in solution with the C-PCM solvation model. J Comput Chem 24:669–681

    CAS  PubMed  Google Scholar 

  34. Zheng JJ, Xu XF, Truhlar DG (2011) Minimally augmented Karlsruhe basis sets. Theor Chem Acc 128:295–305

    CAS  Google Scholar 

  35. Lin Y-S, Li G-D, Mao S-P, Chai J-D (2013) Long-range corrected hybrid density functionals with improved dispersion corrections. J Chem Theory Comput 9:263–272

    CAS  PubMed  Google Scholar 

  36. Marenich AV, Cramer CJ, Truhlar DG (2009) 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 113:6378–6396

    CAS  PubMed  Google Scholar 

  37. Neese F, Wennmohs F, Becker U, Riplinger C (2020) The ORCA quantum chemistry program package. J Chem Phys 152:224108

    CAS  PubMed  Google Scholar 

  38. Neese F (2018) Software update: the ORCA program system, version 4.0. Wiley Interdiscip Rev Comput Mol Sci 8:e1327

    Google Scholar 

  39. Sciortino G, Maseras F (2023) Microkinetic modelling in computational homogeneous catalysis and beyond. Theor Chem Acc 142:99

  40. Besora M, Maseras F (2018) Microkinetic modeling in homogeneous catalysis. Wiley Interdiscip Rev Comput Mol Sci 8:e1372

    Google Scholar 

  41. Ianni JC (2019) Kintecus. Version 6.8 edn. http://www.kintecus.com

  42. Pliego JR Jr, Riveros JM (2012) New insights on reaction pathway selectivity promoted by crown ether phase-transfer catalysis: model ab initio calculations of nucleophilic fluorination. J Mol Catal A - Chem 363–364:489–494

    Google Scholar 

  43. Bartsch RA, Zavada J (1980) Stereochemical and base species dichotomies in olefin-forming E2 eliminations. Chem Rev 80:453–494

    CAS  Google Scholar 

  44. Marcus Y, Hefter G (2006) Ion pairing. Chem Rev 106:4585–4621

    CAS  PubMed  Google Scholar 

  45. Tshepelevitsh S, Kütt A, Lõkov M, Kaljurand I, Saame J, Heering A, Plieger PG, Vianello R, Leito I (2019) On the basicity of organic bases in different media. Eur J Org Chem 2019:6735–6748

    CAS  Google Scholar 

Download references

Funding

The authors thank the support of the agencies CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil), FAPEMIG (Fundação de Amparo a Pesquisa do estado de Minas Gerais, Brazil), and CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil).

Author information

Authors and Affiliations

  1. Departamento de Ciências Naturais, Universidade Federal de São João del Rei, São João del Rei, MG, 36301-160, Brazil

    Luis F. Resende & Josefredo R. Pliego Jr.

Authors
  1. Luis F. Resende
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Josefredo R. Pliego Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JRPJ contributed to the study conception and design. DFT calculations and data collection were performed by LFR. JRPJ performed the microkinetic analysis. The manuscript was written by LFR and JRPJ. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Josefredo R. Pliego Jr..

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 80 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Resende, L.F., Pliego, J.R. Modeling the alkylation of amines with alkyl bromides: explaining the low selectivity due to multiple alkylation. J Mol Model 30, 107 (2024). https://doi.org/10.1007/s00894-024-05902-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00894-024-05902-7

Keywords

Search

Navigation