1Dipartimento di Chimica e Biologia “A. Zambelli”, Universita degli Studi di Salerno, Via Giovanni Paolo II
132, 84084 Fisciano, SA, Italy.
2Physical Sciences and Engineering Division, King Abdullah University of Science and Technology, KAUST
Catalysis Center, Thuwal, 23955-6900, Saudi Arabia
ABSTRACT. The demand for more sustainable world is pushing chemical industry
towards using chemical building blocks from renewable resources or to develop chemical processes better corresponding to the principles of the green chemistry. This goal requires developing new catalytic processes using molecules derived from renewable sources. In this scenario we report here on a computational mechanistic study devoted to clarify the coupling of bromine substituted lactide (Br-LA) with tetrahydrofurane (THF) in presence of a N-heterocyclic carbene (NHC). The computational work clearly indicated that the reaction is catalysed by a bromine anion formed in the initial reactivity of the NHC with Br-LA. Contrary to common knowledge, the NHC is not playing any role in the catalytic cycle.
1 Introduction
Increasing energy demand has often pushed science and technology revolutions. At the beginning of the 20th century, it was the increasing gasoline demand from the emerging automotive market that spurred the transformation of a basically coal economy into the oil economy we still experience. At the beginning of the 21th century it is the energy demand from an increasing world population, together with the increasing levels of atmospheric CO2, that is pressing science and technology for another revolution. In this context catalysis and chemistry can play a remarkable role towards building a sustainable world. In fact, it has been estimated that catalysis contributes to roughly 30% of the Gross World Product (GWP), and thus developing more sustainable processes by using chemical building blocks from renewable sources, or by developing more efficient and energy less expensive chemical processes, is one of the missions of contemporary chemistry. Among the most promising methodologies is organopolymerization of monomers from renewable sources.
Figure 1: Schematic representation of the reactivity observed when Br-LA is treated in THF in
presence of the N-heterocyclic carbene IMes.
Indeed, organopolymerization is today a preferred method for the synthesis of polymers when metal- free products or processes are of primary concern. In this context, the high Brønsted basicity and
O O O O MLA O O O O Br Br-LA DMF (50 ppm) IMes 1 N N IMes Mes Mes O IMes P1 IMes ROP O O n O O Br O O O O O Br > 20 g (100%) [Cat] O O O O O Br n
nucleophilicity, coupled with good leaving group features, has made catalysts based on N- heterocyclic carbene (NHC) based particularly attractive, due to the unique reactivity and selectivity they promote in different types of organic reactions, including polymerizations. Among the most relevant examples is the ring-opening polymerization (ROP) of lactide [1,2] for the synthesis of relatively high molecular weight biodegradable and biocompatible poly(lactide) (PLA).
Aiming at synthesizing functionalized PLAs with enhanced properties, we started from a Br- substituted L-lactide (Br-LA) presenting a bromine substituent on one of the sp3 C atoms of LA. While attempting to polymerize Br-LA with N-heterocyclic carbene (NHC) catalysts in tetrahydrofurane (THF), we found that Br-LA undergoes exclusive coupling with the solvent molecule (THF) to form the chiral bromo-diester 1 in Figure 1. This Br-LA + THF coupling reaction is completely selective (in a precisely 1:1 fashion), readily scalable (> 20 g), and extremely efficient (with only 50 ppm NHC catalyst loading). Density functional theory (DFT) calculations at the University of Salerno were performed to clarify the mechanism of this novel coupling reaction of Br- LA with THF [3], in analogy to previous work on the polymerization of polar monomers [4].
2 Methods
Molecular dynamics (MD) simulations were performed to explore the preferential approach between the reactants using the Born–Oppenheimer scheme as implemented in the CP2K Quickstep code [5]. The electronic structure calculations were carried out at the DFT level by using the Perdew–Burke– Ernzerhof exchange and correlation functional. The CP2K program employs a mixed basis set approach with Gaussian-type orbitals (GTO) and plane waves (PWs). An energy cut-off of 300 Ry is used for the plane-waves basis set. A triple-ζ basis set with a double polarization function, in conjunction with the Goedecker–Teter–Hutter pseudopotentials, was used for all the atoms. The systems were introduced in a cubic box of 15x15x15 Å3. Distance between reacting atoms was frozen at given values and was used approximate reaction coordinate for short 1ps long MD simulations. Selected structures from the MD simulations were used as starting geometries for static DFT calculations.
The static DFT calculations were performed by using the Gaussian 09 package [6]. Geometries were optimized at the generalized gradient approximation (GGA) level using the BP86 functional and the SVP basis set. The reported free energies were built through single point energy calculations on the BP86/SVP geometries using the hybrid meta GGA M06 functional and the triple-ζ TZVP basis set. Electrostatic and non-electrostatic solvent effects were included with the PCM model using THF as the solvent. Thermal energies and entropy effects were calculated at the BP86 level with a temperature of 298 K and a pressure of 1354 atm. Most of the calculations were performed on the CRESCO platform [7].
3 Results
Initially the general reactivity of a basic and nucleophilic NHC, IMes, towards Br-LA was explored. As for the basic behavior, IMes can remove a proton from the CH group of Br-LA, with a free energy barrier of 10.3 kcal/mol, leading to the ion-pair [IMesH]+Br– together with the zwitterionic cyclic
species X (Figure 2). Removing a proton from one of the CH3 groups to form the ion-pair [IMesH]+Br– together with MLA is disfavored by 5.6 kcal/mol in terms of free energy, despite the
very stable product Y is formed. As for the nucleophilic behavior, IMes can interact with both carbonyl groups of Br-LA. The preferential route is for attack to the carbonyl that is less hindered (colored in red, Figure 2) with a trans orientation of the attacked C=O and of the Br atom. This corresponds to the concerted ring opening of Br-LA and Br– elimination from the neighboring C
atom with a free energy barrier of 6.9 kcal/mol only. The resulting product is the acylazolium bromide Z, 21.4 kcal/mol below reactants. Dissociation of this ion-pair costs 7.4 kcal/mol. Overall,
the results shown in Figure 2 indicate that the easiest reaction pathway corresponds to nucleophilic attack of NHC to the Br-LA with ring-opening of Br-LA and elimination of a free Br– anion.
Figure 2. Reactivity of IMes towards Br-LA (numbers in red are free energies in kcal/mol).
In the following step we investigated the reactivity with THF starting from Br–, within the “bromide cycle”, as well as from the acylazolium, within the “NHC cycle”, see Figure 3. Within the NHC cycle THF is activated by the acylazolium and it is attacked by Brvia transition state B-C in Scheme 3, and a free energy barrier of 25.2 kcal/mol. The opening of THF ring leads to the zwitterionic intermediate C, followed by regeneration of the free NHC with formation of the coupling product 1 laying nearly 11 kcal/mol below reactants. Within the bromide cycle it is a free Br– anion that acts as the catalyst triggering the opening of the Br-LA ring via transition state D-E and a free energy barrier of 17.2 kcal/mol, leading to Br– plus the acyl bromide intermediate E, see Figure 3 [3].
Figure 3. NHC catalytic cycle (left) and bromide catalytic cycle (right) proposed for the coupling of
Br-LA with THF. The numbers in red are the free energies of intermediates and transition states relative to the starting species (IMes + THF + Br-LA in the NHC cycle and [IMesH]+Br– + THF + Br-LA in the bromine cycle). All free energies are in kcal/mol.
The subsequent reaction of E with THF proceeds via transition state E-1 and a fee energy barrier of 15.1 kcal/mol from E, leading to the coupling product 1 and liberation of the free Br– anion.
N N R R O O O O Br + O O O O N N R R Br Z -21.4 A 0.0 O O O O N N R R H O O O O N N R R H N N R R O O O O Br H N N R R O O O O Br H2C H A-X 10.3 X -1.1 Y -26.6 A-Y 15.9 Br Br O O O O Br A-Z/A-B 6.9 N N R R O O O O N N R R Br + B -14.0
Comparison of the NHC and of the bromide cycles shows that the energy span of the NHC cycle, corresponding to 25.2 kcal/mol from B to B-C, is 7.2 kcal/mol higher in energy than the largest energy window in the Br– cycle, 18.0 kcal/mol from D to E-1. This indicated that the real catalyst
promoting the observed reactivity is Br–, while IMes plays the role of a co-catalyst promoting the
liberation of Br– from Br-LA [3].
2 Conclusions
In summary, DFT calculations were fundamental to demonstrate that the coupling reaction of Br-LA and THF proceeds through a catalytic cycle where the real catalyst is the Br– anion, rather than the most intuitive cycle where the NHC is the catalyst. This successful story has required enormous computational resources since: i) Before exploring the Br– catalytic all the more reasonable routes involving the NHC as catalyst were explored; ii) The remarkable conformational flexibility of these systems required very expensive DFT-MD simulations to explore potential approaches of the different molecules before refining the catalytic cycle via standard static DFT methods, typically used to investigate reactivity.
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