NMR Investigation Substantiated by Density-Functional Calculations

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Product Distribution Control for Glucosamine Condensation: NMR Investigation Substantiated by Density-Functional Calculations Lingyu Jia, Zhenzhou Zhang, Yan Qiao, Christian Marcus Pedersen, Hui Ge, Zhihong Wei, Tiansheng Deng, Jun Ren, Xingchen Liu, Yingxiong Wang, and Xianglin Hou Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.6b05057 • Publication Date (Web): 26 Feb 2017 Downloaded from http://pubs.acs.org on February 27, 2017

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Industrial & Engineering Chemistry Research

Product Distribution Control for Glucosamine Condensation: NMR

Investigation

Substantiated

by

Density-Functional

Calculations Lingyu Jia,ab Zhenzhou Zhang,bc Yan Qiao,c Christian Marcus Pedersen,d Hui Ge,c Zhihong Wei,c Tiansheng Deng,a Jun Ren,e Xingchen Liu,*c Yingxiong Wang,*a and Xianglin Hou*a a

Shanxi Engineering Research Center of Biorefinery, Institute of Coal Chemistry, Chinese Academy of Sciences, Taiyuan, People’s Republic of China E-mail: [email protected], [email protected], [email protected]; Fax: +86 351 4041153; Tel: +86 351 4049501

b

Graduate University of Chinese Academy of Sciences, Beijing, People’s Republic of China

c

State Key Laboratory of Coal Conversion, Institute of Coal Chemistry, Chinese Academy of Sciences, Taiyuan, People’s Republic of China

d

Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen, Denmark

e

College of Chemical Engineering and Environment, North University of China, Taiyuan 030051, China

ABSTRACT Selective conversion of glucosamine (GlcNH2) to deoxyfructosazine (DOF) and fructosazine (FZ) with additives was investigated. Significantly enhanced yield of DOF can be improved to 40.2% with B(OH)3 as additive. Chemical shift titration (1D 1

H and 13C NMR) and 2D NMR including 1H-13C HSQC and 1H-1H COSY are used

to

investigate

intermolecular

interactions

between

B(OH)3

and

GlcNH2.

Diffusion-ordered NMR spectroscopy (DOSY) was further employed to identify intermediate species. Mechanistic investigation by NMR combined with ESI-MS discloses that a mixed 1:1 boron complex was identified as the major species, shedding light on the promotional effects of B(OH)3, which is substantiated by DFT. 1

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Boron coordination effects make ring-opening and subsequent dehydration reaction thermodynamically

and

kinetically

more

favorable.

Dehydration

of

dihydrofructosazine is a key step in controlling overall process (49.7 kcal/mol). Interestingly, chelating effect results in substantial reduction of this free energy barrier (31.5 kcal/mol). Notably, FZ was gradually becoming the main product (yield up to 25.3%) with H2O2 as oxidant. KEYWORDS: product distribution; additive effect; NMR spectroscopy; DFT calculations; GlcNH2 condensation

1. INTRODUCTION Chitin biomasses, a linear polymer, not directly in conflict with food supply, are the second most abundant natural biopolymer on Earth after cellulose.1-4 Currently, the polymers and their soluble monomer derivatives, N-acetyl-D-glucosamine (GlcNAc) or

D-glucosamine

(GlcNH2) have been used for waste water treatment,

cosmetics, and pharmaceuticals.5 Its potential is however much greater. Unlike most other forms of biomass, chitin biomasses contain biologically-fixed nitrogen, which is a more suitable starting point for high value-added nitrogen chemicals.6-9 Nitrogen-containing compounds, widely used in the pharmaceutical and food industry, are crucial for modern life. For example, pyrazinamide exhibits antidiabetic activity against immunological and anti-inflammatory diseases.5 Thus, turning chitin biomasses into nitrogen-rich chemicals would benefit economies and the environment. Chitin-derived GlcNH2 has been converted into a complex mixture of products including nitrogen containing organic compound pyrazine, such as deoxyfructosazine (DOF) and fructosazine (FZ), which are gaining increased attention in food and pharmaceutical industry.10-12 Nevertheless, the main difficulty in the abovementioned transformations is that the ratio of target products cannot be selectively controlled. This is mainly due to the fact that the reaction pathway is profoundly affected by reaction conditions, particularly by the catalysts used, pH of the reaction mixtures, 2


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and the reaction temperature.11, 13 Precise product distribution control, therefore, is still a substantial challenge for GlcNH2 conversion. Selective conversion of GlcNH2 into DOF or FZ would be important due to their distinct physiological and pharmaceutical activities.10,

13, 14

For example, DOF has effect on treatment and

prevention of diabetes or complications of diabetes, while FZ confers higher DNA breakage activity than DOF.10 Hrynets et al. have showed that FZ played a more significant role as an antimicrobial agent against the heat-resistant.14 In addition, non-volatile (polyhydroxyalkyl)pyrazine derivatives, DOF and FZ, both are water-soluble substance making separation and purification difficulty. According to our mechanistic investigation, the isotopic-labelling experiments disclose that there are two parallel pathways open to the intermediate dihydrofructosazine.12 DOF is formed via a dehydration process while FZ was formed simultaneously through dehydrogenation. Inspired by this, thus, we wondered whether the pathways for the GlcNH2 conversion can be selectively controlled. It is well known that boric acid, B(OH)3, a weak, noncorrosive, and nontoxic acid, could enhance the selectivity in a variety of reactions on carbohydrates, particularly enhancing dehydration process.7,

15

It is evident that the reactivity and preferred

reaction pathways of B(OH)3 reagents are related to their aggregation states, thus, any information regarding these intermediate states can enhance our understanding and ability to tailor organic reactions to the desired products.16 Hydrogen peroxide, H2O2, is an ideal oxidant for liquid-phase reactions.17 Indeed, the use of H2O2 has received much attention presumably due to its reasonable price and low environmental impact as it generates water as the only byproduct.18 An appropriate choice of additives can tune product distribution, thereby providing a cost-effective route for the synthesis of these valuable chemical intermediates. Herein, B(OH)3 as additive markedly facilitating DOF formation was firstly evaluated. Chemical shift titration (1D 1H and 1

13

C NMR) and 2D NMR including

H-13C HSQC and 1H-1H COSY are used to investigate the intermolecular interactions

between B(OH)3 and GlcNH2. Diffusion-ordered NMR spectroscopy (DOSY) was further introduced to identify intermediate species in this study. We also employ DFT 3



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to reveal the role of B(OH)3 in promoting dehydration reaction. In addition, the reactivity of GlcNH2 with H2O2 as additive for FZ selective production was performed. 2. EXPERIMENTAL SECTION

2.1.

Materials. D-GlcNH2·HCl (99.8%, white crystalline powder) was obtained

from Golden-Shell Biochemical Co. Ltd. [C2C1Im][OAc] was purchased from Shanghai Cheng Jie Chemical Co. Ltd. DMSO-d6 (99.9%, atom D) and deuterium oxide (D2O, 99.9% atom D) were supplied by Qingdao Teng long Microwave Technology Co. Ltd. Boric acid, B(OH)3, hydrogen peroxide, H2O2 (30 wt% water solution, special class), and other chemicals were purchased from Sinopharm Chemical Reagent Co. Ltd. All reagents were used without further purification.

2.2.

NMR Sample Preparation. For observing the effects of B(OH)3 on

GlcNH2 conversion, samples were prepared by adding different molar ratios of B(OH)3 into GlcNH2 solutions (1 mmol) with 0.5 ml DMSO-d6 at room temperature (the molar ratio of B(OH)3/GlcNH2 = 0:1, 0.1:1, 0.3:1, 0.5:1, 1:1, 2:1, 5:1). Similarly, samples of catalytic reaction were prepared by adding different amounts of B(OH)3 into GlcNH2 solutions (1 mmol) in the presence of [C2C1Im][OAc] as catalyst (0.1 mmol).

2.3.

General Reaction Procedures. The condensation reaction was carried

out at 90 °C for 180 min with different molar ratio of B(OH)3 additive (0 mmol, 0.3 mmol, 0.5 mmol, 0.7 mmol, 1.0 mmol, and 2.0 mmol). Similar procedures were performed for the selective production of FZ. Briefly, GlcNH2 and [C2C1Im][OAc] (molar ratio 1:1) with different volume of H2O2 (30% water solution) (0 ml, 0.1 ml, 0.3 ml, 0.5 ml, 0.7 ml, 1.0 ml, and 1.5 ml) in 1 ml DMSO solution were introduced into the reactor at 80 °C for 180 min. Quantitative 1H NMR spectroscopy was employed to quantify the yields of DOF and FZ, as well as the GlcNH2 conversion. Yields were calculated as: Yield = 2 ×

× 100% 4


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2.4.

Characterization. Liquid phase 1H and 13C nuclear magnetic resonance

(NMR) spectra were obtained with a Bruker AV-III 400 spectrometer (9.39 T) equipped with auto sampler (400.13 MHz for 1H, 100.61 MHz for

13

C). 2D

heteronuclear single quantum coherence (1H-13C HSQC) spectroscopy with Bruker’s “hsqcedetgpsisp2.3” pulse program19 and homonuclear shift correlation (1H-1H COSY) with multiple quantum filter and pulse program ‘mqsgp1d2’ for setup20 were collected at 298.15 K. All spectra were acquired using DMSO-d6 for field-frequency lock. Samples were further qualitatively identified by the positive-ion ESI mass spectrum on a Bruker MicrOTOF-Q III.12

2.5.

Diffusion NMR Experiments. The standard Bruker pulse sequence

(ledbpgp2s) incorporating longitudinal eddy current delay was used for 1H DOSY experiments.21, 22 For diffusion measurements, the delay δ was set to 800-2000 µs and ∆ was set to 100-200 ms. The pulse-field gradients were incremented in 32 steps from 2% to 95% of the maximum gradient strength in a linear ramp. The individual slices of pseudo-2D diffusion spectra were phased and baseline corrected. Diffusion coefficients of each 1H DOSY signals were generated from T1/T2 analysis. All the DOSY experiments were performed at 298.15 K, since DOSY spectra often include artifacts generated by temperature fluctuation.

2.6.

Computational Methods. Density functional theory (DFT) calculations

were performed with the Gaussian 09 package.23 The standard B3LYP functional with 311+G(d,p) basis set were used in all geometry optimizations and frequency calculations of the whole models.24 It can provide accurate geometrical parameters and energies with low computational cost, especially for organic molecules. Transition states (TS) were located by the OPT=TS method and confirmed by the intrinsic reaction coordinate (IRC) approach, to verify that each transition state was connected with the corresponding reactants and products.12 The transition state is a first-order saddle point of the potential energy surface, with only a single imaginary frequency. The obtained reactants and products were verified as being situated in the energy minima points of the potential energy surface, with only real frequencies. In all 5



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cases, the convergence criteria for the self-consistent field (SCF) procedure25 was set to 10-8 a.u. Optimization without any additional information sets the RMS force criterion26 to 3*10-4 a.u. Dispersion corrections were computed with a locally modiﬁed version of Grimme’s dftd3-program with a ‘zero-damping’ function.27 It does not only improve the description of noncovalent interactions but also of the basic properties and particularly the reaction energies. The Gibbs free energies corrected by zero point energies (ZPE) with harmonic oscillator approximation were computed at 298.15 K. The solvation effect was incorporated in all the calculations using the implicit polarizable continuum solvation model (PCM).28

3. RESULTS AND DISCUSSION 3.1.

B(OH)3 Effects on DOF Formation. Our isotopic-labelling experiments

indicated that DOF was mainly formed through dehydration step.12 Previously, Chen et al. has systematically evaluated the performance of a wide range of additives, and found that B(OH)3 is the most effective additive for dehydration reactions.7 Inspired by such research, we wondered whether B(OH)3 could facilitate GlcNH2 selective dehydration to producing DOF. In the control experiment, i.e. absence of B(OH)3, DOF and FZ were simultaneously detected as the main products with the yields of 27.6% and 13.5%, respectively.12 Notably, when substoichiometric amount of B(OH)3 (the molar ratio of B(OH)3/GlcNH2 = 0.3) was added to the reaction mixtures, DOF was detected as the main products with the yield of 30.7%, which could be further confirmed by the characteristic low field signals (154.7 ppm, 153.3 ppm, 144.1 ppm, and 142.3 ppm) in the

13

C NMR spectrum (Figure S1).10 FZ was also detected, but its yield was much

low (2.1%). Purification of products via recrystallization afforded DOF, which were qualitatively identified by 1H NMR,

13

C NMR, 1H-1H COSY, and 1H-13C HSQC

spectra (Figure S2-S5). Further increase in the content of B(OH)3 results in a rapid increase in the yield of DOF and a sharp decrease in yield of FZ. The yield of DOF improved markedly from 0.3 equivalents and reached a maximum between 0.5 and 6


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1.0 equivalent (the highest yield of 40.2%, as seen in Figure 1). Addition of stoichiometric or higher amounts of B(OH)3 produces virtually DOF (Figure S6). All these results indicate that not only the FZ could be suppressed, but also the DOF could be enhanced in the presence of B(OH)3, thus leading to dramatically low yield of FZ and high yield of DOF. The observed yields drop at relatively high B(OH)3 content (2 mmol) presumably due to the formation of more stable sugar-B(OH)3 complexes, which is inhibiting further conversion.29, 30 Moreover, it was found that the intensity of signals due to side products (depicted by black dashed line) in the stacked 1H NMR spectra gradually decreased with adding B(OH)3 into reaction system (Figure S6). Our hypothesis is that sugar-B(OH)3 coordination is responsible for the selectivity.31 To determine this specific interaction on product distribution, a series of reactions varying the B(OH)3 content were introduced to reaction mixtures to investigate the effect of B(OH)3 on the reaction selectivity.

Yield of FZ Yield of DOF

45 40 35

Percent (%)

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30 25 20 15 10 5 0

0

0.3

0.5

0.7

1

2

Molar ratios of B(OH)3/GlcNH2

Figure 1. Effects of B(OH)3 amounts on product distributions catalyzed by [C2C1Im][OAc].

3.2.

Chemical Shift Titrations. To obtain further understanding on B(OH)3

facilitated GlcNH2 transformation into DOF, we turned to NMR spectroscopy.32, 33 Our NMR study showed that GlcNH2, when freshly dissolved in DMSO-d6, is predominantly an α-anomer (see Figure 2a for 1H and Figure 3a for 13C NMR).10 By 7



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adding different molar ratios of B(OH)3, significant changes were observed in both 1H and 13C NMR spectra. In the 1H NMR spectrum, in the absence of B(OH)3, the –NH and -OH resonances were sharp (Figure 2a). However, peaks belonging to the proton on OH groups gradually become broad and finally disappear in the 1H NMR spectra as increasing B(OH)3 contents (pointed by the arrows in Figure 2). In addition, several peaks arise and gradually disappear with increasing B(OH)3 amounts (at 7.6 ppm, 7.5 ppm, 6.5 ppm and 5.9 ppm, depicted by black dash-lines). These rising peaks is likely to be assigned to the linear form of GlcNH2.10 Notably, a series of new peaks are clearly detected and indicated by the light-green frame in Figure 2b-g, which reveal the existence of a sugar-borate complex. In accordance with these changes, new sets of resonances were also clearly observed in the stacked

13

C NMR spectra

(characteristic resonance peaks at δ = 90.1, 75.5, 68.8, 64.4, 63.9 and 54.8 ppm), most of which experience a marked shift (depicted by black star in Figure 3b-g). The peaks at around 55 ppm are split upon the addition of B(OH)3, which are enlarged and depicted in Figure S7. It is believed that these new peaks originated from the boron complex intermediates, and the relative intensity assigned to the boron complex keep increased with increasing the B(OH)3 contents compared with adjacent free sugar signals (Figure 2 and 3).34

8


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Figure 2. 1H NMR of pure GlcNH2 (a) and with different molar ratio of B(OH)3 at room temperature (b-g). (g) B (O H ) 3 / G lcN H2 5:1

(f) B (O H ) / G lcN H 3 2 2:1

(e) B (O H ) 3 / G lcN H 2 1:1

★■

■

■

★

■

6

★

■

■

★

7

★

5

★ ■

(d) B (O H ) / G lcN H 3 2 0.5:1

■

★

■

■

(c) B (O H ) / G lcN H 3 2 0.3:1

4

★

★

★

★

3

★

★★

■

(b) B (O H ) / G lcN H 3 2 0.1:1

2 ★ ■

(a) P ure G lcN H 2

110

105

Figure 3.

100

13

★

★ ■

α-C4

α-C1

■

★★

α-C3 α -C5

★

α-C6

■

■

■

DM SO

α -C2

1

95

90

85

80

75 70 f1 (p p m )

65

60

55

50

45

40

35

C NMR of pure GlcNH2 (a) and with different molar ratio of B(OH)3 at

room temperature (b-g). denotes the peaks of α-anomer; denotes the peaks

9



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assigned to boron complex of the α-anomer. Note: the peaks at around 55 ppm are split upon the addition of B(OH)3, which may not be obviously seen in the figure.

3.3.

2D HSQC and COSY NMR Analysis. To gain further insight and assign

these new rising peaks, 2D heteronuclear single quantum correlation (1H-13C HSQC in Figure 4) and homonuclear shift correlation (1H-1H COSY in Figure S8) measurements

were

performed,

which

could

reveal

correlations

between

proton−carbon and proton−proton, respectively.35 1H-13C HSQC NMR spectrum yielded characteristic cross peaks for all components, namely, GlcNH2 units and its boron complex. The Cα-Hα correlations in the GlcNH2 units10 were observed at δC/δH 89.3/5.25 (C1-H1), 72.7/3.57 (C4-H4), 70.6/3.17 (C3-H3), 70.2/3.59 (C5-H5), 60.9/(3.60, 3.50) (C6-H6), 54.9/(2.90, 2.80) (C2-H2), depicted by arrows in Figure 4. Prominent correlations at δC/δH 90.1/5.32 (C1-H1), 75.5/3.56 (C4-H4), 68.8/3.65 (C3-H3), 64.4/3.82 (C5-H5), 63.9/(3.88, 3.70) (C6-H6), 54.8/2.99 (C2-H2) attributed to boron complex were also fairly well resolved (depicted by the numbers in Figure 4). Notably, in one 13C NMR dimension, the signals of C3 (3) and C5 (5) on the boron complex markedly shift upfield (signal move to smaller ppm) compared with other carbons (C1, C4, C6) shift downfield (signal move to larger ppm). Thus, complexes with an acyclic structure at C3/C5 may be formed in solution. In addition, according to the HSQC spectrum, no carbon atoms are connected with proton peaks mentioned in previous 1H NMR spectra (7.6 ppm, 7.5 ppm, 6.5 ppm and 5.9 ppm, pointed by grey-frame in Figure 4), which arise firstly and finally disappeared (depicted by black dash-lines in Figure 2). Thus, these signals were attributed to active hydrogen groups (depicted by red dots in Figure 4).35 Furthermore, 1H-1H COSY was performed to collect further evidence to support these above results. The H-H correlations corresponding to GlcNH2 were observed and pointed by arrows in Figure S8.10 Notably, prominent signals corresponding to boron complex were also found (at δH/δH 8.25s/3.0dd, 7.55d/5.33t, 5.93d/3.65m, 5.68d/3.59m, 5.25t/3.0dd, 3.66m/3.0dd). Thus, B(OH)3 indeed interacts with two active groups and forms a boron containing complex. 10


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Figure 4. 2D 1H-13C HSQC NMR spectrum of GlcNH2 with B(OH)3 in DMSO-d6 solution (the molar ratio of B(OH)3/GlcNH2 = 0.5:1).

3.4.

Diffusion NMR Measurements. Conventional 1D and 2D NMR

spectroscopy

can

provide

valuable

information

about

boron

complexes.7

Unfortunately, our initial attempts using 1H NMR were somewhat discouraging due to signal overlap.10 Resonances of methine protons of boron complex from 3.9 to 3.5 ppm overlapped with those from GlcNH2 units (depicted by green-frame in Figure 2). This considerable spectral overlap in the central region of the spectrum might obscure differences that could be present. Diffusion ordered NMR spectroscopy (DOSY) has emerged as an effective tool for studying non-covalent interactions in solution, in which one dimension represents chemical shift data while the second dimension resolves species by their diffusion properties.21, 36, 37 Since diffusion depends on size, coordination reduces diffusion rates. Thus, homonuclear 1H DOSY methods have been developed to differentiate individual species in a multicomponent solution based on their mobilities.36 Interestingly, two different components were clearly identified in the diffusion 11



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dimension (Figure 5). This new set of NMR signals (pointed by red dashed line) moves slower (D = 1.32 × 10-10 m2 s-1) than the free GlcNH2 units (D = 1.35 × 10-10 m2 s-1, pointed by blue dashed line), indicating complexation and a significant formula weight increase.22 It was noteworthy that diffusion dimension separation of free α-GlcNH2 and boron complex was observed to exhibit an average 3.0% difference in relative diffusion coefficient (Table S1). Only one set of new peaks appeared in the 2D 1H DOSY and no extra diffusion signals observed. The aggregation number of boron complex was further confirmed by Mass spectrometry. Notably, a characteristic ion peak at m/z 206 was clearly observed (depicted in Figure S9). It was believed to be the 1:1 boron complex intermediate. The elemental composition of m/z 206 ion, measured by ESI mass spectrum, was C6H12N1O6, which agreed with GlcNH2 (C6H13N1O5) + B(OH)3 (H3BO3) - 2H2O. The intermediate exhibiting 1:1 stoichiometry is formed and this supports the NMR results. Since in DMSO-d6 solution B(OH)3 could interact with hydroxyl and amino groups resulting in the formation of boron containing complex, one may wonder if this mechanism would work in the catalytic reaction system. For this purpose equimolar amount of B(OH)3 additive was added to GlcNH2 solution in the presence of 0.1 mmol [C2C1Im][OAc], and the

13

C NMR spectrum recorded (Figure S10).

Except for the isomer peaks of GlcNH2, a series of new resonances are clearly observed, indicating the formation of boron complex in the real reaction system. Thus, the boron complex is intermediate for further conversion. This provides a plausible explanation for the promotional effect of B(OH)3.16

12


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Figure 5. 1H DOSY NMR spectrum of GlcNH2 with B(OH)3 in DMSO-d6 at 25 °C. Reaction conditions: 2 equivalent of B(OH)3 was added into 1 equivalent of GlcNH2 in 0.5 ml DMSO-d6.

3.5.

Computational Studies. 3.5.1. Ring Opening and Dehydration Pathways in

the absence of B(OH)3. Several experimental results based on NMR and MS data have provided evidence as to the nature of boron species and the coordination properties between sugars and B(OH)3. In particularly, we were interested in determining how the presence of B(OH)3 could affect the relative energies of species along the reaction pathway, therefore, a study using molecular modeling was devoted to elucidate the reaction mechanism in detail.38 The calculation results along the dehydration pathways in the absence of B(OH)3 were firstly illustrated. Starting from α-glucosamine (1A), two ring opening and dehydration pathways were studied. The optimized structures of all reactants and products are depicted in Figure S11. In the first model, the conversion of α-glucosamine (1A’) to the open-chain form (2A) through a four-centered transition state (TS1) occurs via an intramolecular proton migration between the oxygen atoms O1 and O5, while simultaneously breaking the C1-O5 bond and forming a C1-O1 double bond, which is shown in 13



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Scheme 1.39 The free energy profile is presented in Figure 6. The activation free energy for ring opening is calculated to be 42.4 kcal/mol. Subsequently, intermediate dihydrofructosazine (3A, - 9.0 kcal/mol) was formed via intermolecular nucleophilic addition of two open-chain molecules (2A). And then 3A dehydration through a four-centered transition state (TS2) with a moderately high free energy (49.7 kcal/mol) leads to the formation of 4A (- 14.2 kcal/mol). The free energy barrier is found to be very high, making it the rate-determining step in this reaction. Finally, the stable product DOF (5A) is generated with - 46.8 kcal/mol exothermicity via rearrangement from 4A. Overall, because of large activation barriers, thus, the mechanism involving ring opening of 1A (42.4 kcal/mol) and dehydration of intermediate 3A (49.7 kcal/mol) with such a sterically hindered four-centered transition states, as pictured in Scheme 1, is kinetically less favored and unlikely under moderate conditions.40

Scheme 1. Proposed Condensation Processes of GlcNH2 via Four-membered Transition States. Previously, theoretical study of glucopyranose interconversion assisting by a few water molecules were performed by Lewis et al.41 They concluded that the reaction barrier for the pyranose ring opening was strongly reduced by water assistance. Inspired by this, thus, in the second model, the ring opening process was promoted by inclusion of one explicit water molecule. The mechanism of the pyranoses (1B) to the aldehyde form (2B) occurs with a bridging water molecule between O5 and OH1, where the ring-opening reactions proceed through a six-membered transition state (TS3) (Scheme 2).42 In this model, one water molecule takes part in the proton transfer reaction, leaving its proton and receiving another from the GlcNH2 structure (1B, 11.5 kcal/mol endothermicity), followed by the formation of acyclic GlcNH2 (2B, 14


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15.5 kcal/mol endothermicity) The free energy barrier is 26.1 kcal/mol (Figure 6). Thus, the calculations indicate that the ring opening mechanism would be more likely in the presence of a water molecule.39 Subsequent dehydration of 3B results in the formation of 4B (- 13.0 kcal/mol) via a six-centered transition state (TS4), assisted by a water molecule with an activation free energy of 39.6 kcal/mol. Finally, DOF (5B) is generated with - 46.8 kcal/mol exothermicity via rearrangement of 4B. Although the dehydration process of 3B through TS4 is thermodynamically favorable than that of 3A through TS2, the activation free energy barrier is about 40 kcal/mol, making this reaction are energetically unfavorable and would be unlikely at moderate temperatures.12

Scheme 2. Proposed Condensation Processes of GlcNH2 via Six-membered Transition States. 3.5.2. Ring Opening and Dehydration Pathways in the Presence of B(OH)3. To elaborate the role of B(OH)3 in reaction selectivity, molecular modeling was investigated to determine the aggregation states along the reaction pathways.38 In neutral DMSO-d6 solution, trigonal borate B(OH)3 has a tendency to form a 1:1 cyclic ester complex with the diol moiety in GlcNH2 molecule, which has been confirmed by ESI-MS spectroscopy (charateristic peak at m/z 206). The formation of a sugar borate complex at C4/C6 carbon atoms of cyclic GlcNH2 is energetically slightly more favorable than at other carbon atoms, as shown in Figure S12.7 Our calculations suggest that the overall process ring-opening of 1C (3.0 kcal/mol) to 2C (6.5 kcal/mol) through TS5 is thermodynamically and kinetically more favorable than ring-opening of 1B (11.5 kcal/mol) to 2B (15.5 kcal/mol) through TS3 (Figure 6). The free energy 15



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barrier via TS5 is 25.4 kcal/mol. During the interaction, complexes with an acyclic structure may also be formed. This is consistent with the reported 13C NMR chemical shift values, induced on C3 (δ = 68.8 ppm, signal move to smaller ppm) and C5 (δ = 64.4 ppm, signal move to smaller ppm) to form sugar borate complex (Figure 4).16 We also computed the free energy of formation of B(OH)3 complex with acyclic GlcNH2 at C3/C5, and it was found to be energetically more favorable (- 2.8 kcal/mol).29 B(OH)3 tend to coordinate with the acyclic GlcNH2 at cis-diol OH3/OH5 positions (2C’) presumably due to its low steric strain. However, the calculated reaction free energy for the formation of acyclic GlcNH2 with boron coordinated to C4/C6 positions (2C) is endothermic by 6.5 kcal/mol. Evidently, the condensation step to a six-membered boron intermediate dihydrofructosazine is made impossible in complex 2C’ since the oxygen on C3 is bound to boron and consequently water cannot be eliminated.12 Thus, the more stable borate complex intermediate (3C) may be possibly formed by the intermolecular nucleophilic addition between complex 2C’ and the free GlcNH2 (2B) via dehydration (Scheme 3). Our calculation clearly discloses that the mono-coordinated

B(OH)3–sugar

interactions

could

markedly

stabilize

the

intermediate (3C, -34.4 kcal/mol exothermicity) and transition state (TS6, -2.9 kcal/mol). The calculated activation free energy for this process is approximately 31.5 kcal/mol, which are compatible with the observed catalytic performance of the B(OH)3 under mild conditions. Substantial reduction in this free energy barrier demonstrates that complexation indeed plays a key role in promoting the dehydration of dihydrofructosazine intermediate, favoring DOF production. Indeed, experimental results found that the yield of DOF selectively increased as the concentration of B(OH)3 increased, most likely as a consequence of stronger sugar–borate chelate complexes being formed. Thus, DFT calculations are consistent with experimental observations.

16


Page 17 of 25

Scheme 3. Proposed Condensation Processes of GlcNH2 in the Presence of B(OH)3.

60 TS1

TS1

TS2

40 TS3

Free Energy / kcal mol-1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


TS4

TS5

TS5

20 1C

0

1A 1A'

2B

1B 2C 1A 2A 1C

2A 2C

TS4 2C'

3B

TS6

3A

4B 4A

-20

-40

3C

TS5 TS3

4C

5B 5A

TS6

Figure 6. Free energy profiles for the selective conversion of GlcNH2 to DOF at 298.15 K.

3.6.

H2O2 Effect on FZ Formation. One may wonder whether FZ could be

selectively controlled. Thus, we further expanded our study to selectively control FZ formation.

Previously, an oxidative

(dehydrogenation) mechanism 17


from a


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six-membered heterocycle intermediate dihydrofructosazine leading to FZ under basic conditions was proposed.10, 12 Nevertheless, these methods cannot achieve a selective degradation. In order to further investigate the selective FZ formation from intermediate dihydrofructosazine via oxidation, the following experiments were conducted. Different volumes of H2O2 (30% water solution) as the oxidant agent were introduced into the reaction mixtures (the molar ratio of GlcNH2/[C2C1Im][OAc] = 1). With the H2O2 content increasing, as seen in Figure 7, the DOF yield decreased gradually, whereas the FZ yield increased initially. Adding 0.3 ml H2O2 reduces the DOF yield from 11.2% to 7.7%, and improves the FZ yield from 6.0% to a maximum yield of 25.3%. This result indicates that H2O2 act as oxidizing agents facilitating the dehydrogenation process while inhibiting the dehydration of GlcNH2 to DOF. When 0.5 ml of a H2O2 solution was added to the reaction mixture, only FZ was detected, which could be further confirmed by the clear characteristic low field signals (155.5 ppm and 141.9 ppm) in the 13C NMR (Figure S13). Though high content of H2O2 can dramatically reduce the formation of DOF, but it is unfavorable for high yield of FZ production presumably due to over-oxidation. Further increase in the content of H2O2 results in conversion of GlcNH2 to by-products, with formic acid as the main side-product confirmed by the signals at 168.4 ppm in the 13C NMR (Figure S13) and 8.3 ppm in the

1

H NMR (Figure S14).43 Purification of the products via

recrystallization afforded FZ, which were qualitatively identified by 1H NMR,

13

C

NMR, 1H-1H COSY, and 1H-13C HSQC spectra (Figure S15-S18). Further studies are needed to optimize the scale-up of this reaction. The results obtained from the experimental work disclosed that the reaction pathways for GlcNH2 condensation could be controlled by using simple, environmental friendly and cheap additives.

18


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Yield of DOF Yield of FZ

35 30 25

Percent (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


20 15 10 5 0 0

0.1

0.3

0.5

1

1.5

Volume of H2O2 (ml)

Figure 7. Effect of H2O2 amounts on product distributions catalyzed by [C2C1Im][OAc].

4. CONCLUSIONS Herein, the reaction pathways for DOF and FZ formation can be selectively controlled from a mechanistic aspect by taking advantage of additive effects. DOF was selectively achieved via dehydration process in the presence of B(OH)3, while FZ was the main product with H2O2 as oxidation agent facilitating dehydrogenation process. Under optimized conditions, the yield of DOF reaches 40.2% by using B(OH)3 as additive. For comparison, FZ was gradually becoming the main product (yield up to 25.3%) with H2O2 as oxidant. In addition, mechanistic investigation by NMR studies combined with results of ESI-MS spectroscopy disclosed the formation of boron complex exhibiting 1:1 stoichiometry. DFT studies were carried out to determine their reactivities in the catalytic reaction. It turns out that the B(OH)3-sugar interaction exerted significant influences on the stabilities of transition state and intermediates as well as the energy barriers associated with each elementary reaction step, and hence promotes DOF formation. In addition to looking at the reactivity of FZ formation, future studies will involve investigating the kinetics of this reaction.

19



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Acknowledgements The calculations were performed on LvLiang Cloud Computing Center. The authors would like to acknowledge the financial support from the Major State Basic Research Development Program of China (973 Program) (No. 2012CB215305) and Natural Science Foundation of China (No. 21106172, 21403273). Christian Marcus Pedersen acknowledges the CAS President’s International Fellowship Initiative (2015VMB052). Research Project was supported by Shanxi Scholarship Council of China.

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GRAPHIC ABSTRACT

25


NMR Investigation Substantiated by Density-Functional Calculations

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