Participation of the Cyanide Group in the Reaction Mechanism of Benzoxazole Formation: Monitoring by Continuous Flow Cell NMR ^†

Abstract

Benzoxazoles are recognized as significant building blocks in organic synthesis and materials science. This work observed the formation of benzoxazole from o-aminophenol and o-hydroxybenzaldehyde using online ¹H NMR (continuous flow cell, 80 MHz). The identification of changes in the functional group was complemented by ATR-FTIR analysis. Additionally, the kinetic roles of phenylboronic acid and cyanide in the one-pot condensation-cyclization reaction are examined. Real-time monitoring has revealed three observable events: the rapid condensation of the aldehyde and o-aminophenol to produce the imine; the formation of the boron complex in the presence of phenylboronic acid; and the cyanide-assisted cyclization that converts the intermediate into benzoxazole. The findings clarify the transformations that control throughput and provide valuable insights for optimizing reagent loadings under environmentally friendly conditions.

1. Introduction

In catalyzed reactions, catalysts accelerate a desired transformation by lowering the activation barrier and biasing pathway selection among competing channels. Promoters are distinct from catalysts in that they typically exhibit negligible turnover in isolation but enhance the performance of a catalyst, for example, by tuning the electronic environment, adsorption thermodynamics, or transport to the active site; the effect can manifest as higher activity, altered selectivity, or improved catalyst stability [1]. When catalysts and promoters are used together, synergistic effects often occur. This means that there can be changes in the rate constants of elementary steps, the thermodynamic equilibria of intermediates, or the kinetic partitioning between different mechanistic pathways. Therefore, understanding the mechanisms of reactions requires careful analysis to find which steps are controlled by kinetics, which are influenced by thermodynamics (pre-equilibrium), and where phenomena such as saturation or inhibition might arise [2].

Otherwise, benzoxazoles are versatile heteroaromatic compounds in medicinal and materials chemistry [3,4,5,6,7,8,9]. Various protocols involve the condensation of aldehydes with o-aminophenols followed by oxidative cyclization and dehydration under mild conditions, including metal-free, metal-catalyzed, and promoter-assisted variations [10,11,12,13,14,15,16,17,18,19].

Despite the rich method literature, the relative kinetic roles of (i) imine formation (condensation), (ii) boron complexation (such as phenylboronic acid as promoter, and considering published evidence on the boron complex formed between phenylboronic acid and the imine) [16,17,18], and (iii) cyanide-enabled aerobic cyclization have not been consistently analyzed under either batch or flow conditions [20,21]. In this study, we utilize benchtop 1H NMR [22,23,24,25,26], with an online flow cell [27,28,29], supplemented by ATR-FTIR, to: (i) determine the kinetic order of the condensation step (imine formation), (ii) investigate whether boron complexation influences the reaction rate (for example, by altering equilibrium or stabilizing the transition state), and (iii) assess how the cyclization step (forming benzoxazole) depends on the concentration of cyanide.

2. Materials and Methods

Reagents. Salicylaldehyde (1), 2-aminophenol (2), phenylboronic acid (PBA), and KCN were used as received (≥99%). Deuterated NMR solvents: MeOD, CDCl₃, DMSO-d₆; TMS as internal standard. Reagents and solvents were obtained from Sigma Aldrich (St. Louis, MO, USA).

All reactions were carried out under ambient temperature (≈25 °C) and pressure in a 10.0 mL total volume with the following stoichiometry: 1.0 equiv of 1 and 2; PBA at 0.1, 0.5, or 1.0 mol %; KCN at 0.5, 1.0, or 1.5 equiv. PBA was dissolved in minimal MeOH and KCN in minimal H₂O, and then the two solutions were combined. The PBA content and water activity are mechanistically relevant because boronic acids form boroxines and boronate esters in dynamic equilibria that influence dehydration.

A benchtop NMR (Magritek, Spinsolve 80 MHz, Aachen, Germany) with a continuous flow cell acquired ¹H NMR spectra every 5 min without interrupting flow. ATR FTIR (PerkinElmer, Spectrum 100, Shelton, CT, USA) tracked C=O, C=N, and O–H bands to support assignments. Typical ¹H NMR handles: aldehydic CHO (~10 ppm), imine CH (~9 ppm), and diagnostic aromatic resonances of benzoxazole 4 (~8 ppm). Evidence indicates the formation of boron-complex A from imine 3 and the subsequent formation of benzoxazole 4 (Figure 1) [16].

Rate orders were obtained by initial rate analysis from early, linear regime data while varying the initial concentration of a single component at constant others, and integrated rate fitting to appropriate forms. The influence of PBA was tested by varying its loading at fixed substrate concentrations. Cyanide dependence was examined by varying KCN while holding other parameters constant. All measurements were performed in replicate; fits were evaluated by residual inspection and goodness of fit metrics.

3. Results and Discussion

The initial-rate analysis and integrated fits indicate that the condensation step follows a second-order rate law, being first-order in both aldehyde and aminophenol. In contrast, the rate of boron complex formation appears to be independent of the concentration of PBA within the ranges examined. Lastly, the step involving cyanide addition shows zero-order behavior with respect to benzoxazole, suggesting that the cyanide concentration does not influence the rate-limiting step under these conditions. This could indicate that a cyanide-dependent pre-equilibrium is saturated. Figure 2 illustrates the kinetic behavior of the reaction conducted in a continuous flow cell with online NMR in methanol (MeOH). In part (a), the red line represents the rate of aldehydic proton consumption, while the yellow line indicates the rate of imine formation. In part (b), the red line shows the rate of imine consumption, and the yellow line represents the rate of benzoxazole formation. Appendix A displays the stacked ¹H NMR spectra from the continuous flow cell follow-up of the imine formation initial reaction (Figure A1), as well as the spectrum of the isolated imine in CDCl3 (Figure A2), and the FTIR-ATR spectra of raw materials 1 and 2, as well as the imine intermediary 3 (Figure A3).

The rapid second-order reaction in the condensation step follows a classic mechanism. This involves a nucleophilic attack of aminophenol 2 on the aldehyde carbonyl 1, leading to the formation of a hemiaminal, which is then dehydrated. Afterward, the data indicate that the yield is controlled during the intermediate phase by boron complex A formation. In the final phase, while cyanide promotes oxidative cyclization, the formation of benzoxazole 4 occurs in a zero-order reaction. This means that the concentration of benzoxazole remains constant over time and is independent of the amount of cyanide used (0.5, 1.0, and 1.5 equivalents).

Together, these data indicate that throughput is controlled upstream by the bimolecular condensation, not by downstream borate or cyanide events. The second-order dependence in the condensation step aligns with a classical pathway (nucleophilic attack of the aminophenol on the aldehyde to give a hemiaminal, followed by dehydration). The borate complex is readily detected but kinetically innocent under our conditions, consistent with an off-cycle or fast equilibrium role that does not limit flux to product. Finally, zero-order behavior in CN⁻ rules out CN participation in the rate-determining transition state (within the tested domain), or indicates that CN-dependent activation is saturated, making subsequent, CN-independent chemistry rate-limiting. The proposal mechanistic pathway (Figure 3) begins with condensation (imine formation) to give intermediate 3, followed by reversible complexation with PBA to yield boron-complex A, and finally cyanide-promoted oxidative cyclization to benzoxazole 4.

Practical implications: to accelerate the process, increasing either aldehyde or aminophenol concentration is effective (bimolecular control), whereas increasing boron or cyanide is not; catalyst choice may be guided toward promoters that accelerate condensation, rather than downstream cyclization. The kinetic neutrality of boron and cyanide under these conditions suggests scope to lower their loadings without throughput penalties, improving process mass intensity.