Screwing NaBH4 through a Barrel without a Bang: A Kneaded

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Screwing NaBH4 through a barrel without a bang: a kneaded alternative to fed-batch carbonyl reductions. Valerio Isoni, Ken Mendoza, Eleen Lim, and Soo Khean Teoh Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 22 Jun 2017 Downloaded from http://pubs.acs.org on June 22, 2017

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Organic Process Research & Development

Screwing NaBH4 through a barrel without a bang: a kneaded alternative to fed-batch carbonyl reductions. Valerio Isoni*, Ken Mendoza, Eleen Lim, Soo Khean Teoh Institute of Chemical and Engineering Sciences, 1 Pesek Road, 627833, Jurong Island, Singapore

*Corresponding author: [email protected]

1 ACS Paragon Plus Environment


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Abstract In this work the application of green chemistry principles such as process intensification and the replacement of reagents and solvents to more benign alternatives were coupled with the advantages of continuous manufacturing. The reduction of lipophilic aromatic aldehydes using an aqueous alkaline solution of NaBH4 was achieved by means of mechanical shearing and kneading provided by a custom made batch reactor at lab-scale and twin screw extruder at kilo scale. The process was run continuously for 16 minutes to yield 1.41 kg of product (89% purity). The benefits of running the process in a continuous manner instead a conventional fed-batch mode were discussed in terms of both environmental and economic factors. Keywords: Process intensification, continuous, carbonyl reduction, green chemistry 2 ACS Paragon Plus Environment

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Introduction In the past decade we observed a steady increase of publications on flow/continuous chemistry, 1,2,3 special editions, seminars, conferences and associated dedicated journals. The advantages in terms of safety, throughput or energy demand for continuous process over the half a millennium old batch technology have been extensively reported, including the possibility of accessing exothermic 4 5 transformations without the need of cryogenic facilities. , However a sticky problem still persists: 6 handling of solids in a continuous manner. It is known, particularly for microreactors, that the presence of solids is a source of clogging of the microchannels. Research groups around the world managed to alleviate the problem for light precipitate by using ultrasounds in lab experiments to break the solids into smaller and more flowable particles;7 at larger scale several examples of slurries handled in a continuous manner have been reported for secondary manufacture applications such as crystallization and co-crystallization by using oscillating baffled reactors or twin screw systems.8 However challenges still exist for continuous handling of highly concentrated reactive slurries or dense phase reaction mixtures for primary manufacture, limiting de facto the potential of molecular solid-state chemistry for continuous processing. Efforts in mechanochemistry and liquid assisted grinding (LAG) synthesis have been growing steadily in the last 15 years, with numerous publications of synthesis of both organic and inorganic substrates suitable for pharmaceutical process, at lab scale.9,10,11,12,13,14,15,16,17 Despite the promise of higher throughput and intrinsically safer processes, a 18 shortage of publications reporting examples demonstrated at least at pilot scale is evident. A common problem of scaling up ball milling, by far the most common way of achieving both mechanochemical and solid state chemistry transformations for synthetic purposes, is the heat generated during the milling and its efficient removal to avoid side reactions. However, ball milling is not the only viable option. Another possibility is to adapt the technologies from other fields or disciplines to fine chemical processing, for example polymerization of high-viscosity polymers and devolatilization, reactive polymer blending and chemical modification of polymers food processing,19,20 biomass treatment,21,22 mineral chemistry (alumina-based catalysts), reactive extrusion,23,24,25 acid 26,27,28 productions and esterification, by using twin screw extrusion (TSE) technology. With the intent of taking advantage of both the benefits of dense phase chemistry and continuous processing to achieve goals that align safety, low waste generation and better energy efficiency towards good processes, we embarked on a challenge for the continuous reduction of benzaldehydes at kilogram scale via continuous treatment with NaBH4 using a commercially available equipment which served as an unconventional reactor: a continuous granulator (ConsiGma-25™). Continuous reduction using NaBH4 is not unprecedented in the literature; an elegant example has been reported in the literature using HPLC pumps and columns packed with Celite, NaBH4 and LiCl for both carbonyl reductions and 29 reductive amination. However, we felt that the need of organic solvents to solubilize the substrates and the use of a packed column that have to be regenerated after a period of time might not be the greenest option available for such transformations. Based on our previous experience both in solvent selection and batch-to-continuous methodologies, we focused on investigating an alternative access 30,31 to fed-batch carbonyl reduction via continuous aqueous reactive extrusion.

Results and discussion NaBH4 is a convenient reducing agent that finds application in all sorts of laboratories, from 32 educational to high-end research. However, it might come as a surprise that reduction of aldehydes is not very commonly reported in process literature. This could be explained by the fact that process chemists, despite the versatility of carbonyl group for functional group interconversion, tend to avoid 33 aldehydes as intermediates for API synthesis since they are prone to oxidation. However, if the aldehydes could be reacted as soon as they are formed or at least quickly enough to avoid storing them for long periods of time, we could take advantage of the flexibility of the carbonyl groups to access synthetic routes previously thought to be too risky at scale. One way to achieve this situation is by continuous processing. Our idea was to perform such organic chemical reactions throughout mechanical mixing of the reagents in solid and/or liquid form, taking



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advantage of twin screw technology (i.e. granulator, melt extruder, etc.) to yield the desired product in a continuous manner. An example we decided to investigate is the exothermic reduction of poorly water-soluble aromatic aldehydes with NaBH4, both under solventless and LAG conditions (using water as the solvent). Aromatic aldehydes were chosen as substrates due to their negligible water solubility resulting in problematic behavior in batch when aqueous systems were used as solvent medium (the substrates “float”, causing mass transfer limitations). In industry, such a chemical transformation is typically performed using a water-miscible solvent such as tetrahydrofuran (THF); an alkaline solution of NaBH4 is added to in a fed-batch fashion avoid thermal runaway due to exothermic nature of the reduction. Carbonyl reduction: the journey from batch to continuous Initial screening and development work was conducted in batch mode. This approach is not uncommon, in particular when a smaller version of the equipment intended for the scale up (e.g. twin screw extruder) in not readily available at lab scale. For this, gram-scale experiments were carried out in a custom-made high-shear batch reactor using a modified food blender (power 550W, 14000 RPM) leaving a 5 mm gap between the tip of the blade and the beaker’s wall (Figure 1). The reaction beaker was itself positioned inside a bigger beaker containing a known amount of water (jacket) and two thermocouples to monitor the inner temperature change.

Figure 1. Left. Modified household food blender used for grams-scale solid state chemistry investigations with two thermocouples used to monitor the jacket’s temperature. Right. Close-up of the impeller/blade used for the laboratory scale experiments. The original “blending foot” that protected the blade was removed with the aid of a hacksaw. A series of reaction conditions were examined: initial screenings were performed using the reagents in solid state to assess the feasibility of the chemical transformation. Reduction of aromatic aldehydes in solid state was attempted using 0.26-1.1 equivalents of NaBH4 for 20 sec. The rationale for such a short reaction time was to mimic the requirements for the continuous granulator run (residence time of circa 16 sec. using the slowest rotational speed available). For each benzaldehyde, we observed partial conversion into the desired product before the addition of aqueous reagents for the work-up (water or NaOH 1M). During work up, frothing of the reaction mixture was observed and upon isolation of the crude product, 1H NMR analysis showed complete or near complete conversion into the desired product (benzyl alcohols). Following this behavior, the authors investigated the use of aqueous alkaline NaBH4 solution instead of solid NaBH4 under shearing conditions for the reduction of the solid benzaldehydes reported in Table 1. Under these reaction conditions the target products were obtained swiftly and in high yield (90-98%). For comparative purposes, a set of experiments were also conducted using “green” solvents which would not react with NaBH4, namely 2-MeTHF and CPME.34,35 Despite the high concentration of solute in those solvents (8.4M in CPME, 10.0M in 2MeTHF), the reduction went off sluggishly in both ethereal solvents without reaching completion within 5 hours, perhaps due to mass transfer limitation of the NaBH4 granules under magnetic stirring. A


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similar effect was noticed when the reaction was performed under solventless conditions at 55 °C, 36 beyond the 4-chlorobenzaldehyde’s melting point (47-49°C, lit. ). As shown in Figure 2, the NaBH4 granules did not react with the aldehyde under magnetic stirring for 15 minutes. However, when a drop of water or NaOH solution was added, a vigorous effervescence was observed together with an adiabatic temperature rise (∆T≈ 60 °C) and product formation, supporting the idea of mass transfer limitation in the absence of either thorough mixing or an aqueous medium. In view of these observations, we decided to focus on deploying stabilized aqueous NaBH4 solution in as a means to reduce solid aromatic aldehydes under shearing conditions. Alkaline aqueous solutions of NaBH4 have been used for different applications due to their relative long shelf life.37

(B)

(A)

Figure 2. (A) Molten 4-chlorobenzaldehyde and suspended NaBH4 granules at 55°C after 15 min. (B) Reaction mixture upon addition of 2 drops of 1M NaOH. In this control experiment, magnetic stirring was used in place of mechanical stirring to show that no reaction takes place between the aldehyde and NaBH4 even if the aldehyde is in the liquid state (A). However, addition of 2 drops of aqueous NaOH was sufficient to facilitate mass transfer and immediate reduction of the aldehyde (B). Aldehyde

NaBH4 eq.

Mixing type

1.00

Solvent -

Temp (°C) 23

Time 20 sec

Conversion % 30 (90)**

-

23

20 sec

24 (82)**

Aq. NaOH (1.0 M)

23

Screwing NaBH4 through a Barrel without a Bang: A Kneaded

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