Process Intensification of Continuous Flow Synthesis of Tryptophol

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Process Intensification of Continuous Flow Synthesis of Tryptophol Yogeshwar Ramdas Dubhashe, Vishal Manohar Sawant, and Vilas Gajanan Gaikar Ind. Eng. Chem. Res., Just Accepted Manuscript • DOI: 10.1021/acs.iecr.7b04483 • Publication Date (Web): 09 Feb 2018 Downloaded from http://pubs.acs.org on February 10, 2018

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Industrial & Engineering Chemistry Research

Process Intensification of Continuous Flow Synthesis of Tryptophol

Yogeshwar R. Dubhashe, Vishal M. Sawant and Vilas G. Gaikar* Department of Chemical Engineering Institute of Chemical Technology Matunga, Mumbai – 400 019, India

*Author to whom correspondence is to be addressed Email: [email protected] Phone:91-022-33612013

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Abstract: A continuous flow synthesis of tryptophol is developed in a tubular reactor at different temperatures and flow rates, by Fischer indole synthesis route using phenyl hydrazine hydrochloride (PHH) and 2, 3-dihydrofuran (DHF) as starting materials. The maximum conversion of PHH was 93% and the yield of tryptophol was 72% in 6 min. A kinetic model is proposed for the process by taking into account the formation of intermediate species. The reactor was simulated in COMSOL platform for temperature profiles in the reactor, which were subsequently used to estimate the kinetic parameters of the reaction. The reaction was further intensified by executing the reaction in a continuous microwave reactor (CMWR), at different flow rates and at different power. The maximum conversion of PHH was obtained to be 91% and the yield of tryptophol was 95% in 5 min using CMWR. Keywords: Tryptophol, Continuous process, microwave, process intensification, COMSOL, Kinetics.


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1. INTRODUCTION: Tryptophol belongs to the family of indoles, bearing C-3 hydroxyl ethyl side chain. The indole moiety, as a structural component, occurs in a wide variety of biologically active compounds.1–3 Tryptophol is a key intermediate for synthesis of indoramine, an anti-adrenergic agent.4 The Fischer indole reaction is the most commonly adopted method for tryptophol synthesis. It is a two-step reaction of hydrazone formation followed by its [3+3] sigma tropic rearrangement under acidic conditions.5 The other reported methods give poorer yields with much longer reaction times. For example, reduction of ethyl 3-indolyl acetate by using lithium aluminium hydride (LiAlH4) gave poor yields of tryptophol, while the synthesis from indolyl acetic acid and ethyl 3-indolyl glyoxylate requires reaction time of 12-14 h at 250°C.6 Tryptophol can also be prepared in quantitative yields by reduction of methyl o-amino cinnamate; an adduct derived from iodoaniline and methyl acrylate.7 Borane tetrahydrofuran complex was used as a reducing agent for the reduction reaction reported by Pinto et al8 to obtain tryptophol. Reduction of methyl ester of indole acetic acid with zinc9 and sodium10 also have been reported with 72 and 81% yields of tryptophol. Several heterogeneous catalysts have been reported with the distinct advantage of easy reaction work up, isolation of product and lower waste generation. For example, palladium catalysts (Pd/C, Pd/NaY) in dimethylformamide (DMF) as solvent, gave 98% yield of tryptophol, at 393K, starting with 2-iodoaniline and triethyl [4-(triethylsilyl) but-3ynyloxy] silane.11 One pot synthesis of tryptophol using MCM-41 silica as the catalyst gave 45 to 50% yields of tryptophol in 4h.12 The Fischer indole synthesis of tryptophol in quantitative yields was reported by Campos et. al.13 using 4% H2SO4 as a catalyst in 50% aq. N, N-dimethyl acetamide (DMA) solutions. Apparently, DMA made the reaction mixture homogeneous that led to increased yields of



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tryptophol. An environmentally friendly method has been reported for synthesis of tryptophol using phenyl hydrazine hydrochloride (PHH) and 2, 3-dihydrofuran (DHF) in the presence of montmorillonite K-10 as catalyst at 80°C in 3h with 88% yield of tryptophol.14 The Fischer indole synthesis was also reported in a low melting mixture of tartaric acid-dimethyl urea where the melt acts as a catalyst and also a medium for the reaction,15 while reaction in Bronsted acidic ionic liquid resulted in 85-97% yields of indoles at 383K in 3h.16 Recently, the introduction of continuous flow reactors in synthesis of fine and specialty chemicals has become popular because of their many advantages such as higher heat and mass transfer rates, easier scale-up, reproducibility, precise control over the reaction parameters and in most cases higher efficiency and productivity.17–21 Process intensification using microwave is widely employed in academia and to some extent at industrial scale for reduction in reaction time and improvements in product yield in many cases.22 The earliest examples of continuous flow synthesis of a similar compound, 7-ethyl tryptophol, were reported by Su et al23 and Bernhard et al24 who demonstrated that the transformation of batch to continuous operation led to increased yield of the product. In this paper, we report process intensification of tryptophol synthesis in microwave assisted continuous tubular reactor, minimizing the side product formation by appropriately identifying controlling factors that decide the selectivity. The experimental data were obtained initially by conducting the reaction in a coiled tubular reactor at different temperatures, and flow rates employing conventional method of oil bath heating. The coiled tubular reactor was simulated in the COMSOL platform to develop better understanding of the process. Also, the kinetic analysis of reaction was performed for identifying the temperature dependence of the competing reactions. 4 ACS Paragon Plus Environment

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2. MATERIALS AND METHODS 2.1 Materials and Experimental set up Phenyl hydrazine hydrochloride (99.0%) and conc. HCl (35-38%) were obtained from S. D. Fine-chem Limited, Mumbai. Tryptophol and 2, 3- dihydrofuran (98.0%) were procured from Alfa Aesar, Mumbai. Glycerol (99.9%) was purchased from Thomas Baker Ltd. All other chemicals were purchased from commercial sources and were used without further purification. i) Synthesis of Tryptophol in a coiled tubular reactor A coiled tubular reactor (4 mm i.d., 6 mm o.d., 3.66 m length, 26 turns of SS 304 coil), with the provision of external heating arrangement, was fabricated in-house (Scheme 1). In a typical run, PHH solution (10 g/dm3) was prepared in aq. glycerol solution (70% v/v). 2, 3-DHF (4.9 g) was dissolved in 900 cm3 of aq. glycerol solution (70% v/v) and stirred with 100 cm3 of aq. 0.21M HCl solution for 30 min at 303K. Both the solutions were continuously pumped separately into the tubular reactor using a peristaltic pump (Ravel peristaltic pump RH-P100S) at predetermined flow rates. The mixture flowed through the tubular coil reactor with the temperature indicated by an indicator at the exit of the tube. This exit temperature was maintained by temperature controller of the heating arrangement. The reaction mixture, at the exit, was cooled to 298K in a double pipe heat exchanger (SS 304, 4 mm i.d., 6 mm o.d., 300 mm length). The reaction stream was finally analysed by reverse phase HPLC method. The experiments were conducted at different flow rates and temperatures.



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Scheme 1: The flow reactor experimental set up.

See Figure S1 in supporting information for Photograph of reactor set up.

ii) Synthesis of Tryptophol in a continuous microwave tubular reactor A continuous microwave reactor (Scheme 2) was designed and fabricated in our laboratory. The system consisted of a quartz reactor tube (16 mm internal diameter and 20 mm outer diameter, 700 mm length) kept eccentrically in the microwave cavity (88 mm internal diameter and 94 mm outer diameter) so that, maximum electric field power can be utilized. The microwave cavity was provided with three equally spaced ports of equal size (Port size 72 mm X 34 mm) of the waveguide. The waveguide was connected to a magnetron launcher (LG magnetron, model 2M214). The PHH solution (10 g/dm3) was prepared in aq. 70% glycerol solution. 2, 3-DHF (4.9 g) was dissolved in 900 cm3 of aq. glycerol solution (70% v/v) and stirred with 100 cm3 of aq. 0.21M HCl solution for 30 min at 303K. Both the solutions were continuously pumped separately into the microwave reactor using a peristaltic pump (Ravel peristaltic pump RH-P100 S) at predetermined flow rates. The mixture flowed through the quartz tube irradiated


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continuously at a power of 900W. The reaction mixture, at the exit, was cooled to 298K in a heat exchanger (Coiled tube, SS 304, 4 mm i.d., 3 m length,). The product mixture stream was finally analyzed by reverse phase HPLC method. The experiments were conducted at different input microwave power and at various predetermined flow rates. After, completion of the reaction run, the entire reaction mass (200 cm3) was collected and subjected to the solvent extraction process. The extraction was performed three times with ethyl acetate (200 cm3 x 3). The organic phase obtained was washed with saturated aqueous sodium bisulphite solution to remove unreacted DHF, if any. The organic phase was distilled to recover solvent as a distillate and Tryptophol as product residue Scheme 2: Continuous microwave tubular reactor set up:

See Figure S2 in supporting information for Photograph of reactor set up.

iii) HPLC method of Analysis The samples of reaction mixture were analyzed by Jasco PU 2080-Plus liquid chromatograph, with Jasco MD 2010-Plus PDA detector, using a reverse phase RP-C18 column



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(250 mm x 4.6 mm). Water: Acetonitrile (50:50 v/v) mixture was used as a mobile phase and the elution was carried out at a flow rate of 0.4 cm3/min. iv) Simulation of the coiled tubular reactor for velocity and temperature profiles: The coil reactor was simulated using physics model of COMSOL (ver. 5.1). The Flow (SPF) model in combination with heat transfer in fluids was used to determine the velocity profile and temperature profile of the reaction mixture along with the length of the reactor. The time-dependent mode was used to solve partial differential equations in the time domain. The coiled tubular reactor consisted of two parts, a) coil and b) 'T' junction for mixing of the two reactant solutions. Physics Controlled Meshing (Normal) was used for the simulation [Figure S3 (a) and (b) in supporting information]. The mesh size was selected keeping in mind reduction of computational burden while preserving the main objective of the work of obtaining the temperature profile along the length of the reactor. 3. RESULTS AND DISCUSSION 3.1 Synthesis of Tryptophol in coil tubular reactor using conventional method of heating 3.1.1 Effect of reaction temperature and residence time The reaction of 2, 3-DHF (I) with PHH (III) gives hydrazone as an intermediate. The 2, 3-DHF ring opens first in the presence of H+ ions to form 4-hydroxylbutanal (II), which condenses with PHH to give hydrazone (IV) with the elimination of a water molecule. The hydrazone, so formed, rapidly undergoes [3+3] sigma tropic rearrangement reaction to give tryptophol (V) as the final product (Scheme 3).


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Scheme 3: Reaction Scheme for formation of tryptophol including other side products

The conversion of PHH increased with increasing temperature and residence time, as shown in Figure 1. This resulted in formation of hydrazone and the products such as tryptophol (V), cinnoline derivative (VI) and polyindole (VII) (Scheme 3). The conversion of PHH was 53% in 345s of residence time, at 353K, which increased to 72 % as the temperature was raised to 373K in the same reaction time [Figure 1 (a)]. The corresponding yield of tryptophol also increased from 28% to 66% [Figure 1 (b)]. The increased yield of tryptophol is due to enhanced rearrangement reaction of hydrazone. This indicates that cyclization of hydrazone to tryptophol is slower at lower temperatures and requires higher temperatures to speed up the rearrangement



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step indicating higher activation energy of the latter reaction. When the reaction temperature was increased further to 428K, the conversion of PHH increased to 93% and the yield of tryptophol increased to 72%.

(a)

(b)

Figure 1: Effect of residence time on tryptophol synthesis at various reactor temperatures. At higher temperatures, two side products, a cinnoline derivative and polyindole, were also obtained in the process. The cinnoline derivative was a product of another cyclization reaction of hydrazone while polyindole was a dimer formed by a consecutive reaction between tryptophol and one more molecule of 2, 3-DHF. The tryptophol synthesis is thus, a complex set of series and parallel reactions. A preferable way to intensify such a multistep reaction network is to optimize process parameters to inhibit side products formation, particularly using the temperature dependency of each step of the reaction network. The reactions were conducted at two more temperatures, 413 and 423K, in order to obtain the kinetic parameters of all the identified reactions.


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3.2 Simulation of temperature profile in coil reactor with conventional heating The temperature distribution and velocity profile of fluid along the length of the tubular reactor were derived for different flow rates and temperatures. It was observed that, for 8 cm3/min flow rate, the velocity distribution is less distorted in a radial direction along the length of the tubular reactor which results into negligible distortion in the radial temperature distribution. The low temperature of the feed at the entrance of the coil, which gradually increases from feed temperature of 303K to the desired exit temperature as it passes through the reactor and attains the set reactor wall temperature after a certain length of the reactor. The velocity profile and temperature profile for 8 cm3/min are given as figure S4 (a) and (b) respectively in supporting information. Also, similar temperature profiles were observed for higher flow rates and temperatures. Figure 2, shows typical temperature profiles of the reaction mixture as a function of reaction mixture flow rate and along the length of reactor (temperature: 353K, flow rates: 8 to 16 cm3/min). The set temperature is attained by the reaction mixture within 500 mm length of the tubular reactor (Figure 2). Also, shift in region of temperature profile as a function of feed flow rate (from 8 to 16 cm3/min) can be seen in Figure 2. These temperature profiles become useful in analyzing the kinetics of the reaction as described later. Once the temperature is reached to its set value, it remains constant throughout the rest of the reactor


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(a)

(b)

Figure 2: Simulated temperature profiles along the length of the coiled reactor at different flow rates for the set reactor temperature of 353K [(a): Temperature profile till change in temperature observed along the length of reactor, (b): Temperature profile along the entire length of reactor] [See Figure S5 for temperature profiles at (a) 363K, (b) 373K, (c) 413K, (d) 423K and (e) 428K)]

3.3 KINETIC ANALYSIS 3.3.1 Synthesis of Tryptophol in coil tubular reactor The experimental data obtained from the coil tubular reactor and the temperature profiles obtained from COMSOL simulation were considered to develop a homogeneous kinetic model for the reaction network. The reaction kinetic model is a set of differential equations consisting of a mass balance equations25 for each species and an energy balance equation25 along the length



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of the tubular reactor. At steady state conditions, the continuity and energy equations reduce to a set of ordinary differential equations. To obtain the kinetic parameters for the reaction network of the synthesis of tryptophol, a non-isothermal homogeneous plug-flow model25 was considered for the reactor. The reactor was modeled as a tubular reactor with a constant cross-sectional area (Ac) and a constant wall temperature. The steady-state model equation25 for each species is given by

= ∑

..… (1)

Where, Fj is the molar flux of component j (j = 1−6); ∑ is the corresponding net rate of utilization of species j, summed over all reactions i; and V is the volume of the tubular reactor. The total molar flux (Ft) is the sum of all molar fluxes in the reactor at any point, which, in turn, determines the volumetric flow rate and velocity of reaction stream at any point in reactor ∑ () = ()

….. (2)

The concentration of each component j can thus be expressed as =

….. (3)

An energy balance on the tubular reactor leads to the equation25

=

( ) !("#$ ) %

(

….. (4)

&'

Where,‘Ua’ is the overall heat-transfer coefficient,‘Ta’ is the temperature, outside the reactor wall, ‘HRX’ is the heat of reaction for the ith reaction and ‘a’ is the heat-transfer area per unit volume. The overall heat-transfer coefficient26, Ua, was obtained from individual heat-transfer coefficients and resistance of tube wall


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)* =

, , , 5 234 6789 8:6 + -./0 1 5 , 6 , 6 +6

….. (5)

The outside convective heat-transfer coefficient (ho) was large with respect to the inside heattransfer coefficient (hi). Therefore, the last term in the denominator was neglected. ‘hi’ was calculated in terms of the Nusselt number and thermal conductivity of the reaction mixture as applicable under the given hydrodynamic conditions27. ;

Process Intensification of Continuous Flow Synthesis of Tryptophol

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