Automated On-Demand Titration of Organometallic Reagents in

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Automated On-Demand Titration of Organometallic Reagents in Continuous Flow Aaron A. Bedermann,† T. Andrew McTeague,† and Timothy F. Jamison* Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States

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S Supporting Information *

that are very difficult to observe with the human eye can be readily monitored by the absorbance. Third, the ability to fully automate the titration stands to produce a much safer and reproducible process.15

ABSTRACT: The use of strong organometallic bases and nucleophiles is commonplace in modern organic synthesis. That they react with a wide range of functional groups requires accurate and precise stoichiometry in reactions that utilize them. For best results, these bases are titrated prior to use, and such titrations can be timeconsuming and variable due to human error near the end point. Herein, we describe an automated method for titrations of multiple commercial organometallic reagents enabled by continuous flow. Through utilizations of continuous monitoring via UV−vis spectroscopy and a feedback loop developed within LabVIEW, titrations with enhanced reproducibility were provided over current batch procedures. KEYWORDS: automated, organometallic, titration, continuous flow

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SYSTEM DESIGN The continuous flow titration system was designed as shown in Figure 1. Solutions of titrant and organometallic reagents were

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INTRODUCTION Organometallics1 such as organoalkali,2 organozinc, and organomagnesium reagents3 are commonly used as bases, nucleophiles, chelating reagents, or for the generation of reactive intermediates via deprotonation, metal−halogen exchange, or transmetalation. Given the high reactivity of these exceptionally versatile reagents and their instability toward oxygen and water,4,5 it is critical that an accurate measurement of their concentration, via a titration, be obtained prior to use. This is particularly important for reactions in which precise equivalents of the organometallic reagent are necessary, e.g. thermodynamic enolate generation,6 side product suppression,7 or selective functionalization.8 While routine, performing titrations9 is time-consuming and exposes the user to hazardous, sometimes pyrophoric, reagents. Furthermore, the accuracy of the obtained value is subject to environmental and user-related error. For example, most titration methods rely upon the formation and visualization of a colored intermediate at the equivalence point, which can be difficult to distinguish. With these considerations in mind, we looked to improve the precision, efficiency, and safety of titrations through the development of a continuous flow platform. A flow system offers several benefits for performing titrations. First, it enables exquisite control over the mixing profile and reaction temperature owing to the short path length and increased interfacial area offered within a small diameter reactor.10−13 Second, the titration process can be monitored using in-line UV−visible spectroscopy.14 Small color changes © XXXX American Chemical Society

Figure 1. (a) General schematic for flow titrations. BRP = back pressure regulator. (b) Photograph of the automated titration system.

introduced into the system using Harvard syringe pumps (PhD Ultra series, Pump 1, Pump 2) and combined using a threeway Y-mixer (M1) prior to entering the reactor coil (R1). The components were then allowed to mix within the tubing at room temperature for the allotted time and subsequently passed through the modified in-line Avantes UV/vis flow cell. Back pressure (either 20 or 40 psi) was applied to the system to ensure consistent flow rates and, upon exit, the reaction solution was quenched in a dry ice/isopropanol bath. Received: December 10, 2018

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DOI: 10.1021/acs.oprd.8b00434 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Communication

With the exception of potentiometric titrations, most of the methods and reagents developed for titrations rely upon the formation of a colored intermediate at the equivalence point. Traditionally, this end point is visually observed. Depending on the concentration and coloration of the organometallic reagent and indicator utilized, however, the end point may be difficult to distinguish. In contrast to the human eye, UV/vis adsorption spectroscopy can easily discern subtle changes in color based on small shifts in the spectra. For the development of a continuous flow titration platform, we first validated this principle using an Avantes UV/vis flow cell. A range of readily available indicators, N-pivaloyl toluidine (1),9l 2-hydroxybenzaldehyde phenylhydrazone (2),9o and 4-phenylbenzylidene benzylamine (3)9f were chosen as model substrates to enable the titration of a variety of organolithium, Grignard reagents, and bis(trimethylsilyl)amine (HMDS) salts. A solution of each was prepared in THF and then titrated, and the UV/vis profiles for each were recorded (Figure 2). In all cases, the adsorption shift in the UV/vis profile, upon formation of the highly colored anion, is easily observed. This is even true for the more difficult to observe end point of 2-hydroxybenzaldehyde phenylhydrazone (2) which exhibits a subtle transition from yellow to orange between the corresponding mono- and dianionic forms, respectively. It is worth noting that the obtained data are past the saturation point for the UV/vis detector (absorbance > 1), thereby prohibiting quantitative analysis. However, due to the titration method chosen, the binary answer of whether the anion of the indicator is present is sufficient for a qualitative analysis. For system optimization, the titration of n-butyllithium using N-pivaloyl-o-toluidine (1) as the indicator was utilized. To ensure accurate and precise titrations, the residence time was first optimized to ensure the organometallic reagent and titrant solutions were fully mixed prior to UV/vis analysis. Interestingly, the reaction solution is immediately colored upon exiting the Y-mixer due to rapid dianion formation of 1. The anion then deprotonates the remaining unreacted 1 as it passes through the reactor coil, and the color dissipates prior to the equivalency point. A similar phenomena is prominent during batch titrations just before reaching the end point. Through extensive optimization, it was found that a residence time of 2.5 min was sufficient to ensure consistency in the obtained UV/vis readings, compared to the corresponding batch titrations, and as such, this residence time was used as a conservative estimate for all further studies. In an effort to reduce the minimum residence time of the system, the use of enhanced mixing techniques was also investigated (stainless steel frits, helical static mixers, packed beds, and continuously stirred tank reactor or CSTR), but no benefit above a standard tube reactor was observed. With the optimal results obtained using standard 1/16th inch diameter PFA tubing, the system does not require the use of expensive static mixers or laborious packed beds and can be easily assembled from standard commercially available flow parts.16 We next turned our attention to the development of an appropriate algorithm to efficiently and accurately assess the concentration of an unknown solution. As demonstrated previously,17 LabVIEW, a development environment for graphical programming commonly used for data acquisition and instrument control, is a particularly powerful tool to achieve this, allowing for an optimization algorithm to be easily programmed and interfaced with reaction pumps. In the continuous flow titration system, the flow rate of indicator, and

Figure 2. UV/vis profile of selected indicators. For all titrants, the gray line is 1 equiv n-BuLi. (a) Npivaloyl toluidine (1). (b) 2-Hydroxybenzaldehyde phenylhydrazone (2). (c) 4-Phenylbenzylidene benzylamine (3).

therefore the number of mmol of indicator within the reactor, is kept constant, similar to the batch procedure. At the end point, the number of mmol of organometallic and indicator are equivalent, allowing the concentration of the organometallic reagent to be calculated directly from its corresponding flow rate. For this purpose, a binary search, which samples progressively smaller subsets of an array, was utilized. In comparison to a linear search function, performing the optimization in this manner not only saves time but also reduces the necessary amounts of reagents, thus minimizing waste. In the automated system (Figure 1), the user defines a range within which they expect the concentration of the B

DOI: 10.1021/acs.oprd.8b00434 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Communication

selected titrants. For each continuous flow titration, a batch titration was performed in tandem with the same solution of organometallic reagent to ensure agreement in the obtained values. The batch titrations were performed in accordance with literature procedures by adding the organometallic reagent dropwise to the titrant solution until the end point was visually observed.9f,l,o As shown, the automated continuous flow titration system performed exceptionally, producing identical values to batch for a majority of the organometallic reagents screened using N-pivaloyl toluidine (1), 2-hydroxybenzaldehyde phenylhydrazone (2), and 4-phenylbenzylidene benzylamine (3) (Table 1).

organometallic species to be. The software then converts this range into the corresponding flow rates, calculates a midpoint, and performs the first iteration. Depending on whether or not a signal is observed at this flow rate, the software then takes a step in the corresponding direction which is half the size of the previous step. This process is then performed iteratively until the desired level of precision is obtained (Scheme 1). Scheme 1. Automation Procedure Flow Diagram

Table 1. Scope of Automated Continuous Flow Titration System organometallic n-BuLi s-BuLi t-BuLi MeLi n-BuLi i-PrMgCl PhMgCl n-C6H13MgBr MeMgBre LDA NaHMDS KHMDS

indicator concentration in flow 1 1 1 1 2 2 2 2 2 3 3 3

1.62 ± 0.01 1.40c,d 1.58c,d N/A 1.59 ± 0.03b 2.06c 2.06c 1.01c 0.90c 1.02 ± 0.01b 0.96c N/A b

concentration in batchb 1.62 ± 1.42 ± 1.54 ± N/A 1.57 ± 2.03 ± 2.06 ± 0.97 ± 0.97 ± 1.04 ± 0.98 ± N/A

0.01 0.01 0.08 0.06 0.05 0.01 0.02 0.02 0.03 0.02

a

All solutions were commercial samples in Sure/Seal bottles. Concentrations are an average of three reactions. cFlow titration was reproduced over three runs, and the same value was obtained in all cases. dReactor cooled to between −10 and 0 °C. eCommercial 3 M solution diluted to 1 M, 40 psi BPR utilized. b

Using this approach, the concentration of the organometallic reagent can be determined with less than 3% error in only 6 iterations for several different concentration ranges. With an optimized residence time of 2.5 min for the reactor, each iteration in this process takes 7.5 min with equilibration, allowing for titrations to be achieved in 45 min without any user intervention. Depending on the level of precision desired and the size of the search window utilized, the number of iterations, and thereby the time of the overall process, may be reduced by the user. Once assembled, the entire continuous flow system was automated using LabVIEW. Within the user interface, the system provides a range of inputs, including reactor size, syringe diameter, and flow rate. The organometallic concentration ranges and corresponding titrant concentration may be selected or manually entered depending on the preference of the user. These organometallic concentration ranges are determined based upon the indicator concentration and residence time, ensuring the two flow rates are within an order of magnitude. Additionally, while an Avantes UV/vis spectrometer was utilized for this study, the software is programmed to read in data from an Excel spreadsheet, allowing its use with any instrumentation that supports data export to Excel. With these features built in, the user is able to easily configure the system to accommodate the available equipment and desired level of precision. With the system fully assembled, we then sought to demonstrate its versatility by investigating the scope of organometallic reagents which could be titrated with the

A wide range of organolithium, Grignard, and amide bases can all be efficiently titrated with few exceptions. Under the initial system conditions (room temperature, 20 psi), both sBuLi and t-BuLi produced substantially decreased values as compared to batch titrations. Due to the highly exothermic nature of the deprotonation, we hypothesized that the temperature of the reaction solution may be rapidly increasing upon mixing. At these elevated temperatures, alkyllithiums readily react with THF.18 This competing reaction pathway partially consumes the organometallic species, thereby producing a lower titration value. To avoid this, the Y-mixer and reactor were cooled (0 °C), which lead to reproducible titration values that were in close agreement with those obtained in batch. Additionally challenging was the use of MeLi and MeMgBr, which both produced significant quantities of gas and/or solids in-line upon deprotonation, prohibiting accurate UV/vis analysis. For MeMgBr, these issues were overcome at elevated pressure (40 psi) by diluting the solution prior to use.19 In contrast, MeLi continued to produce large quantities of gas at higher pressures (up to 75 psi) and as such was unsuitable for use in the current system. Solutions of KHMDS were also found to be incompatible due to the formation of precipitates in line, even upon dilution. In summary, the research described herein represents the first fully automated on-demand continuous flow titration system developed. Although the in-line monitoring of Grignard reagents species has been demonstrated previously,20 the C

DOI: 10.1021/acs.oprd.8b00434 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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(6) (a) Boeckman, R. K.; del Rosario Rico Ferreira, M.; Mitchell, L. H.; Shao, P. An Enantioselective Total Synthesis of (+)- and (−)-Saudin. Determination of the Absolute Configuration. J. Am. Chem. Soc. 2002, 124, 190−191. (b) Leung, J. C.; Bedermann, A. A.; Njardarson, J. T.; Spiegel, D. A.; Murphy, G. K.; Hama, N.; Twenter, B. M.; Dong, P.; Shirahata, T.; McDonald, I. M.; Inoue, M.; Taniguchi, N.; McMahon, T. C.; Schneider, C. M.; Tao, N.; Stoltz, B. M.; Wood, J. L. Total Synthesis of (±)-Phomoidride D. Angew. Chem., Int. Ed. 2018, 57, 1991−1994. (7) Ronn, M.; Zhu, Z.; Hogan, P. C.; Zhang, W.-Y.; Niu, J.; Katz, C. E.; Dunwoody, N.; Gilicky, O.; Deng, Y.; Hunt, D. K.; He, M.; Chen, C.-L.; Sun, C.; Clark, R. B.; Xiao, X.-Y. Process R&D of Eravacycline: The First Fully Synthetic Fluorocycline in Clinical Development. Org. Process Res. Dev. 2013, 17, 838−845. (8) Schlosser, M.; Lefebvre, O.; Ondi, L. Metal-Bearing and Trifluoromethyl-Substituted Pyrimidines: Generation and Functionalization. Eur. J. Org. Chem. 2006, 2006, 1593−1598. (9) (a) Gilman, H.; Haubein, A. H. The Quantitative Analysis of Alkyllithium Compounds. J. Am. Chem. Soc. 1944, 66, 1515−1516. (b) Gilman, H.; Cartledge, F. K. The Analysis of Organolithium Compounds. J. Organomet. Chem. 1964, 2, 447−454. (c) Eppley, R. L.; Dixon, J. A. Quantitative Analysis of Organolithium Reagents. J. Organomet. Chem. 1967, 8, 176−178. (d) Watson, S. C.; Eastham, J. F. Colored Indicators for Simple Direct Titration of Magnesium and Lithium Reagents. J. Organomet. Chem. 1967, 9, 165−168. (e) Kofron, W. G.; Baclawski, L. M. A Convenient Method for Estimation of Alkyllithium Concentrations. J. Org. Chem. 1976, 41, 1879−1880. (f) Duhamel, L.; Plaquevent, J. C. A Method for Simple Titration of Organolithium Reagents in Ethers or Hydrocarbons Using Metalation of N-Benzylidenebenzylamine as Colored Reaction. J. Org. Chem. 1979, 44, 3404−3405. (g) Lipton, M. F.; Sorensen, C. M.; Sadler, A. C.; Shapiro, R. H. A Convenient Method for the Accurate Estimation of Concentrations of Alkyllithium Reagents. J. Organomet. Chem. 1980, 186, 155−158. (h) Winkle, M. R.; Lansinger, J. M.; Ronald, R. C. 2,5-Dimethoxybenzyl Alcohol: A Convenient Self-indicating Standard for the Determination of Organolithium Reagents. J. Chem. Soc., Chem. Commun. 1980, 87−88. (i) Bergbreiter, D. E.; Pendergrass, E. Analysis of Organomagnesium and Organolithium Reagents Using N-Phenyl-1-naphthylamine. J. Org. Chem. 1981, 46, 219−220. (j) Juaristi, E.; Martinezricha, A.; Garciarivera, A.; Cruzsanchez, J. S. Use of 4-Biphenylmethanol, 4-Biphenylacetic Acid and 4-Biphenylcarboxylic Acid/Triphenylmethane as Indicators in the Titration of Lithium Alkyls. Study of the Dianion of 4Biphenylmethanol. J. Org. Chem. 1983, 48, 2603−2606. (k) Aso, Y.; Yamashita, H.; Otsubo, T.; Ogura, F. Simple Titration Method Using Diphenyl Ditelluride as a Colored Indicator for the Determination of Organolithium and Organomagnesium Reagents. J. Org. Chem. 1989, 54, 5627−5629. (l) Suffert, J. Simple Direct Titration of Organolithium Reagents Using N-Pivaloyl-o-toluidine and/or N-Pivaloyl-oenzylaniline. J. Org. Chem. 1989, 54, 509−510. (m) Kiljunen, H.; Hase, T. A. Titration of Organolithiums and Grignards with 1Pyreneacetic Acid. J. Org. Chem. 1991, 56, 6950. (n) Burchat, A. F.; Chong, J. M.; Nielsen, N. Titration of Alkyllithiums with a Simple Reagent to a Blue Endpoint. J. Organomet. Chem. 1997, 542, 281− 283. (o) Love, B. E.; Jones, E. G. The Use of Salicylaldehyde Phenylhydrazone as an Indicator for the Titration of Organometallic Reagents. J. Org. Chem. 1999, 64, 3755−3756. (p) Bowen, M. E.; Aavula, B. R.; Mash, E. A. Use of 9-Methylfluorene as an Indicator in the Titration of Common Group IA and Group IIA Organometallic Reagents. J. Org. Chem. 2002, 67, 9087−9088. (10) Gutmann, B.; Cantillo, D.; Kappe, C. O. Continuous-Flow TechnologyA Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients. Angew. Chem., Int. Ed. 2015, 54, 6688− 6728. (11) Britton, J.; Raston, C. L. Multi-Step Continuous-Flow Synthesis. Chem. Soc. Rev. 2017, 46, 1250−1271. (12) McQuade, D. T.; Seeberger, P. H. Applying Flow Chemistry: Methods, Materials, and Multistep Synthesis. J. Org. Chem. 2013, 78, 6384−6389.

designed platform is more general in scope and applicable to routine titrations both in batch and in flow. With regard to the titration of organometallic reagents, the automated continuous flow system offers several advantages compared to batch. By using the withdraw feature of the syringe pumps, the user is able to avoid direct exposure to these hazardous reagents, aside from piercing the septum of the reagent’s bottle. Furthermore, through automation of the process, user-related error is minimized, and the reproducibility of the titration is no longer reliant on the user’s expertise. The ability to perform the routine task of titration in an automated fashion also greatly increases the efficiency of the user, allowing them to focus their efforts on more challenging tasks during the process.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.8b00434. All batch titration procedures, optimization studies, titration data, system setup, and LabVIEW information (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Timothy F. Jamison: 0000-0002-8601-7799 Author Contributions †

A.A.B and T.A.M. contributed equally to this work.

Funding

We are grateful to the Novartis-MIT Center for Continuous Manufacturing for financial support. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Dr. Justin A. M. Lummiss, Kosi Aroh, and Dr. Joshua Britton for helpful discussions and Dr. Rachel L. Beingessner for her support in the preparation of this manuscript.

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REFERENCES

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DOI: 10.1021/acs.oprd.8b00434 Org. Process Res. Dev. XXXX, XXX, XXX−XXX