The weight of flash chromatography: A tool to predict its mass intensity from thin-layer chromatography

The weight of flash chromatography: A tool to predict its mass intensity from thin-layer chromatography Freddy Pessel1, Jacques Augé2, Isabelle Billault1 and Marie-Christine Scherrmann*1 Full Research Paper Address: 1Université Paris Sud, ICMMO, UMR CNRS 8182, Bâtiment 420, 91405 Orsay Cedex, France and 2Université de Cergy-Pontoise, LCB, EA 4505, 5 mail Gay-Lussac, Neuville sur Oise, 95031 Cergy-Pontoise, France Open Access Beilstein J. Org. Chem. 2016, 12, 2351–2357. doi:10.3762/bjoc.12.228 Received: 27 July 2016 Accepted: 14 October 2016 Published: 08 November 2016 Email: Marie-Christine Scherrmann* - This article is part of the Thematic Series "Green chemistry". * Corresponding author Guest Editor: L. Vaccaro Keywords: environmental factor; flash chromatography; green metrics; mass intensity; purification © 2016 Pessel et al.; licensee Beilstein-Institut. License and terms: see end of document. Abstract Purification by flash chromatography strongly impacts the greenness of a process. Unfortunately, due to the lack of the relevant literature data, very often this impact cannot be assessed thus preventing the comparison of the environmental factors affecting the syntheses. We developed a simple mathematical approach to evaluate the minimum mass intensity of flash chromatography from the retention factor values determined by thin-layer chromatography. Introduction As part of a more respectful environmental chemistry, many efforts have been made to reduce the impact of chemical transformations by developing high atom-economic reactions, alternative reaction media or high-performance catalysts. The formation of a pure chemical product not only requires reactants, solvents, promoters and catalysts used in the reaction, but also other materials used for the work-up and for the purification steps. The Sheldon E factor [1,2] and the mass intensity MI [3-5], which are defined according to Equation 1 and Equation 2, respectively, are classical metrics based on the economy of material for evaluating the greenness of a process. It is worth noting that these mass-based metrics allowed to quantify the mass of waste but did not take into account their potential for negative effects on the environment. These two metrics are related by Equation 3 [6]. (1) (2) (3) The amount of waste includes the amount of the byproducts, but also the amount of non-reacting starting materials, auxiliaries, catalysts or any additives such as acids, bases, salts, solvents of 2351 Beilstein J. Org. Chem. 2016, 12, 2351–2357. the reaction or solvents required for the work-up and the purification. We demonstrated that the mass intensity could be easily calculated for linear and convergent sequences from the global material economy GME (Equation 4), which is related to the atom economy, the yields of each step, the excess of reactants and the mass of auxiliaries [6,7]. (4) It can be fractioned into three parts: reaction itself (MIR), workup (MIW) and purification (MIP) as shown by Equation 5 [8]. (5) Any value of the E factor which does not take into account the work-up and purification steps is nonsensical, since the values of MIW and MIP are often much higher than the value of MIR. In order to compare the greenness of different processes, each term of Equation 5 has to be known. From the literature data it is possible to retrieve information concerning the amount of reactants, solvents and catalysts allowing the calculation of MIR. Moreover, since the work-up is usually well described, it is easy to gain access to MIW. In contrast, the amount of auxiliaries and solvents used in the purification of products is very often omitted. For example, the mass of silica gel and eluents used are never mentioned, which prevents the reader from calculating MI p , and thus having the actual value of the E factor. The impact of chromatography on sustainability was recently discussed [9] and we propose here a method to evaluate such an item. This tool can also allow the chemist to evaluate, from a thin-layer chromatography (TLC), the minimum mass required to perform a flash chromatography. Our calculations are based on the preparative chromatographic technique largely used by chemists [10-12] and on our own experiments. Results and Discussion The publication of Still et al. [10] describing flash chromatography in 1978 greatly facilitated the post synthesis purifications which were, until then, often carried out by gravity column chromatography that was time consuming and did not always lead to effective separations. Since then, various automated systems equipped with pumps and eventually detectors and using disposable pre-packed silica cartridges were marketed offering great ease of use. The mass intensity of purification by chromatography (MIChr) is the ratio between the total mass used to perform the chromatography (i.e., the sum of the mass of silica ( ) and the mass of eluent (meluent)) and mp, the mass of the product (Equation 6). (6) Mass of silica The size of the column for chromatography and therefore the amount of silica and solvent depends on the mass of the sample and on the difficulty of separation of the products. This difficulty may be evaluated by ΔRf that is the difference between the retention factor Rf of products in TLC (thin-layer chromatography). Based on their experimentations, Still et al. recommended typical column diameters (constant height) and sample loading for difficult separations (0.2 > ΔRf ≥ 0.1) or more easier separations (ΔRf ≥ 0.2) [10]. Using a column height of 5.9 inches (ca. 15 cm) and considering that the silica has a density of 0.5, correlations have been established between the mass of silica to be used and mass (ms) of the sample to be purified (Table 1, Table 1: Mass of silica (in grams) to be used depending on the mass of sample to be purified for manually packed columns and some commercial pre-packed cartridges. Entry Cartridge Particles shape Average particle size (μm) difficult separation moderately difficult separation easy separation 1 Silica gela irregular 40–63 151.2 ms + 0.5 59.8 ms 2 3 RediSepTM EasyVario FlashTM SNAPTM SNAP UltraTM irregular irregular 35–70 15–40 1000 ms 25 ms 33.3 ms 14. ms irregular spherical 40–50 25 10 ms 50 ms 20 ms 10 ms 10 ms 5 ms 4 5 aManually packed glass column. 2352 Beilstein J. Org. Chem. 2016, 12, 2351–2357. entry 1) [12]. For commercial pre-packed cartridge indications are also provided [13-15] and we have selected some data to obtain a general trend (Table 1). should be calculated using Equation 10. A value of 0.64 was found for manually packed columns, while for commercial cartridges, the value of C was 0.66. The mass of silica required to purify ms g of sample may therefore be estimated by Equation 7. Excluding the equation obtained for difficult separations with the RediSepTM cartridge leading to extremely high values of mass of silica (Table 1, entry 2), and partially the equ (...truncated)