Reliable Mechanochemistry: Protocols for Reproducible Outcomes of Neat and Liquid Assisted Ball-mill Grinding Experiments

Summary

We present detailed procedures to produce experimental equilibrium curves of the phase composition as a function of solvent concentration in a solid state system under milling conditions.

Abstract

The equilibrium outcomes of ball mill grinding can dramatically change as a function of even tiny variations in the experimental conditions such as the presence of very small amounts of added solvent. To reproducibly and accurately capture this sensitivity, the experimentalist needs to carefully consider every single factor that can affect the ball mill grinding reaction under investigation, from ensuring the grinding jars are clean and dry before use, to accurately adding the stoichiometry of the starting materials, to validating that the delivery of solvent volume is accurate, to ensuring that the interaction between the solvent and the powder is well understood and, if necessary, a specific soaking time is added to the procedure. Preliminary kinetic studies are essential to determine the necessary milling time to achieve equilibrium. Only then can exquisite phase composition curves be obtained as a function of the solvent concentration under ball mill liquid assisted grinding (LAG). By using strict and careful procedures analogous to the ones here presented, such milling equilibrium curves can be obtained for virtually all milling systems. The system we use to demonstrate these procedures is a disulfide exchange reaction starting from the equimolar mixture of two homodimers to obtain at equilibrium quantitative heterodimer. The latter is formed by ball mill grinding as two different polymorphs, Form A and Form B. The ratio R = [Form B] / ([Form A] + [Form B]) at milling equilibrium depends on the nature and concentration of the solvent in the milling jar.

Introduction

Mechanochemistry using manual or ball mill grinding equipment has become increasingly popular in recent years as an attractive and sustainable alternative to traditional solution methods for the synthesis of materials.¹ It is attractive because it allows for reaction between solids to be achieved effectively and quantitatively. It is a "green" sustainable technique, requiring little or no solvent. Milling or manual grinding can be performed neat, i.e. with no added solvent, or solvent assisted: in the latter, known as "liquid assisted grinding" (LAG),^2,3,4

Protocol

1. Validation of the precise dispensing of organic solvents

1. Validation of precise pipetting of organic solvents in reverse pipette mode
   NOTE: Air displacement pipettes in reverse pipetting mode were selected for a range of LAG solvents (acetone, acetonitrile (MeCN), tetrahydrofuran (THF), ethyl acetate (EtOAc), chloroform (CHCl₃) and dimethylformamide (DMF)) because they soaked very efficiently into the powders of the starting materials (1-1 and 2-2). Preliminary calibration of the reverse pipetting mode with this range of solvents had given more accurate and precise dispensing of the volum....

Results

This protocol is always started by the experimentalist validating his or her pipetting skills and inspecting the quality and performance of the pipettes or syringes used. This is best done by performing training sets on pipetting accurate volumes of the specific solvent intended to be used for the ball mill grinding experiments. The accuracy of the dispensed volumes is validated by weighing checks and this validation is repeated until the desired accuracy and precision is achieved. This v.......

Discussion

While most of the literature on mechanochemistry focuses either on pragmatic outcomes or on reaction mechanisms, this paper addresses the thermodynamic end point of ball mill grinding. From this perspective, kinetic studies are a necessary step to the definition of the final equilibrium plateaus. Through our kinetic and final equilibrium studies, we know that the ball mill grinding reactions here discussed are driven by thermodynamics, resulting in the most stable polymorph composition under the given milling conditions........

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Bis(2-nitrophenyl) disulfide named 1-1	Aldrich	215228-25G	[1155-00-6] (98%)
Bis(4-chlorophenyl) disulfide named 2-2	TCI	D0360	[1142-19-4] (98+%)
1,8-Diazabicyclo [5.4.0]undec-7-ene (dbu)	Acros Organics	160610250	[6674-22-2] (>97.5 % by GC)
2-nitrophenyl-4-chlorophenyl-disulfide named 1-2	in house synthesis		Synthesised by ball mill grinding: 1:1 of 1-1 + 2-2 + 2%M dbu
Form A	in house synthesis		Polymorph of 1-2 prepared by ball mill neat grinding
Form B	in house synthesis		Polymorph of 1-2 prepared by ball mill liquid assisted grinding
Formic Acid	Scientific Laboratory Supplies	56302-50ML	[64-18-6] Mass spectrometry grade
Trifluoroacetic acid (TFA)	ThermoFisher	85183	[76-05-1] Reagent-Plus 99%
Water (H2O)	Rathburn	W/0106/PB17	[7732-18-5] HPLC gradient analysis grade used also for HPLC analysis
Acetonitrile (MeCN),	Merck	160610250	[75-05-8] Hypergrade for LCMS grade LiChrosolv used also for HPLC analysis
Acetone	Fisher Scientific	A/0606/17	[67-64-1] HPLC grade
Methanol (MeOH)	Fisher Scientific	M/4062/17	[67-56-1] LCMS grade
Ethanol (EtOH)	Sigma Aldrich	15727-5L	[64-17-5] laboratory reagent, absolute,
isopropanol (IPA)	Fisher Scientific	P/7508/17	[67-63-0] HPLC grade
Tetrahydrofurane (THF)	Acros Organics	268290010	[109-99-9] For HPLC; 99%8, unstabilised
Ethyl acetate (EtOAc)	Fisher Scientific	E/0906/15	[141-78-6]
Chloroform (CHCl3,)	Fisher Scientific	C/4966/17	[67-66-3] HPLC grade, stabilised with amylene
Dichloromethane (DCM)	Fisher Scientific	D/1857/17	[75-09-2] HPLC grade, unstabilised
Dimethylformamide (DMF)	Alfa Aesar	22915	[68-12-2] very toxic HPLC grade 99+% pure
Dimethylsulfoxide (DMSO)	Alfa Aesar	36480	[67-68-5] very toxic ACS, 99.9% min
Cyclohexane	Fisher Scientific	C/8936/15	[110-82-7] HPLC grade, 99.8+%
Toluene	Fisher Scientific Ltd	T/2306/15	[108-88-3] HPLC grade
Benzene	Sigma Aldrich	401765	[71-43-2] puriss pa reagent
5 -120 mL automatic pipette	Sartorius	Picus eLine	systematic error in specification: for 120mL is ±0.48 mL, for 60 mL is ±0.36 mL, for 12 mL is ±0.24 mL
VIAL screw clear 1.5ml + CAP bakelite solid screw PTFE lined for 10mm vial	Jaytee Biosciences	JW41110 + JW43927	Capped vial used for validating accuracy and precision of dispensed solvent
Crystal Structural Database	The Cambridge Crystallogra-phic Data Centre (CCDC)	Cambridge Structural Database (CSD)	Containing over 900,000 entries from x-ray and neutron diffraction analyses
powder X-ray diffractometer	Panalytical	X-Pert PRO MPD	Equipped with an X’Celerator detector with Cu Kα radiation
powder X-ray diffractometer data Collector software	Panalytical	X’Pert HighScore Plus v3.0	solftware package used to adquire the PXRD data
Rietveld refinement software including Scherrer equation	BRUKER	Version 6 of TOPAS-Academic	To prepare phase composition and crystal size from PXRD scans
HPLC equipment	Agilent	HP1200 Series modular HPLC system	HPLC high pressure binary pump, autosampler, Peltier type column oven with 6 µL heat exchanger and Diode Array Detector with a semi-micro flow cell (1.6uL, 6mm pathlength).
HPLC column	Agilent	1.8mm Zorbax XDB C18,	(4.6mm ID × 50 mm length)
Ball mill grinder	Retsch	MM400	modified: replaced safety cover for external safety screen
14 mL snap closure stainless steel jars	In house		manuctured from 316 stainless steel
14 mL screw closure stainless steel jars	In house		manuctured from 316 stainless steel - contains a PTFE washer
Stainless steel ball bearings:	Dejay Distribution Ltd	7.0 mm (1.37g)	Stainless Steel Balls A.I.S.I. 420 Carbon (0.25/0.35%) & Chromium (12/14%)
"Push a Button" software	Developed at Department of Chemistry		Written in Visual Basic. It activates an electronically controlled switch (relay).
"Push a Button" Solenoid	Magnet Schultz	Type 609RP 12 Volt DC	609RP (RP stands for) R - for spring-return P - for push-rod
"Push a Button" Solenoid holder	Department of Chemistry		To hold solenoid over START button on the MM400
"Push a Button" Relay	KM Tronic	USB one relay	USB Relay Controller - One Channel - HyperTerminal ASCII commands. Connection to a PC's USB port using VCP (Virtual COM port).
re-usable adhesive putty	Bostik	Blu-Tack	Used to hold the jar fixed on the bench.