Disposable cartridge concept for the on-demand synthesis of turbo Grignards, Knochel–Hauser amides, and magnesium alkoxides

Article abstract of DOI:10.3762/bjoc.16.115

Magnesium organometallic reagents occupy a central position in organic synthesis. The freshness of these compounds is the key for achieving a high conversion and reproducible results. Common methods for the synthesis of Grignard reagents from metallic magnesium present safety issues and exhibit a batch-to-batch variability. Tubular reactors of solid reagents combined with solution-phase reagents enable the continuous-flow preparation of organomagnesium reagents. The use of stratified packed-bed columns of magnesium metal and lithium chloride for the synthesis of highly concentrated turbo Grignards is reported. A low-cost pod-style synthesizer prototype, which incorporates single-use prepacked perfluorinated cartridges and bags of reagents for the automated on-demand lab-scale synthesis of carbon, nitrogen, and oxygen turbo magnesium bases is presented. This concept will provide access to fresh organomagnesium reagents on a discovery scale and will do so independent from the operator’s experience in flow and/or organometallic chemistry.

Full text of DOI:10.3762/bjoc.16.115

Disposable cartridge concept for the on-demand synthesis of
turbo Grignards, Knochel–Hauser amides,
and magnesium alkoxides
Mateo Berton*1, Kevin Sheehan2, Andrea Adamo2 and D. Tyler McQuade*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 1343–1356.
1Department of Chemical and Life Sciences Engineering, Virginia
doi:10.3762/bjoc.16.115
Commonwealth University, Biotech Eight, 737 N. 5th St., Box 980100,
Richmond, VA 23219, USA and 2Zaiput Flow Technologies, 300 2nd
Avenue, Waltham, MA 02451, USA
Received: 02 April 2020
Accepted: 25 May 2020
Published: 19 June 2020
Email:
Mateo Berton* - moberton@vcu.edu; D. Tyler McQuade* -
tmcquade@vcu.edu
Associate Editor: I. Baxendale
©
2020 Berton et al.; licensee Beilstein-Institut.
*
Corresponding author
License and terms: see end of document.
Keywords:
Knochel–Hauser base; lithium chloride; magnesium; on-demand;
packed-bed reactors; plug and flow reactor; synthesizer; turbo
Grignard reagent
Abstract
Magnesium organometallic reagents occupy a central position in organic synthesis. The freshness of these compounds is the key for
achieving a high conversion and reproducible results. Common methods for the synthesis of Grignard reagents from metallic
magnesium present safety issues and exhibit a batch-to-batch variability. Tubular reactors of solid reagents combined with solution-
phase reagents enable the continuous-flow preparation of organomagnesium reagents. The use of stratified packed-bed columns of
magnesium metal and lithium chloride for the synthesis of highly concentrated turbo Grignards is reported. A low-cost pod-style
synthesizer prototype, which incorporates single-use prepacked perfluorinated cartridges and bags of reagents for the automated
on-demand lab-scale synthesis of carbon, nitrogen, and oxygen turbo magnesium bases is presented. This concept will provide
access to fresh organomagnesium reagents on a discovery scale and will do so independent from the operator’s experience in flow
and/or organometallic chemistry.
Introduction
Flow chemistry has facilitated: (1) new applications of high- mixing can outcompete unimolecular side reactions [5,6]; (3)
energy or otherwise unsafe chemistry [1,2], enabled by a con- new chemistry by conducting reactions outside of normal oper-
trolled/rapid heat removal and generation and the immediate use ating pressures and temperatures [7,8]; (4) new opportunities
of unstable species [3,4]; (2) flash chemistry, where rapid for the realization of automated chemistry, including
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Beilstein J. Org. Chem. 2020, 16, 1343–1356.
on-demand systems [9-12]. We have recently focused on
systems where solid-reagent cartridges are combined with a
solution-phase reagent, including: (1) copper(I) oxide to
produce N-heterocyclic carbene–Cu(I) complexes for use as
catalysts [13]; (2) proline to perform proline-based catalytic
reactions [14]; (3) zinc powder to produce organozinc halides in
tandem with Negishi couplings [15]; (4) zinc complexes to
produce fluorescent species [16]; (5) sodium borohydride to
reduce carbonyls [17]; (6) red phosphorous to produce
polyphosphides [18]. Our initial foray into this area was born
out of necessity. We wanted to conduct flow reactions that re-
quired solids, and packed beds facilitated the use of solids with-
out clogging. More recently, we began to think about this com-
bination for producing air- and water-sensitive reagents imme-
diately prior to use. In particular, we were interested in
addressing a dichotomy where discovery-scale (50–100 mL)
organometallic reagents are used with uncertain characteristics,
Figure 1: Comparing on-demand coffee and turbo Grignard pod-style
machines.
as opposed to a large scale where the specs are often defined for sphere. Time-consuming titration is recommended but is unreli-
all reagents, including organometallics. The hypothesis is that able as only the basicity is estimated. The freshness of these
unstable/unsafe reagents can be synthesized and used as needed solutions is a key for achieving high conversion because the
for this discovery scale instead of purchasing stock solutions neutralization can alter the aggregation states, producing a sig-
that arrive with uncertain properties and require titration to de- nificant batch-to-batch variability. The direct insertion of
termine the concentrations.
magnesium metal into organic halides is the most common
method used to prepare Grignard reagents but present difficul-
Both commercial and academic flow systems are commonly ties: (1) sluggish reactions with ordinary magnesium turnings
constructed for experienced flow chemists and are designed to [31]; (2) the formation of undesired side products by thermal
maximize a versatile operation to explore a broad range of decomposition and exothermic reactions not suitable for indus-
chemical transformations [11,19-30]. These systems are de- trial processes [32]; (3) the activation of a metallic surface is re-
signed to achieve a generality of operation, and this comes with quired and can introduce safety issues due to the high reactivity
an increase in the cost and complexity of the instruments. Our of the activated metal.
on-demand approach targets the opposite end of the equipment
design spectrum; it requires a low-cost systems designed to Flow chemistry technologies and cartridges containing acti-
carry out only a few specific functions in a safe and robust vated metals can solve most of these issues: (1) the use of acti-
manner. It also demands to be low-cost in order to have any vated magnesium powder packed in a column increases the
potential for real-world applications. In other words, to achieve reaction rate and facilitates safe separation of the metal and
the set goals, innovation is needed to reduce the complexity/ reagent solution; (2) an efficient heat transfer (a large surface
expense of (1) pumps; (2) reactors; (3) valves; (4) fittings, and area-to-volume ratio) provides thermal control during metal ac-
(
5) chemical containers. The design presented here is based on a tivation and the generation of concentrated organometallic solu-
disposable cartridge concept, inspired by pod-based coffee tions; (3) the control over the residence time reduces side prod-
machines (Figure 1). We took inspiration from recent efforts ucts because the organometallic solution is not exposed to high
that demonstrated that simple machines can do valuable chem- temperatures longer than necessary. All these advantages allow
istry [12]. Our “cartridge” encompasses reagent bags, tubing, a more straightforward production and use of these critical
and packed-bed columns of solid reagents and product recep- reagents.
tacle. These components are deployed in a low-cost machine
with a design amenable for the automated lab-scale generation The preparation of organozinc species using zinc packed-bed
of organomagnesium reagents on demand (Figure 1).
columns [15,33-35] provides examples for the progression
toward the on-demand synthesis of other organometallic
Organomagnesium compounds are omnipresent reagents that reagents. While the concept of a reactive packed bed is not new,
serve as nucleophiles and bases. Grignard reagents react with many features must be considered and solved for success, in-
oxygen and water, yielding flammable gases and must be pre- cluding: (1) the column packing–making sure the particle size
pared, stored, and handled under an anhydrous inert atmo- range and how the column is packed provides a system with
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minimal channeling; (2) selecting a column with the right prop- responding bromide or iodide, are limited. Also, the use of a
erties, such as the materials of construction, pressure tolerance, LiCl solution as the reaction medium to increase the Grignard
heat conduction, and diameter/particle size matching; (3) the reagent solubility was prepared from hygroscopic LiCl, which
column orientation and setup–filters, etc.; (4) activation of the implies thorough drying and storage under a moisture-free at-
solid phase. The activation issue is one of the most important mosphere. Finally, the concentration of the Grignard reagents
factors when considering the metal packing. Although our team was limited, being in the range of 0.3–0.5 M, thereby limiting
had success with zinc packing, we still need to develop a new the range of reaction conditions for the discovery chemist. In
approach for magnesium. Magnesium, when activated, is more this study, we started selecting some of the most used organo-
reactive compared to zinc, in part because magnesium is a magnesium halides in synthesis. For this purpose, a ranking of
stronger reducing agent than zinc. Beyond the considerations of the 20 most cited ones, as measured by the citation values ob-
the packing, column, and activation, the solubility of organo- tained from SciFinder, was constructed (Figure 2). Based on our
magnesium reagents is often lower than of the corresponding analysis, methyl, ethyl, isopropyl, butyl, benzyl, and phenyl as
zincates. The low solubility can clog the column or may reduce the residue R were selected as test cases for our proposed
the insertion rate by forming a passivating layer over the metal system.
particle surface.
Over the last two decades, Knochel demonstrated the benefits of
Few examples describe the production of organomagnesium LiCl on the halogen–magnesium exchange rates [43] and on the
species under flow conditions [36-39], and only three use a organomagnesium solubility [44]. The most known example of
practical system with a broad range of substrates [40-42]. The this class is the isopropylmagnesium chloride–lithium chloride
Alcázar group reported the generation and subsequent use of complex (iPrMgCl⋅LiCl), known as turbo Grignard [45]. In ad-
Grignard reagents [40]. In 2018, the Loren group extended the dition to being widely cited, turbo Grignard is a popular
scope of the organozinc reagents made in flow to aryl and discovery-scale tool in the pharmaceutical industry [32] and has
tertiary alkyl halides by the in situ formation of the correspond- shown an excellent selectivity on a large scale [46]. Halomag-
ing Grignard intermediate in the presence of ZnCl2 and LiCl, nesium amide LiCl adducts, e.g., the Knochel–Hauser base
which were subsequently used in Negishi cross-coupling reac- (TMPMgCl⋅LiCl), are also useful reagents for selective depro-
tions [41]. The most recent example, by the Löb group, re- tonations due to their strong basicity and low nucleophilicity
ported a pilot plant reactor including a Mg replenish unit that [47,48]. Knochel-type alkoxides [49], e.g., the 2-methyl-2-
allowed to generate phenylmagnesium bromide (1 M) at flow propoxymagnesium chloride–lithium chloride complex (tert-
rates up to 15 L/h [42].
AmylOMgCl⋅LiCl), are less common in synthesis, but their
high reactivity and solubility, combined with a high tolerance
However, in these publications, alkyl chloride substrates, which towards functional groups, made them advantageous for selec-
are generally more cost-effective but less reactive than the cor- tive transformations.
Figure 2: Ranking of the 20 most cited Grignard reagents (SciFinder March 26, 2019).
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Beilstein J. Org. Chem. 2020, 16, 1343–1356.
Herein, a novel disposable cartridge approach for the
on-demand, discovery-scale preparation of turbo Grignard
reagents, Knochel–Hauser bases, and new Knochel-type alk-
oxides using a stratified bicomponent packed-bed column of
magnesium and lithium chloride is presented. Critical insights,
such as column packing, particle size, metal excess, reagent
scope, order of addition, column stability, reproducibility, and
consideration of solid/liquid reaction models are presented. In
addition, a proof-of-concept, automated pod-type synthesizer
prototype designed to generate up to 100 mmol of fresh
reagents on demand is described. Our objective is to help others
integrate this approach into their quotidian workflow to enable
discovery-scale researchers to increase the reliability of their
developed routes and processes by increasing the quality of
their organomagnesium reagents.
Results and Discussion
1
On-demand reagent prototype
Figure 3: On-demand prototype. A) Inside view of the pump with a
flexible bag containing a yellow liquid laying on an elastomer mem-
brane. B) Detail of the manifold used to select the waste or product
collection. C) Heater cross section, the arrows indicate the air convec-
tion flow path. D) Reagents on-demand system assembled, with the
coil reactor placed in the left reactor area. E) Example of a disposable
cartridge.
Objective: To design and create a simple, robust, disposable,
and low-cost system capable of producing on-demand reagents
for lab-scale purposes using a combination of liquid and solid
pods or cartridges. We envisioned a system that requires: (1)
pumps; (2) tubular reactors; (3) valves; (4) fittings, and (5)
chemical containers.
is accomplished by enclosing the bag in a metal clamshell, with
Challenges: The need to develop new design concepts to contact surfaces made with an elastomer (Figure 3A). When
achieve (1) low-cost high-pressure pumps (10 bar); (2) dispos- compressed air is pumped in the clamshell, it squeezes the bag
able tubular reactors; (3) robust valves; (4) leakproof bonding through the elastomer, and thus dispensing fluid. The elastomer
process, and (5) chemically compatible and high-pressure sheets fully embrace the reagent bag, providing mechanical
containers.
support. In this way, a soft polymer bag can be squeezed at a
relatively high pressure: our prototype achieved pumping pres-
System design: The pod-style concept is achieved by making sures up to about 1 MPa (10 bar). This type of pressure-driven
the entire fluidic circuit that is needed to run a specific chem- pump, where the dispensed liquid is enclosed in a plastic reser-
istry with prearranged, custom-made, and thermally bonded voir, provides the advantage of not dissolving any gas into the
parts. Parts were built of fully perfluorinated materials, provid- liquid during the operation, which is the case for pressurized
ing an excellent chemical resistance. We chose thermal bond- tanks. Additionally, all the wetted parts of the pump are fully
ing because this type of bond can provide a leakproof system disposable (Figure 3E). The metering function required to keep
without the need of fittings. All the fluidic items and reagents the back pressure and a constant flow rate is achieved by the
assembled together represent the “cartridge” (Figure 3E). tubing length and diameter downstream of the pump or by the
Prebuilt disposal cartridges have a long shelf life and can be fluidic network for more complex cases. The flow is pulseless
deployed on demand. The instrument we produced provides the as a result of the fact that it is driven by compressed air.
necessary pumping (Figure 3A), heating (Figure 3C), and
valving (Figure 3B), which are united in an enclosed unit that On-demand reagent (ODR) system design: The ODR proto-
can be loaded with self-contained cartridges (Figure 3E). In type (Figure 3D) is essentially composed of three clamshell
order to build the disposable cartridges, we developed bonding pumps in order to have up to three process fluids. Each bag
protocols to carry out the different types of connections needed contains a valving, so that only specified fluids can be
(
i.e., tube to tube, tube to cartridge, tube to bag, tee, etc.).
dispensed when required by the process. The instrument offers
up to two reaction areas made by aluminum plates. The convec-
Pump concept: The pumping is achieved by developing flex- tion of air is generated with small fans embedded in the alumi-
ible reservoirs made with perfluorinated polymer film (PFA), num plate to improve the quality of the heat transfer to the
and the bags are filled with the fluid to dispense. The pumping reactor. A manifold (Figure 3B) is placed downstream of the
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Beilstein J. Org. Chem. 2020, 16, 1343–1356.
reaction areas where actuators control the direction of the We started reproducing Alcázar’s conditions to obtain organo-
outcome stream. The solvent priming and the activation solu- magnesium bromide reagents from the corresponding alkylbro-
tion are discarded into the waste, and only when product is mides. The activation protocol was slightly modified: a single
generated, the manifold starts to collect. The system’s heating, activating solution composed of 1-bromo-2-chloroethane,
temperature control, and valving are controlled by an Arduino TMSCl, and DIBAL-H in THF/toluene was pumped through
card (not shown–on the back of the system). Different control magnesium powder (98%, 20–230 mesh) at 1 mL/min and
routines can be loaded into the Arduino card as needed.
40 °C (Section 1.2.2 in Supporting Information File 1). Organo-
magnesium bromide reagents (15 mL) were generated in THF
at a 0.5 mL/min flow rate and 25 °C. For each experiment, the
concentration was determined in duplicates by the reaction with
2
Grignard reagents via magnesium-packed
beds
Objective: To generate concentrated organomagnesium solu- a known mass of two different indicators until a color change
tions from alkyl halides using a standardized and reproducible occurred: 2-hydroxybenzaldehyde phenylhydrazone [52] or a
packed bed of magnesium, to develop a consistent activation mixture of benzoic acid and 4-(phenylazo)diphenylamine [53].
protocol using a single activation solution, and to optimize the Iodine can also be used [54]. Similar concentrations were ob-
conditions for the quantitative organic chloride conversion.
tained by NMR titration with 1,5-cyclooctadiene as a standard
Section 1.2.10 in Supporting Information File 1) [55].
(
Challenges: Metal surface activation, organomagnesium solu-
bility, formation of a black side product, performance, and deg- The heat released from the exothermic Grignard reaction done
radation over time.
at 25 ºC was not fully dissipated by the heat exchanger (≈10 ºC
increment). To better understand this exothermic process, we
System setup: A commercial flow chemistry system [50] decided to measure the temperature evolution during the
equipped with a temperature-controlled glass manifold reactor conversion of EtBr (0.5 M) at a 0.5 mL/min flow rate with no
[
51] was used (Figure S1, Supporting Information File 1). We heat controller. Three thermocouples were placed at different
have found that both glass and PFA columns with similar points along the glass column (Figure 4 right). The results
dimensions can be used. To reduce the costs, the flow chem- showed a ≈35 °C increment, which is an underestimation
istry system can be replaced by syringe or HPLC pumps, and because the measurements were taken on the outer surface of
the reactor heating can be accomplished using standard heating the glass column. The data featured a hot spot moving upward
tools (water/oil bath, heating jacket, or a suitable oven). The 10 during the reaction (Figure 4 left), suggesting that magnesium
×
100 mm (ID × length) column was filled with magnesium. A was consumed by the layers at a 0.5 mL/min flow rate, and the
back-pressure regulator (BPR) was added to prevent the gas/ reaction occurred almost exclusively at the interphase
liquid separation and to increase the solvent boiling tempera- EtBr–Mg* and not along the whole column. Since the reactive
ture.
interphase moved upward at the same rate that Mg was getting
Figure 4: Temperature evolution measured with thermocouples along the column outer surface at three different points.
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Beilstein J. Org. Chem. 2020, 16, 1343–1356.
consumed, the heat release was not constant along the column, an iPrMgCl yield of up to 97%. The optimal amount of Mg was
and a steady-state temperature only occurred during a short determined to be 2 equivalents. The yield drop after the
amount of time at a localized area. The temperature gradient consumption of 1 equiv of Mg was first attributed to a chan-
was not observed at higher temperatures (60–100 ºC), and the neling through the packed bed. To test this hypothesis, we fol-
hot spot generated was less than +5 ºC under these conditions. lowed the changes in the column using a 4K webcam for two
types of columns: (1) a firmly packed column and (2) a loosely
During the isopropylmagnesium bromide optimization (Table packed column. The well-packed Mg column did not consume
S4, Supporting Information File 1), solubility issues hindered all the Mg due to the channeling (Figure S8A, Supporting Infor-
the formation of a concentrated solution (>0.8 M). The crystalli- mation File 1), as we proposed. The loosely packed column, to
zation of iPrMgBr in the collection flask forced us to reduce the our surprise, behaved like a fluidized bed, allowing iPrCl to be
initial concentration of the organic halide to 0.9 M, yielding in contact with a larger surface of Mg (Figure S8B, Supporting
iPrMgBr (0.75 M, 82%, note: the yields reported herein refer to Information File 1) and provide a better performance than a
the amount of organometallic reagent produced in a steady well-packed column: 98%.
state; no detectable halide was recovered, and the organometal-
lic reagent purity was high unless otherwise stated, Table S4, System scope: Next, we probed the limit of this transformation
entry 3, Supporting Information File 1). The reactivity order of for primary (bromoethane, bromooctane, chlorobutane, and
organic halides against oxidative addition reactions is R–I > iodomethane) and secondary (2-bromopropane, 2-chloro-
R–Br > R–Cl. To achieve the direct insertion of 2-chloro- propane, and 2-chlorobutane) alkyl halides as well as benzyl
propane, the temperature was increased, and the best result was (chloromethylbenzene) and aryl chlorides (chlorobenzene).
obtained at 80 °C, yielding iPrMgCl (0.78 M, 87%, Table S4,
entry 7, Supporting Information File 1). Since iPrMgCl is more Good to excellent yields were obtained (Table 1). In general,
soluble in THF than the corresponding bromide [56], we were bromo-Grignard reagents tend to be less soluble in THF than
able to use an initial concentration of up to 2.5 M, yielding chloro-Grignard reagents, and other ethereal solvents can be
iPrMgCl (2.23 M, 89%, Table S4, entry 8, Supporting Informa- more appropriate: 2-methyltetrahydrofuran (2-MeTHF) or Et2O.
tion File 1). At a temperature higher than 60 °C, 100 psi BPR The higher solubility of EtMgBr in these solvents allowed us to
were required to prevent the solvent from boiling inside the obtain 2.21 M (88%) in 2-MeTHF and 2.40 M (96%) in Et2O
packed-bed column.
but only 1.08 M (90%) in THF (Table 1, entries 2–4). The con-
centration of n-OctMgBr was also limited to 0.51 M (85%) in
During preliminary experiments, we observed the formation of THF (Table 1, entry 5). The use of Et2O increased the solu-
a black residue that was left after the magnesium consumption. bility up to 1.08 M (90%, Table 1, entry 6). Even chloroben-
While the residue did not affect the column performance for the zene, considered a deactivated species, was converted to
conversion of 10 mL of an iPrCl (2.5 M) solution, larger gener- PhMgCl in an excellent yield (2.32 M, 93%, Table 1, entry 10),
ated volumes increased the pressure drop and eventually led to heating the column to 100 °C. For benzyl chloride, a 2-MeTHF/
clogging of the system. The analysis of the black residue via THF, 9:1 mixture [57] was found to be optimal to reduce the
X-ray photoelectron spectroscopy (Figure S6, Supporting Infor- formation of a Wurtz-type side product, 1,2-diphenylethane
mation File 1) revealed the presence of magnesium, oxygen, (Table S5, Supporting Information File 1), yielding BnMgCl
carbon, and chlorine. Although we do not understand the mech- (0.99 M, 83%, Table 1, entry 11). Noteworthy, a iodomethane
anism, we sought a solution that would enable the column per- (bp 42 °C) solution in Et2O can be converted to the correspond-
formance to remain constant. During the optimization, we tested ing MeMgI in good yield and with a good mass balance using a
Mg chips (99.98%, 6–35 mesh) and observed less black residue. 140 psi BPR (Table 1, entry 12).
Thus, we explored the reaction using different ratios of Mg
3
Turbo Grignards via stratified packed-bed
chips/powder (Figure S7, Supporting Information File 1). We
found that a Mg chip/powder ratio of 1:1 provided more consis- columns containing magnesium and LiCl
tent results over a relatively large amount (≈100 mmol) of Objective: To generate organomagnesium–lithium chloride
organic halide that was converted. We offer two explanations: complexes (turbo Grignards) from alkyl chlorides using a strati-
(
1) the higher purity of Mg chips (99.98%) and (2) the higher fied bicomponent packed-bed column composed of magnesium
surface area (SA) of the Mg powder (≈130 mesh, SA ≈ metal and lithium chloride.
0 cm2/g) than Mg chips (≈20 mesh, SA ≈ 4 cm2/g). We
3
hypothesize that these features provided a large activated Mg Challenges: Metal passivation by lithium chloride coating,
surface for an initial quantitative conversion and a purer but less handling of LiCl (hygroscopic), LiCl equivalent optimization
reactive material that generated less side products, resulting in due to the solubilization over time.
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Beilstein J. Org. Chem. 2020, 16, 1343–1356.
by their solubility. Knochel pioneered the use of lithium chlo-
ride to solubilize organometallic reagents and to increase the re-
activity, most probably due to the disaggregation of oligomers
Table 1: Reaction of organic halides in a packed-bed column of acti-
vated magnesium. Scope of Grignard reagents prepared under flow
conditions.a
[
43,44]. We used this approach to overcome the solubility issue
under continuous conditions. First, we verified that similar
results are achieved in presence and absence of LiCl in solution
for the EtMgBr formation (Section 2.2, Supporting Information
File 1). Because organomagnesium halide–lithium chloride
complexes are believed to be 1:1 RMgX⋅LiCl dimers, and
considering the LiCl solubility limitation of ≈0.5 M in THF, we
decided to design a new system for the generation of highly
concentrated turbo Grignard reagents. Instead of using a solu-
tion of starting material and LiCl, a bicomponent packed-bed
column was assembled. First, ≈4.5 cm of the Omnifit column
was filled with magnesium (chips/powder, 1:1) and the upper
entry RX
T
solvent
[RX] [RMgX] yield
(°C)
(M)b (M)
(%)c
1
2
3
4
5
6
7
8
9
1
1
1
iPrBr
25
25
25
25
25
25
80
THF
THF
0.9
1.2
0.74
1.08
2.21
2.39
0.51
1.08
2.38
2.23
2.37
2.32
0.99
2.36
82d
90
88
96
85
90
95
89
95
93
83f
94
EtBr
EtBr
2-Me-THF 2.5
EtBr
Et2O
THF
Et2O
THF
THF
THF
2.5
0.6
1.2
2.5
2.5
2.5
2.5
n-OctBr
n-OctBr
iPrCl
≈
4.5 cm with anhydrous lithium chloride (Figure 5). The two
components were separated by fiberglass previously dried at
20 °C overnight. We first tested this column with a 1.5 M EtBr
1
sec-BuCl 80
solution, and a comparable EtMgBr⋅LiCl concentration was ob-
tained (1.30 M, 87%, Table 2, entry 1) in comparison to dis-
solved LiCl (1.27 M, 86%, Table S6, entry 6, Supporting Infor-
mation File 1).
n-BuCl
PhCl
BnCl
MeI
80
0
100 THF
1
60
25
2-Me-THFe 1.2
Et2O 2.5
2g
aThe RX solution (20 mL) was pumped at a 0.5 mL/min flow rate
through a column (ID = 10 mm) of Mg* (2 equiv) chips/powder (1:1).
bQuantitative RX conversion. cDetermined by the titration of an overall
RMgX solution (≈15 mL) collected at steady state. d2-Methylpropene
obtained as a major side product. e10% of THF. f1,2-Diphenylethane
was obtained as a single side product. g140 psi BPR.
Table 2: Reaction of organic halides with a stratified packed-bed
column of activated magnesium and lithium chloride. Scope of turbo
Grignard reagents prepared under flow conditions.a
System setup: The same flow system was used as for the gen-
eration of Grignard reagents (Figure S2, Supporting Informa-
tion File 1). The 10 × 100 mm (ID × length) column was half
filled with magnesium (chips/powder, 1:1) and the second half
with anhydrous lithium chloride (Figure 5). The two compo-
nents were separated by fiberglass previously dried at 120 °C
overnight. A 100 psi BPR was added to prevent the gas/liquid
separation and to increase the solvent boiling temperature.
entry RX
T
(°C)
[RX] (M)b [RMgX⋅LiCl] yield
(M)
(%)c
1
2
3
4
EtBr
iPrCl
25
80
1.5
2.5
2.5
2.5
1.30
2.19
2.15
2.13
87
88
86
85
sec-BuCl 80
n-BuCl
80
aThe RX solution (15 mL) in THF was pumped at a 0.5 mL/min flow
rate through a bicomponent column (ID = 10 mm) composed of acti-
vated Mg* (2 equiv) chips/powder (1:1) and anhydrous LiCl (2 equiv)
separated by fiberglass. bQuantitative RX conversion. cDetermined by
the titration of the overall RMgX·LiCl solution (≈10 mL) collected at
steady state.
The separation of the two components was crucial to obtain
reproducible results. When Mg and LiCl were intimately mixed
together, a reactivation of the column failed, likely due to
magnesium surface passivation. The separation of Mg/LiCl
allowed to reuse the column several times with different sub-
Figure 5: Stratified bicomponent column (Diba Omnifit EZ Solvent
Plus) composed of magnesium (chips/powder, 1:1) and lithium chlo-
ride separated with fiberglass for the turbo Grignard reagent synthesis.
Clogging is a common concern in flow chemistry, and during strates. Nevertheless, we do not recommend its reutilization.
our scope exploration, we observed that the concentrations of For optimal results, 2 equivalents of Mg* (chips/powder, 1:1)
the organomagnesium reagents generated were mostly limited and 2 equivalents of LiCl must be used at a single time.
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Beilstein J. Org. Chem. 2020, 16, 1343–1356.
System scope: The bicomponent column was employed to Challenges: Gas formation from amine deprotonation, resi-
obtain the turbo Grignard reagent [45] as well as sec- and dence time optimization due to variations in the amine and
n-butylmagnesium chloride–lithium chloride complexes as THF amide properties.
solutions (≈10 mL). Very good yields were obtained:
iPrMgCl⋅LiCl 2.19 M (88%); s-BuMgCl⋅LiCl 2.15 M (86%), System setup: The same flow system was used as for the gen-
and n-BuMgCl⋅LiCl (2.13 M, 85%, Table 2, entries 2–4).
eration of turbo Grignard reagents (Figure S2, Supporting Infor-
mation File 1). For TMPH, a coil (V = 10 mL, ID = 0.03″) was
The formation of the turbo Grignard reagent (iPrMgCl⋅LiCl) added downstream to increase the residence time (Figure S3,
was scaled up to ≈100 mmol using a 15 × 100 mm column, and Supporting Information File 1).
the results were compared with the Knochel batch protocol [58].
Using our flow procedure, the generation of a higher We synthesized amidomagnesium chloride–lithium chloride
iPrMgCl⋅LiCl concentration (2.10 M instead of 0.89 M) in a complexes (R2NMgCl⋅LiCl) by the in situ formation of turbo
shorter reaction time (1.5 h instead of 12 h) caused a 7-fold Grignard in the presence of the corresponding amine. The reac-
throughput and a 15-fold space–time yield improvement tions were carried out by flowing iPrCl/amine, 1:1 dissolved in
(
Table 3).
THF/toluene, 1:1 at a 0.5 mL/min flow rate and 80 °C. Toluene
was required to solubilize the magnesium amide species.
During the process, propane was generated, but no overpres-
sure was observed. The flammable gas was released after the
BPR, together with the R2NMgCl⋅LiCl solution, in the collec-
tion flask, away from a heat source.
Table 3: Comparison of the batch [58] and flow conditions for the syn-
thesis of iPrMgCl⋅LiCl.
iPrMgCl⋅LiCl
batch flow
mmol of 2-chloropropane
100
0.92
12
100
2.50
1.50
2.10a
100
50
System scope: Bis(trimethylsilyl)amine (HMDS), dipheny-
lamine (Ph2NH), aniline (PhNH2), and 2,2,6,6-tetramethylpi-
peridine (TMPH) were selected as substrates. Ph2NH, HMDS,
and PhNH2 due to their lower pKa (25, 30, and 31, respectively,
in DMSO) [59] and TMPH due to its broad application in syn-
thesis (Knochel–Hauser base, pKa = 37 in DMSO) [47,59-69].
Excellent yields were obtained: HMDSMgCl⋅LiCl 1.15 M
[
2-chloropropane] (M)
t (h)
iPrMgCl⋅LiCl] (M)
[
0.89
100
7
conversion of 2-chloropropane (%)
throughput (mmol⋅h−1)
normalized space–time yieldb
1
15
aPropene and 2,3-dimethylbutane as side products. bSpace–time yield
mmol⋅mL−1⋅h−1): batch: 0.065, flow: 0.980.
(
(
98%), Ph2NMgCl⋅LiCl 1.16 M (97%), and PhNHMgCl⋅LiCl
(
1.15 M, 96%, Table 4, entries 1–3).
For TMPH, a 10 mL coil (20 min residence time tR) was added
due to the slower reaction rate, and the iPrCl amount was opti-
mized to 1.2 equivalents (Scheme 1). Even if the addition of a
coil increased the residence time for the TMPMgCl⋅LiCl syn-
4
Knochel–Hauser bases via stratified
packed-bed columns containing magnesium
and LiCl
Objective: To generate amidomagnesium lithium chloride com- thesis up to 25 min, our flow setup was 9 times faster than the
plexes (Knochel–Hauser bases) from turbo Grignard formed in batch version, which usually takes 24 h at room temperature
situ and the corresponding amine using stratified bicomponent [47,67]. The reaction was carried out by flowing iPrCl/TMPH,
packed-bed columns composed of magnesium metal and lithi- 1.2:1 dissolved in THF/toluene, 1:1 at a 0.5 mL/min flow rate
um chloride.
and 80 °C.
Scheme 1: Continuous flow synthesis of TMPMgCl⋅LiCl with a stratified packed-bed column of activated magnesium and lithium chloride.
1350

Beilstein J. Org. Chem. 2020, 16, 1343–1356.
Table 4: Reaction between amines and isopropylmagnesium chloride
generated in situ. Knochel–Hauser bases synthesis using a stratified
packed-bed column of activated magnesium and lithium chloride.a
Table 5: Comparison between batch [47,67] and flow conditions for
the synthesis of (TMPMgCl⋅LiCl).
TMPMgCl⋅LiCl
batch
flow
mmol of 2-chloropropane
100
1.20
1.05
36
100
1.20
1.00
4
[
2-chloropropane] (M)
TMPH] (M)
[
entry
R2NH
[RX] (M)
[R2NMgX⋅ yield (%)
t (h)
TMPMgCl⋅LiCl] (M)
LiCL] (M)
[
1.03
2
0.97
22
1
2
3
HMDS
Ph2NH
PhNH2
1.2
1.2
1.2
1.17
1.16
1.15
98
97
96
throughput (mmol⋅h−1)
normalized space–time yielda
1
10
aSpace–time yield (mmol⋅mL−1⋅h−1): batch: 0.016, flow: 0.160.
aA 2-chloropropane (1 equiv) and amine (1 equiv) THF/toluene, 1:1
solution (1.2 M, 30 mL) was pumped at a 0.5 mL/min flow rate and
80 °C through a column (ID = 10 mm) of activated Mg* (2 equiv) chips/
powder, 1:1 and anhydrous LiCl (2 equiv) separated with fiberglass.
bQuantitative RX conversion. cDetermined by the titration of an overall
R2MgCl·LiCl solution (≈25 mL) collected in the steady state.
We also found that LiBr could be used. The reaction was
carried out under the same conditions. The high solubility of
LiBr provided solutions that remained clear for days
As a drawback, we observed LiCl precipitation in the flask ≈2 h (TMPMgCl⋅LiBr 0.84 M, 84%, Scheme 2).
after collection. A clear solution can be recovered by filtration
5
Alkoxide bases via stratified packed-bed
through dried fiberglass using a cannula without a drastic con-
centration decrease. The same reaction was done in batch using columns containing magnesium and LiCl
turbo Grignard generated in flow, and the same result was ob- Objective: To generate magnesium alkoxide–lithium chloride
served, proving that LiCl is coming from iPrMgCl⋅LiCl. The complexes by telescoped reactions of turbo Grignards with tert-
analysis of the precipitate by NMR and GC–MS, after being amyl alcohol using stratified bicomponent packed-bed columns
washed with pentane at 0 °C and dried under vacuum, showed composed of magnesium metal and lithium chloride, a T-mixer,
no evidence of organic compounds. It seemed that and a coil reactor.
TMPMgCl⋅LiCl coordinated less LiCl than the corresponding
iPrMgCl⋅LiCl and triggered LiCl crystallization. To solve this Challenges: Alcohol incompatibility with the activating solu-
issue, the packed-bed column temperature was decrease from tion and alkoxide solubility.
8
0 °C to 40 °C to reduce the amount of LiCl dissolved in the
iPrMgCl⋅LiCl solution. Under these conditions, we were able to System setup: The same flow system was used as for the gen-
obtain TMPMgCl⋅LiCl 0.97 M (97%) as a solution (≈40 mL) eration of turbo Grignard reagents. Extra feed was added be-
that remained clear for much longer (Scheme 1). We suggest to tween the packed-bed column and the coil (V = 10 mL, ID =
directly react the TMPMgCl⋅LiCl solution in flow or to tele- 0.03″) for the tert-amyl alcohol addition (Figure S4, Supporting
scope the reagent in batch with the next step. The Information File 1).
Knochel–Hauser base was also scaled up to ≈100 mmol using a
1
5 mm ID column. Using our flow procedure, a similar Finally, we explored the formation of sterically hindered
TMPMgCl⋅LiCl concentration (≈1.0 M) compared to the oxygen bases by a direct alcohol deprotonation. Knochel-type
Knochel protocol was obtained [47,67], but the reaction time tert-amyl magnesium alkoxide (t-AmylOMgCl⋅LiCl) 1.0 M
was reduced from 36 h to 4 h, providing a 10-fold increment in (95%) was obtained (≈15 mL) by the reaction of the corre-
throughput and space–time yield (Table 5).
sponding alcohol (1.0 equiv) and turbo Grignard (1.2 equiv)
Scheme 2: Continuous flow synthesis of TMPMgCl⋅LiBr with a stratified packed-bed column of activated magnesium and lithium bromide.
1351

Beilstein J. Org. Chem. 2020, 16, 1343–1356.
Scheme 3: Continuous flow synthesis of t-AmylOMgCl⋅LiCl with a stratified packed-bed column of activated magnesium and lithium chloride.
under flow conditions at 25 °C (Scheme 3). For in duplicates using 2-hydroxybenzaldehyde phenylhydrazone.
t-AmylOMgCl⋅LiCl, the concentration was determined using a
mixture of benzoic acid and thymolphthalein as an indicator The results demonstrated a continuous and stable generation of
[
70].
iPrMgCl⋅LiCl (≈100 mmol) in the steady state under similar
ODR prototype conditions. A certain volume of the starting ma-
terial solution (6 mL) was discarded to prevent the dilution of
6
On-demand reagent proof of concept
Objective: To reiterate the turbo Grignard and Knochel–Hauser iPrMgCl⋅LiCl at the beginning and at the end of the experiment
base synthesis on the ODR prototype.
due to solvent diffusion. We stipulate that these results illus-
trate that our system provides a high-quality material for the
Challenges: The changes in the reactor material from reusable discovery-scale needs. This approach is not suitable for a large
glass to disposable perfluorinated columns and the modifica- scale and is not designed to be scaled. The goal is to aid
tion in the bicomponent (Mg/LiCl) configuration from a single discovery efforts to increase the reagent reliability.
stratified column to two separated monocomponent columns.
The synthesis of ≈10 mL turbo Grignard, iPrMgCl⋅LiCl, and
System setup: The internal diameter of the perfluorinated ≈10 mL of the Knochel–Hauser base derived from HMDS,
tubular reactor used on the ODR prototype was limited to 6.3 HMDSMgCl⋅LiCl, was reiterated on the ODR prototype. Simi-
mm to maintain an efficient heat transfer. Due to this ID limita- larly, an iPrMgCl⋅LiCl yield of 86% was obtained (Scheme 4)
tion and the heater dimensions, we decided to separate Mg and using the optimized conditions established on a commercial
LiCl in two tubular reactors.
flow system with a single reusable bicomponent glass column
Table 2, entry 2) and with two separated disposable monocom-
(
First, the concentration stability in the steady state and the scal- ponent columns (Figure 6). The cartridge is composed of three
ability up to ≈100 mmol was verified using two perfluorinated solution bags (THF, the activating solution, and the iPrCl solu-
tubular reactors of 9.5 mm (ID) on the Vapourtec flow system. tion) and two tubular reactors (Mg chips/powder and LiCl)
The first column containing Mg was heated at 80 °C, using a connected in-series (Figure S5, Supporting Information File 1).
temperature-controlled glass manifold [51]. The LiCl column
was kept at 25 °C. The concentration was followed over time For HMDSMgCl⋅LiCl, the same cartridge configuration was
during the conversion of 2-chloropropane in THF (56 mL, 2.2 used (Figure S5, Supporting Information File 1), and a slightly
M) into iPrMgCl·LiCl (50 mL, 1.91 M, Figure 6). Ten samples lower yield (83%) was obtained (Scheme 5) compared to the
of 5 mL were collected, and the concentration was determined reaction done on the Vapourtec flow system (Table 4, entry 1).
Scheme 4: Synthesis of iPrMgCl⋅LiCl on the ODR prototype.
1352

Beilstein J. Org. Chem. 2020, 16, 1343–1356.
Figure 6: Steady-state concentration stability during the conversion of iPrCl in THF (56 mL, 2.2 M) into iPrMgCl·LiCl (50 mL, 1.91 M) using two perflu-
orinated disposable monocomponent tubular reactors.
Scheme 5: Synthesis of HMDSMgCl⋅LiCl on the ODR prototype.
This variation was attribute to the unsteady flow rate produced moisture-free setup makes it possible to directly use the hygro-
by propane released during the reaction, and thus affecting the scopic LiCl in a solid form. The back-pressure control allows a
fluid dynamics and the back-pressure control.
high-temperature oxidative addition reaction and enables the
quantitative conversion of less reactive but more cost-effective
The product purities, a quantitative iPrCl conversion, and the alkyl chlorides. Furthermore, a low-cost pod-style synthesizer
yields were confirmed by NMR (Section 5, Supporting Infor- prototype has been designed and built. The reagents were
mation File 1), demonstrating the ODR prototype ability to prepacked in disposable perfluorinated assemblies–bags,
safely produce high-quality organomagnesium reagents on cartridges, and tubings–sealed together using a new thermal
demand.
bonding method. This on-demand concept was demonstrated by
preparing the turbo Grignard reagent and the Knochel–Hauser
base (optimized on a commercial flow system). We predict that
Conclusion
We have developed a new flow setup for the on-demand synthe- with small modifications, this system could be configured to
sis of highly concentrated (≈2 M) turbo Grignards from alkyl produce many different reagents. Our group is currently
chlorides using a stratified packed-bed column of activated working on an organolithium version of this on-demand reagent
magnesium and lithium chloride. The volumes we can produce approach.
reliably are suitable for the target discovery scale audience. The
magnesium activation in a packed-bed column is safer and Experimental
faster in comparison to batch protocols. LiCl enhances the solu- Turbo Grignard: isopropylmagnesium chloride–lithium
bility and reactivity of organomagnesium compounds, and our chloride complex (iPrMgCl⋅LiCl): 2-Chloropropane (2.975 g,
1353

Beilstein J. Org. Chem. 2020, 16, 1343–1356.
3
.46 mL, 37.5 mmol, 1 equiv) was dissolved in THF (11.5 mL) organic-halide solution was flowed through a column (ID =
in a flask under argon. A 2.5 M organic-halide solution was 10 mm, length = 100 mm) of activated magnesium (chips/
flowed through a column (ID = 10 mm, length = 100 mm) of powder, 1:1, w/w, 1.49 g, 60 mmol, 2.4 equiv) and lithium chlo-
activated magnesium (chips/powder, 1:1, w/w, 1.86 g, 75 mmol, ride (2.57 g, 60 mmol, 2.4 equiv) at 0.5 mL/min, 80 °C, and
2
2
8
equiv) and anhydrous lithium chloride (3.21 g, 75 mmol, 100 psi back pressure. After ≈4 min, the outcome solution was
equiv), with a BPR (100 psi) at a 0.5 mL/min flow rate and at collected in a vial under an inert atmosphere.
0 °C. After ≈4 min, the outcome solution was collected in a
vial under an inert atmosphere containing 2-hydroxybenzalde-
hyde phenylhydrazone (20–40 mg). When the yellow-colored
solution turned orange, the turbo Grignard reagent was
collected in a flask under argon. When the starting material
solution ran out, the organomagnesium collection was main-
tained for 4 min (≈2-fold the residence time), flowing THF at
Supporting Information
All details for the flow procedures and reactors assembly
(full part list, flow system photos, and ODR prototype
protocols) and all experimental data of the chemical
reactions (optimization, packed-bed particle size study, and
concentration determination) and NMR spectra.
0
.5 mL/min, yielding 88% of the isopropylmagnesium
chloride–lithium chloride complex as clear 2.19 M solution
≈10 mL).
(
Supporting Information File 1
Additional experimental data.
Knochel–Hauser base: lithium dichloro(2,2,6,6-tetram-
ethylpiperidinato)magnesate (TMPMgCl⋅LiCl): 2-Chloro-
propane (4.284 mg, 4.99 mL, 54.0 mmol, 1.2 equiv) and
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-115-S1.pdf]
2
4
,2,6,6-tetramethylpiperidine (TMPH, 6.420 g, 7.67 mL,
5.0 mmol, 1.0 equiv) were dissolved in THF (16.2 mL) and Acknowledgements
toluene (16.2 mL) in a flask under argon. The mixed solution of We thank Bernat Moreno (https://www.marroiak.com/) for his
the organic halide (1.2 M) and the amine was flowed through a artwork of Figure 1 comparing on-demand coffee and turbo
column (ID = 10 mm, length = 100 mm) of activated magne- Grignard pod-style machines.
sium (chips/powder, 1:1, w/w, 2.23 g, 90 mmol, 2 equiv) and
lithium chloride (3.85 g, 90 mmol, 2 equiv) at 0.5 mL/min, Funding
4
0 °C, and atmospheric back pressure. After ≈4 min, the We thank the DARPA for financial support (Army W31P4Q-
outcome solution was collected in a vial under an inert atmo- 18-1-0001).
sphere containing 2-hydroxybenzaldehyde phenylhydrazone
(
20–40 mg). When the yellow-colored solution turned orange, ORCID® iDs
the mixture was flowed through the coil at 0.5 mL/min, 80 °C, Mateo Berton - https://orcid.org/0000-0002-9983-3656
and 100 psi back pressure. When the starting material solution
ran out, THF/toluene, 1:1 was pumped at 0.5 mL/min to main- Preprint
tain the mixture flowing. After ≈20 min, the gas released was
observed, and the outcome solution was collected in a vial
under an inert atmosphere containing 2-hydroxybenzaldehyde
A non-peer-reviewed version of this article has been previously published
as a preprint doi:10.3762/bxiv.2020.40.v1
phenylhydrazone (20–40 mg). When the yellow-colored solu- References
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