Reaction Cycling for Kinetic Analysis in Flow

Article abstract of DOI:10.1021/acs.joc.0c00216

A reactor capable of efficiently collecting kinetic data in flow is presented. Conversion over time data is obtained by cycling a discrete reaction slug back and forth between two residence coils, with analysis performed each time the solution is passed between the two. In contrast to a traditional steady-state continuous flow system, which requires upward of 5× the total reaction time to obtain reaction progress data, this design achieves much higher efficiency by collecting all data during a single reaction. In combination with minimal material consumption (reactions performed in 300 μL slugs), this represents an improvement in efficiency for typical kinetic experimentation in batch as well. Application to kinetic analysis of a wide variety of transformations (acylation, S_NAr, silylation, solvolysis, Pd catalyzed C-S cross-coupling and cycloadditions) is demonstrated, highlighting both the versatility of the reactor and the benefits of performing kinetic analysis as a routine part of reaction optimization/development. Extension to the monitoring of multiple reactions simultaneously is also realized by operating the reactor with multiple reaction slugs at the same time.

Full text of DOI:10.1021/acs.joc.0c00216

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Article
Reaction cycling for kinetic analysis in flow
Ryan J Sullivan, and Stephen G. Newman
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00216 • Publication Date (Web): 23 Mar 2020
Downloaded from pubs.acs.org on March 26, 2020
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Ryan J. Sullivan and Stephen G. Newman*
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Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa,
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0 Marie-Curie, Ottawa, Ontario, Canada, K1N 6N5.
ABSTRACT: A reactor capable of efficiently collecting kinetic data in flow is presented. Conversion over time data is obtained by
cycling a discrete reaction slug back-and-forth between two residence coils, with analysis performed each time the solution is passed
between the two. In contrast to a traditional steady state continuous flow system, which requires upwards of 5 × the total reaction
time to obtain reaction progress data, this design achieves much higher efficiency by collecting all data during a single reaction. In
combination with minimal material consumption (reactions performed in 300 μL slugs), this represents an improvement in efficiency
for typical kinetic experimentation in batch as well. Application to kinetic analysis of a wide variety of transformations (acylation,
S Ar, silylation, solvolysis, Pd catalyzed C–S cross-coupling and cycloadditions) is demonstrated, highlighting both the versatility
N
of the reactor and the benefits of performing kinetic analysis as a routine part of reaction optimization/development. Extension to the
monitoring of multiple reactions simultaneously is also realized by operating the reactor with multiple reaction slugs at the same time.
an inability to unambiguously discriminate between potential
reaction mechanisms without relying on chemical intuition.
INTRODUCTION
Measuring reaction kinetics is a powerful tool for enabling
1
optimization, mechanistic investigation, and scale-up. Despite
this, collection of kinetic data is often overlooked in lieu of less
rigorous methods due to the laborious experimentation
required. Recent advances in hardware, such as sampling tools
and programmable liquid handling robotics, have sought to
A. Traditional kinetics in batch
n data points = 1 expt
limited ability to automate
2
alleviate this problem. Mathematically simpler approaches to
analyzing data, such as the visual variable time normalization
method, have also been successful in reducing the barrier to
B. Traditional kinetics in flow
C. This work: Cycling a
3
expt. 1
analysis
studying kinetics in routine applications.
reaction slug
Continuous flow systems offer numerous advantages over
batch systems such as ease of automation, incorporation of
online analytics, efficient mixing, and access to a larger range
expt. 2
expt. 3
cycle 1
cycle 2
cycle 3
4
analysis
of temperatures and pressures. Knowledge of the reaction
n data points = n expts
ease of automation
and analysis
n data points = 1 expt
efficiency of batch and
benfits of flow
kinetics is crucial for optimizing residence time and reagent
concentration to maximize throughput. However, acquiring
kinetic data is often considered an area where batch reactors are
5
superior due to convenient sampling over time (Figure 1A). In
Figure 1. (A) Generation of reaction profiles in batch is
accomplished by aliquot sampling over time. (B) Generation of
reaction profiles in flow is accomplished by running a new steady-
state experiment for each data point. (C) This work: A flow reactor
capable of analyzing progress over time by cycling a reaction slug.
contrast, time and space are coupled in a typical flow reactor,
where a reaction’s residence time is a function of the flow rate
and distance travelled. Sampling over time must thus be carried
out as a sequence of experiments with varied flow rate (Figure
6
1
B). While effective, this approach is wasteful of both time and
Given the growing number, diversity, and utility of advanced
materials. To highlight this disadvantage, Blackmond and co-
workers monitored the progress of an aldol reaction that
8
flow systems and the expanding scope of reactions that can be
9
5
performed equally well or better when run in flow, we believed
required 40 minutes to reach completion. Due to the need to
development of a simple and reliable method to obtain kinetic
data from continuous systems would be invaluable. Flow
reactors have proven particularly useful in the automated
recovery and recycling of reaction components such as catalysts
adjust flow rates and wait for steady state before collection of
each data point, a 5-fold increase in total reaction time and
material consumption was required for flow compared to batch.
Solutions to this problem have so far focused on using
stepped or gradient flow rates and model fitting software to
1
0
or auxiliaries through the implementation of recycling loops.
With this inspiration, we envisioned cycling an entire reaction
7
circumvent the need to collect steady-state samples. However
1
1
solution by performing the reaction in discrete slugs pushed
by an inert, immiscible carrier fluid (Figure 1C). Analyzing the
reaction once every loop provides reaction progress data.
these are limited by the complicated mathematics required, and
applications have thus far been restricted to relatively simple
reactions. Furthermore, these methods sometimes suffer from
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Herein, we describe the design and implementation of such a
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reactor that enables straightforward acquisition of kinetic data.
The versatility of this system is demonstrated through the study
of a range of reaction types using varied solvents, temperatures,
and kinetic analysis methods. The value of routinely performing
kinetic analysis is additionally highlighted in the observation of
non-intuitive rate behaviour for seemingly simple
transformations. The setup is assembled from commercially
available components, and data quality was comparable or
superior to batch sampling. We thus believe that flow kinetics
via reaction cycling will be useful for both routine analysis and
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as a component in more complex automation platforms.
RESULTS AND DISCUSSION
Cycling a reaction slug through a reactor requires an inlet and
outlet for the carrier stream to continuously enter and exit while
somehow retaining the slug. In order to provide these essential
features, we focused on developing a valve arrangement that
facilitated cycling the slug along a looping figure eight path.
This was accomplished by repurposing a commercially
available 6-port, two-way injection valve and an 11-port, 10-
Figure 2. A schematic of the reactor coils and valves used to cycle
a single reaction slug through a sampling valve multiple times,
facilitating sequential sampling for reaction progress monitoring.
1
3
position selector valve by altering the fluid connectivity at the
port connections and designing a custom rotor for the selector
valve (see Figure S1 in the supporting information for full
With the ability to cycle an inert slug confirmed, we next
turned to the room-temperature acylation reaction between
benzoyl chloride (1) and benzyl alcohol (2) as a well understood
transformation to determine if reactions performed in the
cycling flow reactor exhibited the same kinetic behaviour as
14
details). The modifications necessary are inexpensive and
easy to implement. The principle of operation is that when the
reaction slug is in coil A it is directed to coil B and when in coil
B it is directed back to coil A (Figure 2). Each time the slug is
passed back and forth between the two reaction coils it travels
through an intermediate zone where analysis is performed.
While a range of online analysis tools can be envisioned,15 we
elected to use a sampling valve that removes a small aliquot for
off-line analysis, keeping the system cost and complexity low.
under typical batch conditions. We selected Bu
3
N (3) as the
2
9e
organic base to avoid solid handling issues,
N as the inert
18
carrier stream to move the reaction slug through the reactor,
and the method of variable time normalization analysis
3
(
VTNA) to analyze the data (Figure 3). In addition to
performing experiments with the cycling flow reactor, all
experiments were repeated using a traditional batch set-up (i.e.,
a round-bottom flask) for validation of the results obtained.
While small droplets have been widely used as reaction slugs
1
1
in automated screening and optimization platforms, we used
large slugs (>50 cm in length) to avoid problems with rate
Identical results were observed in both cases, finding first
order behaviour for both 1 (Figure 3A) and 2 (Figure 3B) and a
partial reaction order of ~0.5 for 3 (Figure 3C). Related tertiary
amine mediated acylation reactions are known to proceed by a
1
1a
acceleration occurring at droplet/carrier stream interfaces and
reaction solvent/reagent bleed/carryover into the carrier stream
16
or subsequent slugs. The immiscible carrier stream used can
be either gaseous (e.g., N ) or liquid (e.g., aqueous, fluorous,
etc.) depending on the desired application; we demonstrate both
options using N and water respectively as carrier streams in
19
nucleophilic catalysed mechanism, and the positive reaction
2
order observed for 3 agrees with this, although the partial order
suggests a complex mechanism may be operative. By
normalizing to all reaction components, a straight line is
obtained with a slope equal to the rate constant (Figure 3D).
Replication of experiments in batch showed indistinguishable
kinetic profiles (e.g. Figure 3E) and found a value for the rate
constant in excellent agreement with the value found using the
cycling flow reactor (2% difference), confirming the validity
and transferability of the collected data.
2
different examples. The residence coils and remaining reactor
materials can be selected for compatibility with the chemistry
and conditions of interest; we opted for 0.5 mm ID PFA tubing
for simplicity and optical transparency.
The ability to cycle slugs of solvent using the reactor was first
examined. Solvent slugs with varying viscosity (H
toluene, CHCl ) could be cycled using N as the carrier stream
without slug break up to provide a range of sampling intervals
~1.5–10 min between sample collections) over various
2
O, EtOH,
3
2
(
temperatures (0–90 °C or ~5 °C below the atmospheric solvent
boiling point of solvent). Above a certain limit, excessively high
flow rates resulted in slug break up due to excessive shear forces
with the reactor walls, but the accessible sampling intervals
were more than sufficient to study the kinetics for the majority
1
7
2
of reactions. When using H O as the carrier stream,
temperatures above solvent atmospheric boiling points could be
used in combination with the application of system back
pressure.
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Satisfied that the reactor operated as desired, we next
O
O
1
2
3
+
explored the ability to rapidly obtain kinetic data for a variety
HO
Ph
Ph
Cl
Ph
O
4
Ph
of reactions (Table 1). An S Ar reaction at 80 °C (entry 1) and
Bu N (3)
N
3
1
2
toluene, r.t.
a silylation at 0 °C (entry 2) were examined to assess the reactor
performance over a range of temperatures. The cycling flow
reactor performed well in both cases, yielding identical reaction
profiles with equivalent or slightly superior data quality (less
noise) compared to parallel experiments in batch. The
solvolysis of a secondary alkyl halide was probed using a
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A
B
C
0
0
0
0
.4
.3
.2
.1
0
0
.5 M 1
0.5 M 2
1.0 M 2
0.6 M 3
1.0 M 3
1.0 M 1
pseudo-first order approach to distinguish between an S
N
1 or
0
5

10
0
5
10
0
10
20
[3]1/2t
S 2 mechanism, as well as demonstrate the ability to perform
N
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[1] t
1
[2] t
1
an Eyring analysis by varying the reaction temperature (entry
3). A Pd catalysed C–S cross-coupling reaction was examined
using the method of initial rates to show the applicability
towards air- and moisture-sensitive chemistry and complex,
multi-step reaction mechanisms (entry 4). Lastly, the ability to
perform all necessary reactions simultaneously as consecutive
slugs to maximize data collection efficiency was demonstrated
with the analysis of a Diels-Alder cycloaddition (entry 5). The
D
E
y = 0.00667x
= 0.994
0.4
standard
0.4
0.2
0
2
R
excess 1
excess 2
excess 3
0
0
0
.3
.2
.1
0
flow
obs = 6.67 10–3 L3/2mol–3/2s–1
k
batch
t
0
25
50
75
0
(2 m0 in 40
2 2
carrier fluid was also changed from N to H O for this example
to demonstrate the flexibility in choice of carrier solvent and the
ability to conduct experiments above the atmospheric boiling
[1] [2] [3]1/2t
1
1
)
3
point of the solvent (CHCl ).
Figure 3. Kinetic data obtained using the cycling flow reactor. (A)
VTNA plot showing 1 order in 1. (B) VTNA plot showing 1
order in 2. (C) VTNA plot showing ~0.5 order in 3. (D) VTNA plot
to calculate rate constant. (E) Overlay of data collected using flow
reactor and batch data. Standard conditions: 0.5 M 1, 0.5 M 2, 0.6
M 3 in toluene, room temperature.
st
st
Table 1. Reactions investigated using the cycling flow reactor
Entry
Reaction
Analysis
method
Demonstrating
Rate equation
found
O
F
N
Elevated
rate = [5][6]
+ HN
O
1
VTNA
VTNA
O N
2
DBU (7)
MeCN, 80 ºC
temperature
0th order in 7
O N
2
5
6
8
I
I
TBS
TBSCl
+
k[9][10][11]2
OH
O
Lowered
2
3
Bu N (3)
BuIm (11)
DCM, 0 ºC
rate =
3
temperature
[3]
9
10
12
16
Br
OEt
N N
Distinguish S 1/S 2;
rate = k[13][14]
0th order in 15
pseudo-
first order
Temperature
variation
EtOH (14)
TosOH (15), 
13
(Eyring analysis)
t
I
S Bu
rate = k[18][17] [3]y
x
O
2
/H O free
2
+ tBuSH
method of
initial
rates
OTBS
OTBS
19
reaction;
0
< x,y < 1
4
5
Pd/t-BuXPhos (18)
Complex
0th order in 12
12
17
Bu N (3)
3
mechanism
THF, r.t.
saturation kinetics
Simultaneous
reactions;
OMe
+
CO Me
2
VTNA
Exceeding solvent
b.p.;
rate = [20][21]
O
CHCl3
70 ºC
2
0
21
22
2
H O carrier phase
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N
Ar reaction at elevated
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The observed rate equation for the S
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temperature was as expected, with first order behaviour
observed for both electrophile 5 and nucleophile 6, and 0 order
Table 2. kobs values for the ethanolysis of 13.a
th
for base 7. Data obtained with the cycling flow reactor was in
excellent agreement with the parallel data collected in batch,
confirming that the choice of large slugs prevented appreciable
loss of solvent to the gaseous carrier phase even when operating
just below the atmospheric boiling point of the solvent.
Investigating the silylation of alcohol 10 at lowered temperature
provided further support that the kinetics obtained using the
cycling flow reactor provide an accurate representation of the
chemistry, with excellent agreement between the flow
generated- and parallel batch generated-data.
Entry
[15] (M)
0.125
[14] (M)
k
obs
1
2
3
4
16.0
0.0542
0.0599
0.0484
0.0384
0.0250
0.125
16.0
14.5b
12.7c
0.125
a
b
c
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All reactions 0.5 M in 13. 10:1 EtOH:t-BuOH as solvent. 4:1
EtOH:t-BuOH as solvent.
In addition, a non-intuitive second order behaviour for the
nucleophilic catalyst 11 and negative order with respect to base
3 were observed. This behavior contrasts with previous studies
of the TBS protection of naphthalen-1-ylmethanol using DMAP
To demonstrate the applicability of our reactor towards O
2
and
2
H O sensitive chemistries and complex reaction
mechanisms, a palladium catalysed C–S cross-coupling
recently reported by Buchwald and co-workers was
investigated. First order behaviour was found for catalyst 18
(Figure 5A) and zeroth order for aryl halide 12 (Figure 5B),
2
2
or 1-methylimidazole as nucleophilic catalysts and Et
3
N as the
2
0
base. In these cases first order in catalyst and no inhibitory
effect of base was observed, highlighting the value of
performing routine kinetic experiments even when changing
substrates.
II
consistent with the previously identified LPd ArX resting
2
2
state, by using the method of initial rates. The reaction orders
for thiol 17 and base 3 proved to be more complex, yielding
curving log-log plots of initial rate vs. concentration (Figure 5C
and D). Both 17 and 3 exhibited saturation kinetics and
For the solvolysis of alkyl bromide 13, selected to
demonstrate the ability to distinguish between potential reaction
mechanisms and determine activation parameters in flow, an
Michaelis-Menten plots of the data fit well yielding vmax and K
M
values for each reagent (Figure 5E and F). These data are
consistent with a rate determining step of either deprotonation
of the palladium bound thiol intermediate III or reductive
elimination of the product from intermediate IV (see Figure 6).
Subsequent DFT calculations concluded that reductive
elimination is the rate limiting step (Figures S23–S25 in the
supporting information). Not only was it possible to obtain high
quality data for this air- and moisture-sensitive reaction using
the cycling flow reactor, it was operationally simpler compared
to the analogous batch experiment that would require sampling
from a flask kept under inert atmosphere.
N
S 2 mechanism was found to be operative. First order
behaviour for 13 was found using integrated rate laws under
pseudo-first order conditions, to demonstrate the applicability
of the reactor for other methods of kinetic analysis (Figure 4A).
First order behaviour in EtOH (14) and zeroth order in acid 15
were determined by examining the effect of changing
concentration on the observed rate constant (Table 2).
Observing the effect of changing temperature on the rate
constant allowed activation parameters to be calculated. An
Eyring analysis of the data (Figure 4B, k = kobs/[EtOH]) yielded
values for the enthalpy (18.9 kcal/mol) and entropy (–15.2
cal/(mol·K)) of activation that were also consistent with an S
mechanism.
N
2
While experiments discussed thus far featured single reaction
slugs cycled and analyzed over time, the ability to perform
multiple reactions simultaneously, and therefore generate all
data necessary for kinetic analysis at the same time, was
envisioned. This is especially appealing for slow reactions,
where the time required to collect all data is particularly tedious.
The Diels-Alder reaction between cyclopentadiene (20) and
methyl acrylate (21) required ~3 h to reach >80% conversion at
21
Br
OEt
EtOH (14)
TosOH (15), 
Ph
Ph
13
16
A
B
-4
7
0 °C, making it an ideal candidate to demonstrate this ability.
-1
-2
-3
-9
14
19
-
-
The volume of the residence coils was increased and the three
necessary reactions (i.e., “standard conditions”, and excess in
each reagent) were injected as sequential slugs in a way that
allowed the flow path to be altered each time all slugs were in
the same residence coil (Figure 7). The carrier phase was also
changed from N to water to allow the reaction to be conducted
above the boiling point of the solvent through application of
backpressure, highlighting another benefit of using a flow
reactor over a batch setup. In this way, all necessary data for
kinetic analysis was collected in ~3 h, as opposed to the ~9 h
that would have been required if running each reaction
consecutively with this flow reactor, or the ~60 h that would be
required to collect equivalent data using the traditional steady-
state approach of changing the flow rate to change residence
time for each data point.
-24
29 H = 18.9 kcal·mol–1
‡
-
-
34 S‡ = –15.2 cal·mol–1·K–1
-39
23
0
10
20
t (min)
30
40
0.0028
0.003
0.0032
–1
1/T (K
)
2
Figure 4. (A) Linear integrated rate law plot showing first order in
electrophile 13. (B) Eyring plot. Standard conditions: 0.5 M 13,
24
0
.125 M 15 in EtOH, 70 °C.
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Pd/t-BuXPhos (18)
OMe
CHCl3
70 ºC
1
2
3
4
5
6
7
8
9
Bu N (3)
+
CO Me
2
3
t
I
tBuSH
S Bu
+
O
Ar
12
THF, r.t.
Ar
17
19
20
21
22
A
C
E
-1
-2
B
D
F
0
-1
-2
0
.4
.3
-
3
4
0
0.2
0.1
0
-3
-
standard
excess 20
excess 21
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
-8
-7
ln[18]
-6
-5
-4
-3
ln[12]
-2
-1
0
500 1000
-1
-
1
2
1
1

[20] [21] 
t
-
-2
-3
-3
Figure 7. Operating with multiple sequential reaction slugs allows
-5
-4
-3
ln[17]
-2
-1
-5
-4
ln[3]
-3
-2
monitoring of multiple reactions simultaneously.
While the system has some limitations, in e.g., handling
multi-phasic or extremely fast reactions, the ability to
efficiently collect reaction progress data in flow, and
applicability to a wide range of reactions and conditions holds
promise for wide applicability.
0
.02
.01
0
0.015
.01
0
0
0.005
CONCLUSION
0
0
0.1
[3] (M)
0
0.1
0.2
0.3
We have developed a reactor that allows reaction progress to
be monitored over time from a continuously cycling reaction
slug. The reactor performance was assessed over a wide range
of temperatures (0–80 °C), solvents (toluene, MeCN, DCM,
[
17] (M)
Figure 5. Initial rate kinetics for C–S cross coupling of ArI 12 and
thiol 17 catalysed by a Pd/t-BuXPhos system. (A) log-log plot of
initial rate vs. [18], (B) log-log plot of initial rate vs. [12], (C) log-
log plot of initial rate vs. [17], (D) log-log plot of initial rate vs. [3],
E) Michaelis-Menten plot of initial rate vs. [17], (F) Michaelis-
Menten plot of initial rate vs. [3]. Standard conditions: 50 mM 12,
3 N
EtOH, THF, CHCl ) and reactions (acylation, S Ar, silylation,
ethanolysis, C–S cross-coupling, Diels-Alder). The ability to
use the reactor to distinguish between potential reaction
mechanisms and determine activation parameters was
demonstrated. Lastly, the ability to perform multiple reactions
simultaneously as consecutive reaction slugs was shown with
the kinetic analysis of a Diels-Alder reaction.
(
7
5 mM 17, 100 mM 3, 3 mM 18 in THF, room temperature.
t
Ar S Bu
LPd0
ArI
The application of the reactor to collect data for a variety of
different methods of kinetic analysis was also demonstrated,
including variable time normalization analysis, pseudo-first
order kinetics, Eyring plots and the method of initial rates. We
believe the development of this reactor marks the first true
equivalent in flow to the generation of reaction progress data in
batch, where analysis over time from a single reaction solution
is the most efficient strategy with regards to both time and
material consumption. Therefore, since this reactor combines
both the efficiency of the traditional batch sampling strategy
with the benefits of flow, we believe this platform will lower
the impediment to routine kinetic analysis, through both stand-
alone operation and in combination with reaction platforms to
automate kinetic experiments and data generation.
(
19)
(12)
I
Ar
Ar
L PdII S Bu
t
L PdII
I
IV
II
Ar
t
H
S Bu
(17)
Bu N•HI
3
L PdII
I
t
H
S Bu
Bu N
3
(
3)
III
Figure 6. Putative catalytic cycle for the Pd catalysed C–S bond
formation. L = t-BuXPhos, ArI = 12.
EXPERIMENTAL
General experimental details. Benzoyl chloride (1), benzyl
alcohol (2), Bu N (3), TBSCl (9), cyclopentadiene (20) and
3
methyl acrylate (21) were distilled before use. All other
chemicals were obtained from commercial sources and used as
received. THF was degassed with Ar and passed through a
PureSolv solvent purification system before use. Solutions for
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 13
thiol cross-coupling reactions were prepared in oven-dried
glassware under an Ar atmosphere.
The N flow was set to 3 mL/min for 2 min (to quickly
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
establish pressure equilibration with the back pressure) then set
to 0.8 mL/min. Valve 1 was set to position 1, valve 2 was set to
position 1 (see Figure S1 in the supporting information) and the
sampling valve was set to collect a sample. The 2-way valve
NMR spectra were collected on a Bruker Avance 400 MHz
1
13
spectrometer. H and C were referenced to residual solvent
signals. GC yields for all kinetic studies were obtained via 5 or
6-point calibration curves using FID analysis on an Agilent
Technologies 7890B GC with 30 m × 0.25 mm HP-5 column.
For all reactions analyzed using VTNA or the method of initial
rates the concentration of the product was determined by GC
and the remaining reagent concentrations were calculated
through mass balance assertion (i.e., stoichiometry). For the
ethanolysis reaction the concentration of starting material (1-
bromoethylbenzene) was monitored. For quantification of the
C–S cross-coupling product 22, the GC response factor (i.e.,
calibration curve slope) was determined by quantifying the
disappearance of aryl iodide 12 and monitoring the appearance
of the product peak for a reaction where conversion of 12 was
taken to completion. For calculation of the unreacted
cyclopentadiene concentration, both the methyl 5-norbornen-2-
carboxylate product and the dicyclopentadiene by-product were
quantified and taken into account.
2
was closed (to interrupt the N flow) and 0.15 mL of each
solution was dispensed by the syringe pump at a rate of 1.5
mL/min to form a 0.30 mL the reaction slug (~5 s). The 2-way
valve was opened to let the reaction slug travel through coil A
to valve 2 to the sampling valve.
Once ~50 μL of the slug passed through the sampling valve,
the valve was actuated and a 15 μL aliquot sample was eluted
with 600 μL EtOAc into a GC vial containing 100 μL MeOH to
quench. Once the remainder of the reaction slug had exited the
sampling valve and fully passed through valve 1 to coil B, valve
1 was set to position 2, valve 2 was set to position 2 (clockwise
rotation) and the sampling valve was set to collect a sample
again.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Notes: 1) Valve 1 is actuated before valve 2 to maintain N
2
pressure behind the reaction slug. If valves are actuated in
reverse order, pressure is released behind the reaction slug
causing interruptions to the flow. 2) The sampling valve is
actuated at this time to empty the sample loop before the
reaction slug returns to the valve and prevent
contamination/dilution of the reaction slug with the solvent
used to flush the sample loop by sending the contents of the
sample loop through the other reactor coil to waste.
Benzyl benzoate (4). To a solution of benzoyl chloride (0.56
g, 4.0 mmol) in toluene (5 mL) was added benzyl alcohol (0.47
g, 4.4 mmol) and Et
0 °C. The resulting suspension was then washed with 1 M HCl
5 mL) and the organic phase dried over Na SO . Evaporation
3
N (0.44 g, 4.4 mmol) and stirred 15 min at
4
(
2
4
of the solvent and purification on silica gel (25  100 mm,
hexanes→5% EtOAc in hexanes eluent) yielded the pure
product as a colourless oil. Yield 0.57 g (67%). Characterization
The reaction slug travelled through coil B, passing through
valve 2 to the sampling valve. As with the first sample, once the
first ~50 μL of the reaction slug had passed through the
sampling valve it was actuated to collect the second sample
which was quenched into a new GC vial in the same manner as
the first sample. Again, after the reaction slug had fully passed
though the sampling valve and valve 1, the valves were
actuated: valve 1 to position 1, valve 2 to position 1 (counter-
clockwise rotation), and the sampling valve to collect a new
sample.
25
data were in agreement with the literature.
-(4-Nitrophenyl)morpholine (8). The compound was
prepared according to the literature procedure and
4
9e
characterization data were in agreement.
tert-Butyl((2-iodobenzyl)oxy)dimethylsilane (12). 2-
Iodobenzyl alcohol (1.2 g, 5.1 mmol) and TBSCl (0.9 g, 6.0
mmol) were dissolved in 1-methylimidazole (5 mL, 63 mmol)
and stirred 10 min at room temperature then 10 min at 35 °C.
The solution was diluted with 50 mL 2:1 EtOAc:hexanes and
washed with 15 mL 5 M HCl then 2  15 mL 1 M HCl and the
This sequence of sample collection + valve actuation was
repeated to collect subsequent samples. To increase the time
organic phase dried over Na
2
SO
4
. The solvent was evaporated
2
increment between samples, the flow rate of N was decreased
rd
to 0.4 mL/min after the 3 sample was collected and to 0.2
and the residue chromatographed on silica gel (25  100 mm,
hexanes → 5% EtOAc in hexanes eluent) to yield the pure
product as a colourless oil. Yield 1.60 g (90%). Characterization
th
mL/min after the 6 sample was collected. This procedure
allowed the collection of aliquots at approximately 1:45, 4:15,
6:30, 10:15, 14:45, 19:00, 29:30 and 40:45 min (the exact
collection time of each sample was recorded and used for the
subsequent data analysis).
9
e
data were in agreement with the literature.
Methyl 5-norbornene-2-carboxylate (22). Cyclopentadiene
(0.93 mL, 11 mmol) and methyl acrylate (0.90 mL, 10 mmol)
Electrophile solution 1: 1 (116 μL, 1.0 mmol), hexadecane
59 μL, 0.2 mmol) made up to 1.00 mL with toluene.
3
were combined in CHCl (20 mL) and refluxed 4 h. The solvent
(
was evaporated and the residue chromatographed on silica gel
to yield the pure product as a colourless oil in ~3:1 mixture of
isomers. Characterization data were in agreement with the
Electrophile solution 2: 1 (232 μL, 2.0 mmol), hexadecane
(59 μL, 0.2 mmol) made up to 1.00 mL with toluene.
26
literature.
Nucleophile solution 1: 2 (103 μL, 1.0 mmol), 3 (286 μL, 1.2
mmol) made up to 1.00 mL with toluene.
Exemplary procedure: Benzoyl chloride + benzyl alcohol.
General procedure. Solutions of 1 with hexadecane were
prepared in toluene (“electrophile solutions”). Solutions of 2
with 3 were prepared in toluene (“nucleophile solutions”). For
each reaction, 0.5 mL of desired electrophile solution and 0.5
mL of desired nucleophile solution were separately loaded into
two 2.5 mL Hamilton glass syringes, installed onto the Chemxy
fusion 200 dual channel syringe pump and primed, then
connected cross-mixer of the flow reactor (see Figure S2 in the
supporting information).
Nucleophile solution 2: 2 (207 μL, 2.0 mmol), 3 (286 μL, 1.2
mmol) made up to 1.00 mL with toluene.
Nucleophile solution 3: 2 (103 μL, 1.0 mmol), 3 (572 μL, 2.0
mmol) made up to 1.00 mL with toluene.
Reaction 1. Electrophile solution 1 + nucleophile solution 1:
0.5 M 1, 0.5 M 2, 0.6 M 3.
Reaction 2. Electrophile solution 2 + nucleophile solution 1:
.0 M 1, 0.5 M 2, 0.6 M 3.
1
ACS Paragon Plus Environment

Page 7 of 13
The Journal of Organic Chemistry
Reaction 3. Electrophile solution 1 + nucleophile solution 2:
0.5 M 1, 1.0 M 2, 0.6 M 3.
Reaction slugs were formed as in the exemplary procedure
and the initial N flow rate was also the same at 0.8 mL/min.
Valve operation was identical. Samples were manually
collected into GC vials containing 100 μL MeOH for quench
using 600 μL of EtOAc to elute from the sample loop. After the
first three samples had been collected the N flow was set to 0.4
2
mL/min and an additional 5 samples were collected. This
allowed collection of reaction aliquots at approximately 1:40,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
Reaction 4. Electrophile solution 1 + nucleophile solution 3:
.5 M 1, 0.5 M 2, 1.0 M 3.
0
1-Fluoro-4-nitrobenzene
+
morpholine.
General
procedure. Solutions of 5 with hexadecane were prepared in
MeCN (“electrophile solutions”). Solutions of 6 with 7 were
prepared in MeCN (“nucleophile solutions”). For each reaction,
0.5 mL of the desired electrophile solution and 0.5 mL of the
desired nucleophile solution were separately loaded into two
3
:40, 5:50, 9:40, 14:20, 18:40, 23:20 and 27:40 min (the exact
collection time of each sample was recorded and used for the
subsequent data analysis).
2
.5 mL Hamilton glass syringes, installed onto the Chemxy
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Electrophile solution 1: 9 (1.50 g, 10 mmol) and hexadecane
fusion 200 dual channel syringe pump, primed, and connected
to the cross-mixer of the flow reactor. The reactor coils were
submerged in an 80 °C water bath. The valves were not
submerged but placed just above the surface of the water.
(586 μL, 2.0 mmol) was diluted to 10.00 mL with DCM.
Electrophile solution 2: 0.55 mL of electrophile solution 1
and hexadecane (264 μL, 0.09 mmol) was diluted to 10.00 mL
with DCM.
Reaction slugs were formed as in the exemplary procedure
and the initial N
2
flow rate was also the same at 0.8 mL/min.
Nucleophile solution 1: 10 (116 mg, 0.50 mmol), 3 (143 μL,
0.6 mmol), 11 (6.6 μL, 0.050 mmol) made up to 0.50 mL with
DCM.
Valve operation was identical. Samples were manually
collected into GC vials using 600 μL of MeCN to elute from the
sample loop, quenching by dilution and cooling. After the first
Nucleophile solution 2: 10 (117 mg, 0.50 mmol), 3 (143 μL,
2
two samples had been collected the N flow was set to 0.5
0
.6 mmol), 11 (3.3 μL, 0.025 mmol) made up to 0.50 mL with
DCM.
Nucleophile solution 3: 10 (176 mg, 0.75 mmol), 3 (143 μL,
.6 mmol), 11 (6.6 μL, 0.05 mmol) made up to 0.50 mL with
DCM.
Nucleophile solution 4: 10 (117 mg, 0.50 mmol), 3 (238 μL,
.0 mmol), 11 (6.6 μL, 0.05 mmol) made up to 0.50 mL with
DCM.
Reaction 1. Electrophile solution 1 + nucleophile solution 1:
.28 M 9, 0.25 M 10, 0.3 M 3, 0.025 M 11.
mL/min, then after two more samples had been collected N
2
flow was set to 0.2 mL/min and 4 more samples were collected.
This allowed collection of reaction aliquots at approximately
0
1
:20, 3:00, 5:30, 8:15, 16:15, 25:00, 35:00 and 44:00 min (the
exact collection time of each sample was recorded and used for
the subsequent data analysis).
1
Electrophile solution 1: 5 (106 μL, 1.0 mmol), 1,3,5-
trimethoxybenzene (134 mg, 0.8 mmol) made up to 1.00 mL
with MeCN.
0
0
0
0
0
Electrophile solution 2: 5 (212 μL, 2.0 mmol), 1,3,5-
trimethoxybenzene (135 mg, 0.8 mmol) made up to 1.00 mL
with MeCN.
Reaction 2. Electrophile solution 1 + nucleophile solution 2:
.28 M 9, 0.25 M 10, 0.3 M 3, 0.013 M 11.
Reaction 3. Electrophile solution 1 + nucleophile solution 3:
.28 M 9, 0.38 M 10, 0.3 M 3, 0.025 M 11.
Nucleophile solution 1: 6 (87 μL, 1.0 mmol), 7 (150 μL, 1.0
mmol) made up to 1.00 mL with MeCN.
Reaction 4. Electrophile solution 1 + nucleophile solution 4:
.28 M 9, 0.25 M 10, 0.5 M 3, 0.025 M 11.
Nucleophile solution 2: 6 (174 μL, 2.0 mmol), 7 (150 μL, 1.0
mmol) made up to 1.00 mL with MeCN.
Reaction 5. Electrophile solution 2 + nucleophile solution 4:
.5 M 9, 0.25 M 10, 0.5 M 3, 0.025 M 11.
Nucleophile solution 3: 6 (87 μL, 1.0 mmol), 7 (300 μL, 2.0
mmol) made up to 1.00 mL with MeCN.
1
-Bromoethylbenzene + EtOH. General procedure. A 1.0
Reaction 1. Electrophile solution 1 + nucleophile solution 1:
M solution of 13 was prepared in EtOH or EtOH:t-BuOH
mixture (“electrophile solutions”) and loaded into a 2.5 mL
Hamilton glass syringe (no background reaction was observed
at room temperature over several hours). Solutions of 15 in
EtOH or EtOH:t-BuOH mixture were prepared and loaded into
a second 2.5 mL Hamilton glass syringe. The two syringes were
installed onto the Chemxy fusion 200 dual channel syringe
pump, primed, and connected to the cross-mixer of the flow
reactor. The reactor coils were submerged in the water bath at
desired reaction temperature. The valves were placed just above
the surface of the water bath.
0
.5 M 5, 0.5 M 6, 0.5 M 7.
Reaction 2. Electrophile solution 2 + nucleophile solution 1:
1.0 M 5, 0.5 M 6, 0.5 M 7.
Reaction 3. Electrophile solution 1 + nucleophile solution 2:
0.5 M 5, 1.0 M 6, 0.5 M 7.
Reaction 4. Electrophile solution 1 + nucleophile solution 3:
0.5 M 5, 0.5 M 6, 1.0 M 7.
TBSCl and 2-iodobenzyl alcohol. General procedure.
Solutions of 9 with hexadecane were prepared in DCM
(electrophile solutions). Solutions of 10 with 3 and 11 were
prepared in DCM (nucleophile solutions). For each reaction 0.5
mL of desired electrophile solution and 0.5 mL of desired
nucleophile solution were separately loaded into two 2.5 mL
Hamilton glass syringes, installed onto the Chemxy fusion 200
dual channel syringe pump and primed, then connected cross-
mixer of the flow reactor. The reactor coils were submerged in
an 0 °C ice-water bath. The valves were not submerged but
placed just above the surface of the ice bath.
Reaction slugs were formed as in the exemplary procedure.
The initial N flow rate was varied depending on the reaction
2
temperature used and are given below for each reaction
temperature. Valve operation was identical. Samples were
manually collected into GC vials using 600 μL of MeCN to
elute from the sample loop, quenching by dilution and cooling.
Electrophile solution 1: 13 (273 μL, 2.0 mmol), 1,3,5-
trimethoxybenzene (269 mg, 1.6 mmol) made up to 2.00 mL
with EtOH.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Electrophile solution 2: 13 (136 μL, 1.0 mmol), 1,3,5- The reactor was purged with N
Page 8 of 13
at 0.8 mL/min for 1 h before
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
trimethoxybenzene (135 mg, 0.8 mmol) made up to 1.00 mL
with 4:1 EtOH:t-BuOH.
experiments were conducted. For each reaction, 0.5 mL of
desired catalyst solution and 0.5 mL of desired substrate
solution were separately loaded into two 2.5 mL Hamilton glass
syringes, installed onto the Chemxy fusion 200 dual channel
syringe pump, primed, and connected to the cross-mixer of the
flow reactor.
Electrophile solution 3: 13 (136 μL, 1.0 mmol), 1,3,5-
trimethoxybenzene (137 mg, 0.8 mmol) made up to 1.00 mL
with 10:1 EtOH:t-BuOH.
TosOH solution 1: TosOH (95 mg, 0.5 mmol) made up to
2.00 mL with EtOH.
Reaction slugs were formed as in the exemplary procedure
and the initial N flow rate was the same at 0.8 mL/min. Valve
2
TosOH solution 2: TosOH (96 mg, 0.5 mmol) made up to
10.00 mL with EtOH.
operation was identical. Samples were manually collected into
GC vials using 600 μL of EtOAc to elute from the sample loop,
quenching by dilution. Five samples were collected at
approximately 1:30, 3:25, 5:25, 7:20 and 9:10 min (the exact
collection time of each sample was recorded and used for the
subsequent data analysis).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
TosOH solution 3: TosOH (47 mg, 0.25 mmol) made up to
1
1
.00 mL with 4:1 EtOH:t-BuOH.
TosOH solution 4: TosOH (46 mg, 0.25 mmol) made up to
.00 mL with 10:1 EtOH:t-BuOH.
Reaction 1. Electrophile solution 1 + TosOH solution 1, 40
Order in catalyst experiments:
°
C. N
min then N
2
flow 0.5 mL/min, samples collected at 3:30, 6:20, 9:30
flow decreased to 0.2 mL/min, samples collected
2
Catalyst solution 1: [PdCl(allyl)] (5.7 mg, 0.016 mmol) and
t-BuXPhos (3.6 mg, 0.032 mmol) were made up to 4.00 mL
with THF.
2
at 17:45, 29:00, 40:00, 51:00 min.
Reaction 2. Electrophile solution 1 + TosOH solution 1, 50
Catalyst solution 2: 0.75 mL of catalyst solution 1 was diluted
to 1.00 mL with THF.
°
1
C. N
1:15 min then N
2
flow 0.5 mL/min, samples collected at 2:15, 5:15, 8:15,
flow decreased to 0.2 mL/min, samples
2
Catalyst solution 3: 0.50 mL of catalyst solution 1 was diluted
to 1.00 mL with THF.
collected at 16:20, 23:10, 29:00, 34:45, 40:20, 46:00 min.
Reaction 3. Electrophile solution 1 + TosOH solution 1, 60
Catalyst solution 4: 0.50 mL of catalyst solution 1 was diluted
to 2.00 mL with THF.
°C. N
min then N
at 10:00, 14:00, 17:45 min then N
2
flow 0.6 mL/min, samples collected at 2:00, 4:15, 6:40
flow decreased to 0.4 mL/min, samples collected
flow decreased to 0.3
2
Catalyst solution 5: 0.50 mL of catalyst solution 4 was diluted
to 1.00 mL with THF.
2
mL/min, samples collected at 23:00, 28:30, 34:10, 39:30, 45:10
min.
Substrate solution 1: 12 (52 μL, 70 mg, 0.2 mmol), 17 (34
μL, 0.3 mmol), 3 (95 μL, 0.4 mmol), hexadecane (58 μL, 0.2
mmol) made up to 2.00 mL with THF.
Reaction 4. Electrophile solution 1 + TosOH solution 1, 70
°
C. N
min then N
at 9:40, 13:30, 17:00 min then N
2
flow 0.6 mL/min, samples collected at 1:45, 4:00, 6:30
flow decreased to 0.4 mL/min, samples collected
flow decreased to 0.3 mL/min,
2
Reaction 1. Catalyst solution 2 + substrate solution 1: 0.05 M
12, 0.075 M 17, 0.1 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl
(6%).
2
samples collected at 22:20, 27:15, 32:45, 37:45 min.
Reaction 5. Electrophile solution 1 + TosOH solution 1, 80
Reaction 2. Catalyst solution 3 + substrate solution 1: 0.05 M
12, 0.075 M 17, 0.1 M 3, 0.002 M Pd(t-BuXPhos)(allyl)Cl
(4%).
°
C. N
min then N
at 7:45, 10:30, 13:15 min then N
2
flow 0.7 mL/min, samples collected at 1:30, 3:30, 5:30
flow decreased to 0.5 mL/min, samples collected
flow decreased to 0.3 mL/min,
2
2
Reaction 3. Catalyst solution 4 + substrate solution 1: 0.05 M
samples collected at 18:00, 23:15, 28:15 min.
1
2, 0.075 M 17, 0.1 M 3, 0.001 M Pd(t-BuXPhos)(allyl)Cl
(2%).
Reaction 4. Catalyst solution 5 + substrate solution 1: 0.05 M
2, 0.075 M 17, 0.1 M 3, 0.0005 M Pd(t-BuXPhos)(allyl)Cl
1%).
Order in ArI experiments:
Catalyst solution 1: [PdCl(allyl)]
Reaction 6. Electrophile solution 1 + TosOH solution 2, 70
°
C. N
min then N
at 10:30, 14:45, 19:00 min then N
2
flow 0.6 mL/min, samples collected at 1:45, 4:15, 6:50
flow decreased to 0.4 mL/min, samples collected
flow decreased to 0.3
2
1
(
2
mL/min, samples collected at 24:10, 30:15, 36:30 min.
Reaction 7. Electrophile solution 2 + TosOH solution 3, 70
2
(4.3 mg, 0.012 mmol) and
°
C. N
min then N
at 10:00, 14:20, 18:15 min then N
2
flow 0.6 mL/min, samples collected at 1:45, 4:10, 6:35
flow decreased to 0.4 mL/min, samples collected
flow decreased to 0.3
t-BuXPhos (10.1 mg, 0.024 mmol) were made up to 4.00 mL
with THF.
2
2
Substrate solution 1: 12 (39 μL, 52 mg, 0.15 mmol), 17 (8.4
μL, 0.075 mmol), 3 (24 μL, 0.1 mmol), hexadecane (15 μL, 0.05
mmol) made up to 0.50 mL with THF.
mL/min, samples collected at 23:30, 29:00, 34:30, 29:50 min.
Reaction 8. Electrophile solution 3 + TosOH solution 4, 70
°C. N
min then N
at 9:50, 14:00, 17:40 min then N
2
flow 0.6 mL/min, samples collected at 1:50, 4:15, 6:45
flow decreased to 0.4 mL/min, samples collected
flow decreased to 0.3 mL/min,
Substrate solution 2: 12 (26 μL, 35 mg, 0.1 mmol), 17 (8.4
μL, 0.075 mmol), 3 (24 μL, 0.1 mmol), hexadecane (15 μL, 0.05
mmol) made up to 0.50 mL with THF.
2
2
samples collected at 23:00, 28:20, 33:50, 39:50 min.
Substrate solution 3: 12 (13 μL, 17 mg, 0.05 mmol), 17 (8.4
μL, 0.075 mmol), 3 (24 μL, 0.1 mmol), hexadecane (15 μL, 0.05
mmol) made up to 0.50 mL with THF.
TBS protected 2-iodobenzyl alcohol + t-BuSH. General
procedure. Solutions were prepared under Ar in oven dried
glassware. A stock solution of Pd(t-BuXPhos)(allyl)Cl was
prepared by combining [PdCl(allyl)]
2
and t-BuXPhos in THF
Substrate solution 4: 12 (6.5 μL, 9 mg, 0.025 mmol), 17 (8.4
μL, 0.075 mmol), 3 (24 μL, 0.1 mmol), hexadecane (15 μL, 0.05
mmol) made up to 0.50 mL with THF.
and aging 10 min (“catalyst solution”). Solutions of 12, 17, 3
and hexadecane were prepared in THF (“substrate solutions”).
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The Journal of Organic Chemistry
Substrate solution 5: 12 (3.2 μL, 4 mg, 0.013 mmol), 17 (8.4
μL, 0.075 mmol), 3 (24 μL, 0.1 mmol), hexadecane (15 μL, 0.05
mmol) made up to 0.50 mL with THF.
Substrate solution 3: 12 (13 μL, 17 mg, 0.05 mmol), 17 (8.4
μL, 0.075 mmol), 3 (12 μL, 0.05 mmol), hexadecane (15 μL,
0.05 mmol) made up to 0.50 mL with THF.
1
2
3
4
5
6
7
8
9
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1
1
1
1
1
1
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2
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Reaction 1. Catalyst solution 1 + substrate solution 1: 0.15 M
12, 0.075 M 17, 0.1 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
Substrate solution 4: 12 (13 μL, 17 mg, 0.05 mmol), 17 (8.4
μL, 0.075 mmol), 3 (6 μL, 0.025 mmol), hexadecane (15 μL,
0.05 mmol) made up to 0.50 mL with THF.
Reaction 2. Catalyst solution 1 + substrate solution 2: 0.1 M
2, 0.075 M 17, 0.1 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
1
1
Substrate solution 5: 12 (13 μL, 17 mg, 0.05 mmol), 17 (8.4
μL, 0.075 mmol), 3 (3 μL, 0.013 mmol), hexadecane (15 μL,
0.05 mmol) made up to 0.50 mL with THF.
Reaction 3. Catalyst solution 1 + substrate solution 3: 0.05 M
2, 0.075 M 17, 0.1 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
Reaction 1. Catalyst solution 1 + substrate solution 1: 0.05 M
12, 0.075 M 17, 0.15 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
Reaction 4. Catalyst solution 1 + substrate solution 4: 0.025
M 12, 0.075 M 17, 0.1 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Reaction 2. Catalyst solution 1 + substrate solution 2: 0.05 M
12, 0.075 M 17, 0.1 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
Reaction 5. Catalyst solution 1 + substrate solution 5: 0.013
M 12, 0.075 M 17, 0.1 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
Reaction 3. Catalyst solution 1 + substrate solution 3: 0.05 M
Order in t-BuSH experiments:
1
1
1
2, 0.075 M 17, 0.05 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
2
Catalyst solution 1: [PdCl(allyl)] (4.3 mg, 0.012 mmol) and
t-BuXPhos (10.2 mg, 0.024 mmol) were made up to 4.00 mL
with THF.
Reaction 4. Catalyst solution 1 + substrate solution 4: 0.05 M
2, 0.075 M 17, 0.025 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
Reaction 5. Catalyst solution 1 + substrate solution 5: 0.05 M
2, 0.075 M 17, 0.013 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
Substrate solution 1: 12 (13 μL, 17 mg, 0.05 mmol), 17 (34
μL, 0.3 mmol), 3 (24 μL, 0.1 mmol), hexadecane (15 μL, 0.05
mmol) made up to 0.50 mL with THF.
Cyclopentadiene + methyl acrylate. Solutions of 21 with
3
hexadecane were prepared in CHCl (“acrylate solutions”). A
Substrate solution 2: 12 (13 μL, 17 mg, 0.05 mmol), 17 (17
μL, 0.15 mmol), 3 (24 μL, 0.1 mmol), hexadecane (15 μL, 0.05
mmol) made up to 0.50 mL with THF.
2
.25 M solution of 20 in CHCl was prepared by diluting freshly
3
distilled 20 (189 μL, 2.25 mmol) up to 1.00 mL with CHCl
3
(“diene solution”).
Substrate solution 3: 12 (13 μL, 17 mg, 0.05 mmol), 17 (8.4
μL, 0.075 mmol), 3 (24 μL, 0.1 mmol), hexadecane (15 μL, 0.05
mmol) made up to 0.50 mL with THF.
Acrylate solution 1: 21 (34 μL, 0.38 mmol), hexadecane (22
μL, 0.075 mmol) up to 0.50 mL with CHCl
Acrylate solution 2: 21 (68 μL, 0.75 mmol), hexadecane (22
μL, 0.075 mmol) up to 0.50 mL with CHCl
Acrylate solution 3: 21 (68 μL, 0.75 mmol), hexadecane (44
μL, 0.15 mmol) up to 0.50 mL with CHCl
3
.
Substrate solution 4: 12 (13 μL, 17 mg, 0.05 mmol), 17 (4.2
μL, 0.038 mmol), 3 (24 μL, 0.1 mmol), hexadecane (15 μL, 0.05
mmol) made up to 0.50 mL with THF.
3
.
3
.
Substrate solution 5: 12 (13 μL, 17 mg, 0.05 mmol), 17 (2.1
μL, 0.019 mmol), 3 (24 μL, 0.1 mmol), hexadecane (15 μL, 0.05
mmol) made up to 0.50 mL with THF.
Slugs were loaded into the loading coil by taking the desired
acrylate solution into a 2.5 mL Hamilton glass syringe,
installing on the Fusion 200 syringe pump, priming and then
connecting to the first tee-mixer (see Figure S8 in the
supporting information). The slugs were loaded as follows: 333
Substrate solution 6: 12 (13 μL, 17 mg, 0.05 mmol), 17 (1.0
μL, 0.0094 mmol), 3 (24 μL, 0.1 mmol), hexadecane (15 μL,
.05 mmol) made up to 0.50 mL with THF.
0
1
1
1
1
1
1
μL of acrylate solution 1, 150 μL of H
solution 2, 150 μL of H O, 167 μL of acrylate solution 3, 50 μL
of H O.
2
O, 333 μL of acrylate
Reaction 1. Catalyst solution 1 + substrate solution 1: 0.05 M
2, 0.3 M 17, 0.1 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
2
2
Reaction 2. Catalyst solution 1 + substrate solution 2: 0.05 M
2, 0.15 M 17, 0.1 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
The diene solution was then loaded into a 2.5 mL Hamilton
glass syringe, installed on the Fusion 200 syringe pump and
primed. The syringe was then connected to the second tee-mixer
Reaction 3. Catalyst solution 1 + substrate solution 3: 0.05 M
2, 0.075 M 17, 0.1 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
(see Figure S9 in the supporting information) and 50 μL was
Reaction 4. Catalyst solution 1 + substrate solution 4: 0.05 M
2, 0.038 M 17, 0.1 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
eluted to prime the tubing.
Reactor valves were set to the following positions: Valve 1,
position 1; valve 2, position 1; sampling valve set to collect
sample and the reactor coils were lowered into a 70 °C water
bath.
Reaction 5. Catalyst solution 1 + substrate solution 5: 0.05 M
2, 0.019 M 17, 0.1 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
Reaction 6. Catalyst solution 1 + substrate solution 6: 0.05 M
2, 0.0094 M 17, 0.1 M 3, 0.003 M Pd(t-BuXPhos)(allyl)Cl.
The SyrDos pump was started at 200 μL/min until the
dienophile solution 1 slug approached the second tee-mixer.
The SyrDos flow rate was then decreased to 133 μL/min and
the diene solution was delivered at 67 μL/min to give a 0.5 mL
reaction slug 0.5 M in 21 and 0.75 M in 20. After the dienophile
solution 1 slug completely exited the loading coil the SyrDos
flow rate was set to 200 μL/min again and the diene pump was
stopped.
3
Order in Bu N experiments:
Catalyst solution 1: [PdCl(allyl)]
2
(4.2 mg, 0.012 mmol) and
t-BuXPhos (10.0 mg, 0.024 mmol) were made up to 4.00 mL
with THF.
Substrate solution 1: 12 (13 μL, 17 mg, 0.05 mmol), 17 (8.4
μL, 0.075 mmol), 3 (36 μL, 0.15 mmol), hexadecane (15 μL,
0.05 mmol) made up to 0.50 mL with THF.
Once the dienophile solution 2 slug approached the second
tee-mixer the SyrDos flow rate was again set to 133 μL/min and
the diene solution was delivered at a rate of 67 μL/min,
initiating the second 0.5 mL reaction slug that was 1.0 M in 21
Substrate solution 2: 12 (13 μL, 17 mg, 0.05 mmol), 17 (8.4
μL, 0.075 mmol), 3 (24 μL, 0.1 mmol), hexadecane (15 μL, 0.05
mmol) made up to 0.50 mL with THF.
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The Journal of Organic Chemistry
and 0.75 M in 20. After the dienophile solution 2 slug
ASSOCIATED CONTENT
Page 10 of 13
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completely exited the loading coil the SyrDos flow rate was set
back to 200 μL/min again and the diene pump was stopped.
Supporting Information. Details of the flow reactor and
equipment, comparison batch kinetic data, flow kinetic data used
for determination of reaction orders, calculated reaction pathway
for the C-S cross-coupling, troubleshooting and limitations,
calibration curves, computational details. This material is available
free of charge via the Internet at http://pubs.acs.org.
As the last slug (dienophile solution 3) approached the
second tee-mixer, the SyrDos flow rate was decreased to 67
μL/min and the diene solution was delivered at 133 μL/min,
initiating the last 0.5 mL reaction plug that was 0.5 M in 21 and
1
.5 M in 20. After the dienophile solution 3 slug completely
AUTHOR INFORMATION
exited the loading coil the SyrDos pump was set to 200 μL/min
again and the diene solution pump was stopped.
Corresponding Author
All three reaction plugs were now formed and travelling
inside coil A. Once the first reaction slug entered the sampling
valve, and ~50 μL had passed through, the sampling valve was
actuated and a 15 μL aliquot sample was eluted with 600 μL
EtOAc into a GC vial. The sample removal line was then
0
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* stephen.newman@uottawa.ca
ORCID
Ryan J. Sullivan: 0000-0001-5540-6962
Stephen G. Newman: 0000-0003-1949-5069
2
flushed with H O. Once the remainder of the reaction slug had
Notes
exited the sampling valve, the sampling valve was set back to
the position to collect a new sample, and the sample removal
line was then flushed with EtOAc.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Once the second reaction slug entered the sampling valve,
and ~50 μL had passed through, the sampling valve was again
actuated and a 15 μL aliquot sample was eluted with 600 μL
EtOAc into a GC vial. The sample removal line was then
Financial support for this work was provided by the University of
Ottawa, the National Science and Engineering Research Council of
Canada (NSERC), and the Canada Research Chair program. The
Canadian Foundation for Innovation (CFI) and the Ontario
Ministry of Economic Development and Innovation are thanked for
essential infrastructure. Debasis Mallik (CCRI flow chemistry
facility) and Peter Zhang (Vici Valco) are thanked for
programming the drivers used to control the sampling valves. R. J.
S. thanks NSERC for a CGS-D award.
2
flushed with H O. Once the remainder of the reaction slug had
exited the sampling valve, the sampling valve was set back to
the position to collect a new sample, and the sample removal
line was then flushed with EtOAc.
Once the third reaction slug entered the sampling valve, and
~50 μL had passed through, the sampling valve was again
REFERENCES
actuated and a 15 μL aliquot sample was eluted with 600 μL
EtOAc into a GC vial. The sample removal line was then
flushed with H O. Once the remainder of the reaction slug had
2
exited the sampling valve, and fully passed through valve 1 to
coil B, valve 1 was set to position 2, valve 2 was set to position
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(clockwise rotation) and the sampling valve was set to collect
4
4, 43024320; (d) Blackmond, D. G. Kinetic Profiling of Catalytic
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Organic Reactions as a Mechanistic Tool. J. Am. Chem. Soc. 2015, 137,
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All three reaction slugs were now travelling through coil B.
Sampling was continued in the same manner as each reaction
plug again passed through the sampling valve. After all three
reaction slugs had passed back into coil A, the reactor valves
were again actuated: valve 1 to position 1, valve 2 to position 1
(2) (a) Fermier, A. M.; Oyler, A. R.; Armstrong, B. L.; Weber, B.
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WO patent WO2002/077614 A2, 2002.
collection. Sampling and valve actuation were repeated to
collect desired samples.
2
Note. In experiments using N as the carrier fluid the entire
reaction slug was formed very quickly (~5 s) to facilitate the
ability to increase the sample interval as the reaction
2
progressed by decreasing the N flow rate without needing to
consider residence time discrepancies between the front and
back of the reaction slug. In these experiments however, the use
of residence time was necessary to facilitate multiple
consecutive reaction slugs and therefore reactions were
initiated at the same flow rate as the carrier flow rate for the
entire reaction progress. In order to increase the interval
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simply skipped at 50, 1:10, 1:30, 1:50, 2:10, 2:20, 2:40 and
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2
:50 min. To skip sample collection, the sampling valve was
Alamillo-Ferrer, C.; Clayton, A. D.; Bourne, R. A.; Codina, A.; Vidal-
Ferran, A.; Adams, R. W.; Burés, J. Kinetic Treatments for Catalyst
Activation and Deactivation Processes based on Variable Time
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reaction slugs had passed from one reactor coil into the other.
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The Journal of Organic Chemistry
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3
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(
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3
0
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1
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3
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9
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Sullivan, R. J.; Newman, S. G. Chiral Auxiliary Recycling in
Continuous Flow: Automated Recovery and Reuse of Oppolzer's
Sultam. Chem. Sci. 2018, 9, 21302134.
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Droplets in Microfluidic Channels. Angew. Chem. Int. Ed. 2006, 45,
73367356; (b) Sesen, M.; Alan, T.; Neild, A. Droplet Control
Technologies for Microfluidic High Throughput Screening (μHTS).
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Controlled Droplet Microfluidic Systems for Multistep Chemical and
Biological Assays. Chem. Soc. Rev. 2017, 46, 62106226; (d) Isbrandt,
E. S.; Sullivan, R. J.; Newman, S. G. High Throughput Strategies for
the Discovery and Optimization of Catalytic Reactions. Angew. Chem.
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M.; Veesler, S. Advances in the Use of Microfluidics to Study
Crystallization Fundamentals. Annu. Rev. Chem. Biomol. 2019, 10,
5983; (g) Hwang, Y.-J.; Coley, C. W.; Abolhasani, M.; Marzinzik, A.
L.; Koch, G.; Spanka, C.; Lehmann, H.; Jensen, K. F. A Segmented
Fflow Platform for On-Demand Medicinal Chemistry and Compound
Synthesis in Oscillating Droplets. Chem. Commun. 2017, 53,
66496652.
(7) (a) Mozharov, S.; Nordon, A.; Littlejohn, D.; Wiles, C.; Watts,
P.; Dallin, P.; Girkin, J. M. Improved Method for Kinetic Studies in
Microreactors Using Flow Manipulation and Noninvasive Raman
Spectrometry. J. Am. Chem. Soc. 2011, 133, 36013608; (b) Moore, J.
S.; Jensen, K. F. “Batch” Kinetics in Flow: Online IR Analysis and
Continuous Control. Angew. Chem. Int. Ed. 2014, 53, 470473; (c)
Schwolow, S.; Braun, F.; Rädle, M.; Kockmann, N.; Röder, T. Fast and
Efficient Acquisition of Kinetic Data in Microreactors Using In-Line
Raman Analysis. Org. Process Res. Dev. 2015, 19, 12861292; (d)
Durand, T.; Henry, C.; Bolien, D.; Harrowven, D. C.; Bloodworth, S.;
Franck, X.; Whitby, R. J. Thermolysis of 1,3-dioxin-4-ones: fast
generation of kinetic data using in-line analysis under flow. React.
Chem. Eng. 2016, 1, 8289; (e) Hone, C. A.; Holmes, N.; Akien, G. R.;
Bourne, R. A.; Muller, F. L. Rapid Multistep Kinetic Model Generation
From Transient Flow Data. React. Chem. Eng. 2017, 2, 103108; (f)
Aroh, K. C.; Jensen, K. F. Efficient Kinetic Experiments in Continuous
Flow Microreactors. React. Chem. Eng. 2018, 3, 94101.
(12) An initial version of this work was deposited in ChemRxiv on
Oct 21, 2019, Sullivan, R. J.; Newman, S. G. Reaction Cycling for
Efficient Kinetic Analysis in Flow. ChemRxiv 2019. Preprint.
https://doi.org/10.26434/chemrxiv.10009013.v1.
(
8) (a) Reizman, B. J.; Jensen, K. F. Feedback in Flow for
Accelerated Reaction Development. Acc. Chem. Res. 2016, 49,
7861796; (b) Mascia, S.; Heider, P. L.; Zhang, H.; Lakerveld, R.;
(13) Only 7 ports and 6 positions are needed. Any selector valve with
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≥7-ports, 6-positions can be substituted by fabrication of a suitable
rotor. See Figure S4 in the supporting information.
Benyahia, B.; Barton, P. I.; Braatz, R. D.; Cooney, C. L.; Evans, J. M.
B.; Jamison, T. F.; Jensen, K. F.; Myerson, A. S.; Trout, B. L. End-to-
End Continuous Manufacturing of Pharmaceuticals: Integrated
Synthesis, Purification, and Final Dosage Formation. Angew. Chem.
Int. Ed. 2013, 52, 1235912363; (c) Adamo, A.; Beingessner, R. L.;
Behnam, M.; Chen, J.; Jamison, T. F.; Jensen, K. F.; Monbaliu, J.-C.
M.; Myerson, A. S.; Revalor, E. M.; Snead, D. R.; Stelzer, T.;
Weeranoppanant, N.; Wong, S. Y.; Zhang, P. On-Demand Continuous-
Flow Production of Pharmaceuticals in a Compact, Reconfigurable
System. Science 2016, 352, 6167; (d) Perera, D.; Tucker, J. W.;
Brahmbhatt, S.; Helal, C. J.; Chong, A.; Farrell, W.; Richardson, P.;
Sach, N. W. A Platform for Automated Nanomole-Scale Reaction
Screening and Micromole-Scale Synthesis in Flow. Science 2018, 359,
(
14) A custom rotor for the selector valve was purchased from Vici
Valco (~$100 USD).
15) Price, G. A.; Mallik, D.; Organ, M. G. Process Analytical Tools
(
for Flow Analysis: A Perspective. J. Flow Chem. 2017, 7, 8286.
(16) (a) Zheng, B.; Ismagilov, R. F. A Microfluidic Approach for
Screening Submicroliter Volumes against Multiple Reagents by Using
Preformed Arrays of Nanoliter Plugs in
Liquid/Liquid/Gas Flow. Angew. Chem. Int. Ed. 2005, 44, 25202523;
b) Chen, D. L.; Ismagilov, R. F. Microfluidic Cartridges Preloaded
a
Three-Phase
(
with Nanoliter Plugs of Reagents: An Alternative to 96-Well Plates for
Screening. Curr. Opin. Chem. Biol. 2006, 10, 226231.
4
29–434; (e) Coley, C. W.; Thomas, D. A.; Lummiss, J. A. M.;
(17) Extremely fast reactions are ideally suited for traditional steady
state flow kinetics experiments, since the time inefficiencies of that
strategy are not problematic when investigating reactions with
incredibly short timescales, and therefore we believe these are best
considered complimentary tools.
(18) Reaction slugs used were 300 μL (≈ 1.5 m long in the 0.5 mm
ID reactor coils) and were sampled from the center of the slug, such
that concerns over solvent loss to the gaseous carrier phase or reaction
acceleration at droplet interfaces were not relevant.
Jaworski, J. N.; Breen, C. P.; Schultz, V.; Hart, T.; Fishman, J. S.;
Rogers, L.; Gao, H.; Hicklin, R. W.; Plehiers, P. P.; Byington, J.; Piotti,
J. S.; Green, W. H.; Hart, A. J.; Jamison, T. F.; Jensen, K. F. A Robotic
Platform for Flow Synthesis of Organic Compounds Informed by AI
Planning. Science 2019, 365, eaax1566.
(9) (a) Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H.
The Hitchhiker’s Guide to Flow Chemistry. Chem. Rev. 2017, 117,
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19) (a) Hubbard, P.; Brittain, W. J. Mechanism of Amine-Catalyzed
Ester Formation from an Acid Chloride and Alcohol. J. Org. Chem.
998, 63, 677683; (b) Oosthoek-de Vries, A. J.; Nieuwland, P. J.;
small amounts of bleed through inconsequential. For further
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information about the situations that lead to bleed through
between slugs see: (a) Sebastian Cabeza, V.; Kuhn, S.; Kulkarni, A.
A.; Jensen, K. F. Size-Controlled Flow Synthesis of Gold
Nanoparticles Using a Segmented Flow Microfluidic Platform.
Langmuir 2012, 28, 70077013; (b) Lee, S.; Park, J.-S.; Lee, T. R. The
Wettability of Fluoropolymer SuOfaces:ꢀ Influence of Surface Dipoles.
Langmuir 2008, 24, 48174826.
(24) Obtaining kinetic data from (near-)refluxing solutions in batch
is hampered by unknown partitioning of volatile components (e.g.,
cyclopentadiene) between the reaction solution and headspace (see ref
4b) while sampling from batch vessels under pressure requires
specialized autoclaves equipped with dip tubes for sample removal. In
flow however, the combination of back pressure to prevent solvent
boiling and no headspace facilitates collection of high-quality kinetic
data above the atmospheric boiling point of reaction components.
(25) Feng, J.; Liang, S.; Chen, S.-Y.; Zhang, J.; Fu, S.-S.; Yu, X.-Q.
A Metal-Free Oxidative Esterification of the Benzyl C-H Bond. Adv.
Synth. Catal. 2012, 354, 12871292.
1
Bart, J.; Koch, K.; Janssen, J. W. G.; van Bentum, P. J. M.; Rutjes, F.
P. J. T.; Gardeniers, H. J. G. E.; Kentgens, A. P. M. Inline Reaction
Monitoring of Amine-Catalyzed Acetylation of Benzyl Alcohol Using
a Microfluidic Stripline Nuclear Magnetic Resonance Setup. J. Am.
Chem. Soc. 2019, 141, 53695380.
(
20) Patschinski, P.; Zhang, C.; Zipse, H. The Lewis Base-Catalyzed
Silylation of Alcohols—A Mechanistic Analysis. J. Org. Chem. 2014,
9, 83488357.
21) For a discussion of typical values for activation enthalpies and
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entropies see: Anslyn, E. V.; Dougherty, D. A. Modern Physical
Organic Chemistry; University Science: Sausalito, 2006.
(22) Xu, J.; Liu, R. Y.; Yeung, C. S.; Buchwald, S. L.
Monophosphine Ligands Promote Pd-Catalyzed C–S Cross-Coupling
Reactions at Room Temperature with Soluble Bases. ACS Catal. 2019,
9
, 64616466.
(23) When using sequential droplets in microfluidic screening
platforms it is sometimes necessary to include “blank” droplets
between reactions to prevent bleed through of materials (for an example
see ref 11f). This was found to be unnecessary in this case, likely
because this reactor uses large reaction slugs (450 μL ≈ 60 cm long
slugs in the 1.0 mm ID reactor coils) rather that droplets making
(26) Meng, D.; Li, D.; Ollevier, T. Recyclable Iron(II) Caffeine-
Derived Ionic Salt Catalyst in the Diels–Alder Reaction of
Cyclopentadiene and α,β-UnsatuOated N-Acyl-oxazolidinones in
Dimethyl Carbonate. RSC Advances 2019, 9, 2195621963.
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