Reaction Cycling for Efficient Kinetic Analysis in Flow

doi.org/10.26434/chemrxiv.10009013.v1

Reaction Cycling for Efficient Kinetic Analysis in FlowRyan Sullivan, Stephen Newman

Submitted date: 21/10/2019 • Posted date: 23/10/2019Licence: CC BY-NC-ND 4.0Citation information: Sullivan, Ryan; Newman, Stephen (2019): Reaction Cycling for Efficient Kinetic Analysisin Flow. ChemRxiv. Preprint.

A reactor capable of efficiently collecting kinetic data in flow is presented. Conversion over time data isobtained by passing a discrete reaction slug back-and-forth between two residence coils, with analysisperformed each time the solution is passed from one coil to the other. In combination with minimal materialconsumption, this represents an improvement in efficiency for typical kinetic experimentation in batch as well.Application to kinetic analysis of a wide variety of transformations is demonstrated, highlighting both theversatility of the reactor and the benefits of performing kinetic analysis as a routine part of reactionoptimization/development. Extension to the monitoring of multiple reactions simultaneously is also realized byoperating the reactor with multiple reaction slugs at the same time.

File list (2)

download fileview on ChemRxivManuscript.pdf (0.94 MiB)

download fileview on ChemRxivSupporting Information.pdf (3.97 MiB)

http://doi.org/10.26434/chemrxiv.10009013.v1

https://chemrxiv.org/authors/Stephen_Newman/5920151

https://chemrxiv.org/ndownloader/files/18051839

https://chemrxiv.org/articles/Reaction_Cycling_for_Efficient_Kinetic_Analysis_in_Flow/10009013/1?file=18051839



Reaction cycling for efficient kinetic analysis in flow

Ryan J. Sullivan and Stephen G. Newman*[a]

Abstract: A reactor capable of efficiently collecting kinetic data in flow

is presented. Conversion over time data is obtained by passing a

discrete reaction slug back-and-forth between two residence coils,

with analysis performed each time the solution is passed from one coil

to the other. 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, SNAr, 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.

Introduction

Measuring reaction kinetics is a powerful tool for enabling

optimization, mechanistic investigation, and scale-up.[1] 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 alleviate

this problem.[2] Mathematically simpler approaches to analyzing

data, such as the visual variable time normalization method, have

also been successful in reducing the barrier to studying kinetics

in routine applications.[3]

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 of

temperatures and pressures.[4] However, acquiring kinetic data is

often considered an area where batch reactors are superior due

to convenient sampling over time (Figure 1A).[5] In 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 traveled.

Sampling over time must thus be carried out as a sequence of

experiments with varied flow rate (Figure 1B).[6] While effective,

this approach is wasteful of both time and materials. To highlight

this disadvantage, Blackmond and coworkers monitored the

progress of an aldol reaction that required 40 minutes to reach

completion.[5] Due to the need to 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

circumvent the need to collect steady-state samples.[7] However

these have been limited by the complicated mathematics required,

and application thus far restricted to relatively simple reactions.

Furthermore, these methods sometimes suffer from an inability to

unambiguously discriminate between potential reaction

mechanisms without relying on chemical intuition.

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 analysing progress over time by cycling a reaction slug.

Given the growing number, diversity, and utility of advanced

flow systems[8] and the expanding scope of reactions that can be

performed equally well or better when run in flow,[9] we believed

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 or auxiliaries through

the implementation of recycling loops.[10] With this inspiration, we

envisioned cycling an entire reaction solution by performing the

reaction in discrete slugs[11] pushed by an inert carrier fluid (Figure

1C). Analyzing the reaction once every loop provides reaction

progress data.

Herein, we describe the design and implementation of such

a 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 behavior for seemingly simple transformations. The

setup is assembled from commercially available components, and

[a] Centre for Catalysis Research and Innovation, Department of

Chemistry and Biomolecular Sciences, University of Ottawa, 10

Marie-Curie, Ottawa, Ontario, Canada, K1N 6N5

E-mail: [email protected]

Supporting information for this article is given via a link at the end of

the document.

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 as a component in more complex

automation platforms.

Results and Discussion

Sequential analysis of a cycling reaction slug is achieved by using

two reactor coils linked by a 6-port, two-way valve and a selector

valve with a minimum of 7-ports, six 6-positions.[12] Simply

changing the port connectivity and installing a modified rotor in

the selector valve allows these valves to act as guides to control

the fluid path.[13] 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, see Figures S1 in the

supporting information for further details). 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,[14] we elected

to use a sampling valve that removes a small aliquot for off-line

analysis, keeping the system cost and complexity low.

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.

To validate the reactor, the room-temperature acylation

reaction between benzoyl chloride (1) and benzyl alcohol (2) was

studied. We selected Bu3N (3) as the organic base to avoid solid

handling issues,[9e] N2 as the inert carrier fluid to move the reaction

slug through the reactor, and the method of variable time

normalization analysis (VTNA)[3] to analyze the data (Figure 3).

Experiments were performed both in a traditional batch set-up (i.e.,

a round-bottom flask) and with the cycling reactor. Identical

results were obtained in both cases, finding first order behavior

for both 1 (Figure 3A) and 2 (Figure 3B) and a partial reaction

order of ~0.5 for to 3 (Figure 3C). Related tertiary amine mediated

acylation reactions are known to proceed by a nucleophilic

catalyzed mechanism[15], and the partial reaction order observed

for 3 suggests that both a catalyzed and uncatalyzed reaction

pathway 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),

confirming the validity and transferability of the collected data.

Figure 3. A) VTNA plot showing 1st order in 1. B) VTNA plot showing 1st 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.

Satisfied that the reactor operated as desired, we next

explored the ability to rapidly obtain kinetic data for a variety of

reactions (Table 1). An SNAr reaction at 80 °C (entry 1) and a

silylation at 0 °C (entry 2) were examined to assess the reactor

performance over a range of temperatures. The flow reactor

performed well in both cases, providing either equivalent or

slightly superior data compared to parallel experiments in batch.

The solvolysis of a secondary alkyl halide was probed using a

pseudo-first order approach to distinguish between an SN1 or SN2

mechanism, as well as demonstrate the ability to perform an

Eyring analysis by varying the reaction temperature (entry 3). A

Pd catalyzed 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 carrier fluid

was also changed from N2 to H2O for this example to demonstrate

the flexibility in choice of carrier solvent and the ability to conduct

experiments above the atmospheric boiling point of the solvent

(CHCl3).

0

0.1

0.2

0.3

0.4

0 5 10

[4] (M

)

[1]1t

A

0.5 M 11.0 M 1

0 5 10

[2]1t

B

0.5 M 21.0 M 2

0 10 20

[3]1/2t

C

0.6 M 31.0 M 3

0

0.1

0.2

0.3

0.4

0 25 50 75

[4] (M

)

[1]1[2]1[3]1/2t

D

kobs = 6.67 10–3 L3/2mol–3/2s–1

y = 0.00667xR2 = 0.994

standardexcess 1excess 2excess 3

0

0.2

0.4

0 20 40

[4] (M

)

t (min)

flow

batch

E

Table 1. Reactions investigated using the flow reactor

Entry Reaction Analysis method Demonstrating Rate equation found

1

VTNA Elevated temperature

0th order in 7

2

VTNA Lowered temperature

3

pseudo-first order Distinguish SN1/SN2;

Temperature

variation

(Eyring analysis)

0th order in 18

4

method of initial

rates

O2/H2O free reaction;

Complex mechanism

0 < x,y < 1

saturation kinetics

5

VTNA Simultaneous

reactions;

Exceeding solvent

b.p.;

H2O carrier phase

The observed rate equation for the SNAr reaction was as

expected, with first order behavior observed for both electrophile

5 and nucleophile 6, and 0th order for base 7. The silylation of

alcohol 10, however, showed non-intuitive second order behavior

for the nucleophilic catalyst 11 and negative order with respect to

base 3. A plausible reaction mechanism that accounts for the

observed reaction orders is given in Scheme 1. There are two

reaction steps leading to the product 12 that are comparably slow:

attack of 1-butylimidazole (11) on TBSCl (9) to form a TBS-BuIm+

intermediate 13, and attack of 2-iodobenzyl alcohol (10) on 13 to

lead to the product. In between these steps a non-productive but

reversible equilibrium with the stoichiometric base (3) depletes

the concentration of intermediate 13 by forming TBS-NBu3+ (14).

The observed rate behavior contrasts with previous studies of

TBS protection using DMAP/Et3N as the catalyst/base.[15] In this

case, no inhibitory effect was observed, suggesting DMAP attack

on TBSCl was the sole limiting step in that case.

For the solvolysis of alkyl bromide 16 an SN2 mechanism

was found to be operative. First order behavior for 16 was found

using integrated rate laws under pseudo-first order conditions

(Figure 4A). First order behavior in EtOH (17) and zeroth order in

acid 18 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 SN2 mechanism.[17]

Scheme 1. Postulated mechanism for the TBS protection of 10 mediated by 3

and 11.

Figure 4. A) Linear integrated rate law plot showing first order in electrophile 16.

B) Eyring plot. Standard conditions: 0.5 M 16, 0.125 M 18 in EtOH, 70 °C.

For the palladium catalyzed C–S cross-coupling recently

reported by Buchwald and coworkers first order behavior was

found for catalyst 21 (Figure 5A) and zeroth order for aryl halide

12 (Figure 5B), consistent with the previously identified LPdIIArX

resting state.[18] The reaction orders for thiol 20 and base 3 proved

to be more complex, yielding curving log-log plots of initial rate vs.

concentration (Figure 5C and D). Both 20 and 3 exhibited

saturation kinetics and Michaelis-Menten plots of the data fit well

yielding vmax and KM 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).

Table 2. kobs values for the ethanolysis of 16.[a]

Entry [18] (M) [17] (M) kobs

1 0.125 16.0 0.0542

2 0.0250 16.0 0.0599

3 0.125 14.5[b] 0.0484

4 0.125 12.7[c] 0.0384

[a] All reactions 0.5 M in 16. [b] 10:1 EtOH:t-BuOH as solvent. [c] 4:1 EtOH:t-

BuOH as solvent.

Figure 5. Initial rate kinetics for C–S cross coupling of ArI 12 and thiol 20

catalyzed by a Pd/t-BuXPhos system. A) log-log plot of initial rate vs. [21], B)

log-log plot of initial rate vs. [12], C) log-log plot of initial rate vs. [20], D) log-log

plot of initial rate vs. [3], E) Michaelis-Menten plot of initial rate vs. [20], F)

Michaelis-Menten plot of initial rate vs. [3]. Standard conditions: 50 mM 12, 75

mM 20, 100 mM 3, 3 mM 21 in THF, room temperature.

Figure 6. Putative catalytic cycle for the Pd catalyzed C–S bond formation. L =

t-BuXPhos, ArI = 12.

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 (23) and

methyl acrylate (24) required ~3 h to reach >80% conversion at

70 °C, making it an ideal candidate to demonstrate this ability. 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 N2 to water to allow the reaction to be conducted

above the boiling point of the solvent through application of

backpressure. In this way, all necessary data for kinetic analysis

y = -0.0542x - 0.7607R² = 0.9974

-3

-2.5

-2

-1.5

-1

-0.5

0 10 20 30 40

ln[1

6]

t (min)

Ay = -9487.3x - 7.6439

R² = 0.9995

-39

-38

-37

-36

-35

-34

0.0028 0.003 0.0032

ln[(

k·h

)/(T

·kB)]

1/T (K–1)

H‡ = 18.9 kcal·mol–1

S‡ = –15.2 cal·mol–1·K–1

B

y = 1.1711x + 5.334R² = 0.9978

-4

-3

-2

-1

-8 -7 -6

ln(r

ate

)

ln[21]

Ay = -0.00006x - 1.48080

-3

-2

-1

0

-5 -3 -1

ln(r

ate

)

ln[12]

B

-3

-2.5

-2

-1.5

-1

-5 -4 -3 -2 -1

ln(r

ate

)

ln[20]

C

-3

-2.5

-2

-1.5

-1

-5 -4 -3 -2

ln(r

ate

)

ln[3]

D

0

0.005

0.01

0.015

0.02

0 0.2

rate

(M

/s)

[20] (M)

rate =0.0198 ∙ [𝟐𝟎]

[𝟐𝟎] + 0.0282

R2 = 0.969

E

0

0.005

0.01

0.015

0 0.1

rate

(M

/s)

[3] (M)

rate =0.0155 ∙ [𝟑]

[𝟑] + 0.0233R2 = 0.965

F

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.

Figure 7. Operating with multiple sequential reaction slugs allows 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.

Conclusion

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, EtOH,

THF, CHCl3) and reactions (acylation, SNAr, 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.

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.

Acknowledgements

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 chemsitry

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.

Conflicts of Interest

The authors declare no conflict of interest.

Keywords: kinetics • flow • variable time normalization analysis

• initial rates • pseudo-first order • acylation • SNAr • silylation •

Diels-Alder • C-S bond formation

[1] a) J. W. Moore, R. G. Pearson, Kinetics and Mechanism, 3 ed., Wiley,

New York, 1981; b) R. I. Masel, Chemical Kinetics and Catalysis, Wiley,

New York, 2001; c) D. G. Blackmond, Angew. Chem. Int. Ed. 2005, 44,

43024320; d) D. G. Blackmond, J. Am. Chem. Soc. 2015, 137,

1085210866.

[2] a) A. M. Fermier, A. R. Oyler, B. L. Armstrong, B. A. Weber, R. L.

Rodriguez, J. V. Weber, J. A. Nalasco, J. Assoc. Lab. Automation 2002,

7, 8388; b) R. Chung, D. Yu, V. T. Thai, A. F. Jones, G. K. Veits, J.

Read de Alaniz, J. E. Hein, ACS Catal. 2015, 5, 45794585; c) C.

Rougeot, H. Situ, B. H. Cao, V. Vlachos, J. E. Hein, React. Chem. Eng.

2017, 2, 226231; d) T. C. Malig, J. D. B. Koenig, H. Situ, N. K. Chehal,

P. G. Hultin, J. E. Hein, React. Chem. Eng. 2017, 2, 309314; e) A. M.

Fermier, A. R. Oyler, B. L. Armstrong, J. V. Weber, J. Nalasco (Ortho-

McNeil Pharmaceutical, Inc., USA .), WO patent 2002077614 A2, 2002.

[3] a) J. Burés, Angew. Chem. Int. Ed. 2016, 55, 20282031; b) J. Burés,

Angew. Chem. Int. Ed. 2016, 55, 1608416087.

[4] a) J. P. McMullen, K. F. Jensen, Annu. Rev. Anal. Chem. 2010, 3, 1942;

b) R. L. Hartman, J. P. McMullen, K. F. Jensen, Angew. Chem. Int. Ed.

2011, 50, 7502–7519; c) S. G. Newman, K. F. Jensen, Green Chem.

2013, 15, 14561472; d) S. V. Ley, D. E. Fitzpatrick, R. J. Ingham, R. M.

Myers, Angew. Chem. Int. Ed. 2015, 54, 3449–3464.

[5] F. E. Valera, M. Quaranta, A. Moran, J. Blacker, A. Armstrong, J. T.

Cabral, D. G. Blackmond, Angew. Chem. Int. Ed. 2010, 49, 24782485.

[6] For example: a) J. P. McMullen, K. F. Jensen, Org. Process Res. Dev.

2011, 15, 398407; b) A. Gholamipour-Shirazi, C. Rolando, Org. Process

Res. Dev. 2012, 16, 811818; c) D. M. Roberge, C. Noti, E. Irle, M.

Eyholzer, B. Rittiner, G. Penn, G. Sedelmeier, B. Schenkel, J. Flow

Chem. 2014, 4, 2634; d) C. A. Hone, A. Boyd, A. O'Kearney-McMullan,

R. A. Bourne, F. L. Muller, React. Chem. Eng. 2019, 4, 15651570.

[7] a) S. Mozharov, A. Nordon, D. Littlejohn, C. Wiles, P. Watts, P. Dallin, J.

M. Girkin, J. Am. Chem. Soc. 2011, 133, 36013608; b) J. S. Moore, K.

F. Jensen, Angew. Chem. Int. Ed. 2014, 53, 470473; c) S. Schwolow,

F. Braun, M. Rädle, N. Kockmann, T. Röder, Org. Process Res. Dev.

2015, 19, 12861292; d) C. A. Hone, N. Holmes, G. R. Akien, R. A.

Bourne, F. L. Muller, React. Chem. Eng. 2017, 2, 103108; e) K. C. Aroh,

K. F. Jensen, React. Chem. Eng. 2018, 3, 94101.

[8] a) B. J. Reizman, K. F. Jensen, Acc. Chem. Res. 2016, 49, 17861796;

b) S. Mascia, P. L. Heider, H. Zhang, R. Lakerveld, B. Benyahia, P. I.

Barton, R. D. Braatz, C. L. Cooney, J. M. B. Evans, T. F. Jamison, K. F.

Jensen, A. S. Myerson, B. L. Trout, Angew. Chem. Int. Ed. 2013, 52,

12359–12363; c) A. Adamo, R. L. Beingessner, M. Behnam, J. Chen, T.

F. Jamison, K. F. Jensen, J.-C. M. Monbaliu, A. S. Myerson, E. M.

Revalor, D. R. Snead, T. Stelzer, N. Weeranoppanant, S. Y. Wong, P.

Zhang, Science 2016, 352, 6167; d) D. Perera, J. W. Tucker, S.

Brahmbhatt, C. J. Helal, A. Chong, W. Farrell, P. Richardson, N. W. Sach,

Science 2018, 359, 429-434; e) C. W. Coley, D. A. Thomas, J. A. M.

Lummiss, J. N. Jaworski, C. P. Breen, V. Schultz, T. Hart, J. S. Fishman,

L. Rogers, H. Gao, R. W. Hicklin, P. P. Plehiers, J. Byington, J. S. Piotti,

W. H. Green, A. J. Hart, T. F. Jamison, K. F. Jensen, Science 2019, 365,

eaax1566.

[9] a) M. B. Plutschack, B. Pieber, K. Gilmore, P. H. Seeberger, Chem. Rev.

2017, 117, 1179611893; b) J. C. Pastre, D. L. Browne, S. V. Ley,

Chem. Soc. Rev. 2013, 42, 88498869; c) S. Newton, C. F. Carter, C. M.

Pearson, L. D. Alves, H. Lange, P. Thansandote, S. V. Ley, Angew.

Chem. Int. Ed. 2014, 53, 4915–4920; d) K. P. Cole, J. M. Groh, M. D.

Johnson, C. L. Burcham, B. M. Campbell, W. D. Diseroad, M. R. Heller,

J. R. Howell, N. J. Kallman, T. M. Koenig, S. A. May, R. D. Miller, D.

Mitchell, D. P. Myers, S. S. Myers, J. L. Phillips, C. S. Polster, T. D. White,

J. Cashman, D. Hurley, R. Moylan, P. Sheehan, R. D. Spencer, K.

Desmond, P. Desmond, O. Gowran, Science 2017, 356, 11441150; e)

S. K. Kashani, R. J. Sullivan, M. Andersen, S. G. Newman, Green Chem.

2018, 20, 17481753; f) M. G. Russell, T. F. Jamison, Angew. Chem. Int.

Ed. 2019, 58, 76787681.

[10] a) I. Vural Gursel, T. Noel, Q. Wang, V. Hessel, Green Chem. 2015, 17,

20122026; b) R. J. Sullivan, S. G. Newman, Chem. Sci. 2018, 9,

21302134.

[11] For examples of reactions performed in discrete slugs or droplets see: a)

H. Song, D. L. Chen, R. F. Ismagilov, Angew. Chem. Int. Ed. 2006, 45,

73367356; b) M. Sesen, T. Alan, A. Neild, Lab Chip 2017, 17,

23722394; c) T. S. Kaminski, P. Garstecki, Chem. Soc. Rev. 2017, 46,

62106226; d) E. S. Isbrandt, R. J. Sullivan, S. G. Newman, Angew.

Chem. Int. Ed. 2019, 58, 71807191; e) N. Candoni, R. Grossier, M.

Lagaize, S. Veesler, Annu. Rev. Chem. Biomol. 2019, 10, 5983; f) B. J.

Reizman, K. F. Jensen, Chem. Commun. 2015, 51, 1329013293; g) Y.-

J. Hwang, C. W. Coley, M. Abolhasani, A. L. Marzinzik, G. Koch, C.

Spanka, H. Lehmann, K. F. Jensen, Chem. Commun. 2017, 53,

66496652.

[12] Valves with a larger number of ports could also be used, providing the

same fluid connectivity is achieved through selection/fabrication of

appropriate routers. For example, in our case we had access to an 11-

port, 10-position selector valve which was used instead of a 7-port, 6-

position selector valve by fabrication of a suitable router. For full details

see the SI.

[13] A simple, minor modification, ~100 USD for a modified router.

[14] G. A. Price, D. Mallik, M. G. Organ, J. Flow Chem. 2017, 7, 8286.

[15] a) P. Hubbard, W. J. Brittain, J. Org. Chem. 1998, 63, 677683; b) A. J.

Oosthoek-de Vries, P. J. Nieuwland, J. Bart, K. Koch, J. W. G. Janssen,

P. J. M. van Bentum, F. P. J. T. Rutjes, H. J. G. E. Gardeniers, A. P. M.

Kentgens, J. Am. Chem. Soc. 2019, 141, 53695380.

[16] P. Patschinski, C. Zhang, H. Zipse, J. Org. Chem. 2014, 79, 83488357.

[17] For a discussion of typical values for activation enthalpies and entropies

see: E. V. Anslyn, D. A. Dougherty, Modern Physical Organic Chemistry,

University Science, Sausalito, 2006.

[18] J. Xu, R. Y. Liu, C. S. Yeung, S. L. Buchwald, ACS Catal. 2019, 9,

64616466.

download fileview on ChemRxivManuscript.pdf (0.94 MiB)



1

Supporting Information for

Reaction cycling for efficient kinetic analysis in flow

Ryan J. Sullivan, and Stephen G. Newman[a]

Centre for Catalysis Research and Innovation, Department of Chemistry and Biomolecular

Sciences, University of Ottawa, 10 Marie-Curie, Ottawa, Ontario, Canada, K1N 6N5

ORCID

Ryan J. Sullivan: 0000-0001-5540-6962

Stephen G. Newman: 0000-0003-1949-5069

E-mail: [email protected]

Contents

1 General experimental details....................................................................................................... 2

2 Details of flow reactor and equipment ........................................................................................ 2

3 Preparation of starting and reference materials. ......................................................................... 9

4 Procedures for batch kinetic experiments ................................................................................. 10

5 Batch kinetics data .................................................................................................................... 13

6 Procedures for flow kinetic experiments .................................................................................. 16

7 Flow kinetic data used to determine reaction orders ................................................................ 26

8 Calculated reaction pathway for the C–S cross-coupling reaction ........................................... 32

9 Troubleshooting and limitations ............................................................................................... 34

10 Calibration curves ................................................................................................................... 36

11 Characterization data of starting and reference materials ....................................................... 37

12 Energies of calculated structures ............................................................................................ 41

13 Cartesian coordinates of calculated structures ........................................................................ 43

14 References ............................................................................................................................... 79

2

1 General experimental details

Benzoyl chloride (1), benzyl alcohol (2), Bu3N (3), TBSCl (9), cyclopentadiene (23) and methyl

acrylate (24) 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 thiol cross-coupling reactions were prepared in oven-

dried glassware under an Ar atmosphere.

NMR spectra were collected on a Bruker Avance 400 MHz spectrometer. 1H and 13C 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 the concentration of the product was determined by GC

and the remaining reagent concentrations were calculated through mass balance assertion (i.e.,

stoichiometry). 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.

Calculations were performed using the Gaussian 09 software suite.1 Structures were optimized at

the M06-L2/def2-SVP3 level of theory with associated ECP for Pd and I,4 and confirmed to be

local minima or transition states by the presence of 0 or 1 imaginary frequencies respectively. For

transition state structures the normal mode vibration corresponding to the imaginary frequency

involved the motion of the correct atom(s) along the reaction coordinate in all cases. Energies were

calculated at the M06-L/def2-TZVP3 level of theory on the M06-L/def2-SVP optimized structures

and incorporated solvation effects using the polarizable continuum model with THF solvent5.

Zero-point and thermal corrections were taken from the M06-L/def2-SVP frequency calculations.

Et3N and PhI were used as model substrates for Bu3N and aryl iodide 12 respectively.

2 Details of flow reactor and equipment

2.1 Flow reactor set up for acylation, SNAr, silylation and ethanolysis experiments

A detailed description of the fluid paths through the valves to achieve cycling of a reaction slug is

given in Figure S1. A schematic of the entire reactor is shown in Figure S2 and a detailed schematic

of the tubing connections and volumes is provided in Figure S3. All tubing in the reactor was 1/16"

O.D., 0.5 mm I.D. PFA with the exception of the N2 line from the mass flow controller to the

reactor which was 1/16" O.D., 0.75 mm I.D. 316 stainless steel (316 SS). PEEK fittings were used

for all connections. The cross mixers and two-way valve were made of PEEK. The 6-port, 2-

position valves and the 11-port, 10-position selector valve were ChemInert valves from Vici Valco,

controlled electronically with both rotational directions operative for the selector valve. All

internal channels were 0.4 mm bore (analytical HPLC dimension).

The 11-port, 10-position valve was fitted with a custom rotor, providing the port connectivity

shown in Figure S4. The use of a 10-position valve is not necessary. This valve was selected based

3

on availability; only six-positions are required so any selector valve with ≥ 6 positions and a

suitably fabricated custom rotor to provide the same fluid connectivity would be sufficient.

PEEK fittings and parts were purchased from UpChurch Scientific. Stainless steel fittings and parts

were purchased from VICI Valco or Swagelok. Back pressure was provided by using as the

receiving flask a 100 mL solvent reservoir equipped with a PTFE cap (Vaporetc) that seals around

1/16" O.D. tubing and connects to a gas supply via a Luer connection. 10 psi of dynamic pressure

was provided by down-regulation of the house compressed air. Photographs of the reactor are

provided in Figures S5–6. A Chemxy fusion 200 dual channel syringe pump equipped with 2.5

mL glass syringes (Hamilton, air-tight) was used for formation of the reaction slug.

Figure S1. Principle of valve operation to cycle reaction slug.

4

Figure S2. Schematic of flow reactor used for the collection of kinetic data for acylation, SNAr, silylation and

ethanolysis reactions.

Figure S3. Tubing connectivity at the three valves. Ports 7 through 10 of the selector valve are unused and port 6 is

plugged.

Figure S4. Port connectivity of custom rotor used in the 11-port, 10-position valve.

5

Figure S5. Photograph of reactor; water is drained from the bath for clarity. Out of view: N2 cylinder and mass flow

controller, step-down regulator for compressed air, computer to control valves.

hot plate

water bath

thermocouple

valves

pressurized receiving

flask (waste)

Fusion 200

syringe pump

N2 feed

line cross-

mixer

shut-off

valve

GC vials

syringe for manual

sample removal

6

Figure S6. Close-up photograph of reactor coils.

2.2 Flow reactor set up for palladium catalyzed thiol etherification experiments

Minimal changes were required to perform the palladium catalyzed reactions under inert

atmosphere (Figure S7). Specifically, the receiving flask was pressurized with N2 instead of

compressed air and the apparatus was purged with N2 at 0.8 mL/min for 1 h before experiments

were conducted. Additionally, due to the lower concentrations used for the cross-coupling

experiments the sampling loop volume was increased from 15 μL to 20 μL to allow collection of

larger aliquots.

Coil A

Coil B

sample

loop

valve 2

valve 1

sampling

valve

7

Figure S7. Schematic of flow reactor used for the collection of kinetic data for the palladium catalyzed thiol

etherification reaction.

2.3 Flow reactor set up for cycloaddition experiments

Modifications required for the collection of kinetic data for the cycloaddition reaction were as

follows (Figure S8–9): The aqueous carrier solvent was delivered by a Hitec-Zang SyrDos 2

continuous dual syringe pump equipped with 0.5 mL glass syringes. A 1.25 mL, 1/16" O.D., 1.0

mm I.D. PFA loading coil with tee mixers before and after was added before the reactor valves to

facilitate formation of sequential reaction slugs and initiate the reactions. The two reactor coils (A

and B) were changed to 2.0 mL, 1/16" O.D., 1.0 mm I.D. PFA, and a spring-loaded 75 psi back

pressure regulator was installed at the reactor exit. PEEK tee-mixers, check valves and back

pressure regulators were purchased from UpChurch Scientific. Photographs of the reactor setup

are provided in Figures S10–11.

Figure S8. Schematic of flow reactor used for the collection of kinetic data for the cycloaddition reaction:

Connectivity to load slugs into loading coil.

8

Figure S9. Schematic of flow reactor used for the collection of kinetic data for the cycloaddition reaction:

Connectivity to initiate reactions and obtain kinetic data.

Figure S10. Photograph of reactor setup used for cycloaddition kinetics. Blue dye (Brilliant blue) added to aqueous

solution for visual contrast. Omitted from image: GC vials and syringes used for reaction initiation/manual sample

collection.

waste

collection

75 psi

BPR

SyrDos 2

pump

aqueous feed

solution

reactor

coils

loading

coil

check

valve

tee-

mixer shut-off

valve

reactor

valves

9

Figure S11. Close-up photograph of loading coil. Syringe pump connected to 1st shut-off valve to load slugs then

connected to 2nd shut off valve to initiate reactions.

3 Preparation of starting and reference materials.

Benzyl benzoate (4). Benzoyl chloride (0.56 g, 4.0 mmol) was combined toluene (5 mL), benzyl

alcohol (0.47 g, 4.4 mmol) and Et3N (0.44 g, 4.4 mmol) and stirred 15 min at 40 °C. The resulting

suspension was then washed with 1 M HCl (5 mL) and the organic phase dried over Na2SO4.

Evaporation 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

data were in agreement with the literature.6 1H NMR (400 MHz, CDCl3) 8.09 (d, J = 7.9 Hz, 2H),

7.57 (t, J = 7.3 Hz, 1H), 7.40 (m, 7H), 5.38 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) 166.6,

136.2, 133.2, 130.3, 1298, 128.7, 128.5, 128.4, 128.3, 66.8.

4-(4-Nitrophenyl)morpholine (8). The reaction solutions used for the generation of the batch

kinetic data were combined, EtOAc (20 mL) was added and the organics washed with 2 10 mL

1 M HCl then dried over Na2SO4. The solvent evaporated and the residue chromatographed on

silica gel (25 100 mm, 5:1 hexanes:EtOAc eluent) to yield 0.30 g of the pure product as an orange

powder. Characterization data were in agreement with the literature.7 1H NMR (400 MHz, CDCl3)

8.15 (d, J = 9.4 Hz, 2H), 6.84 (d, J =9.4 Hz, 2H), 3.87 (t, J = 5.1 Hz, 4H), 3.37 (t, J = 5.2 Hz,

4H). 13C{1H} NMR (100 MHz, CDCl3) 155.1, 139.2, 126.0, 112.8, 66.5, 47.3.

1st shut-off

valve

tee-mixer

check

valve

2nd shut-off

valve

tee-mixer

loading coil

10

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 N-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 organic phase

dried over Na2SO4. The solvent was evaporated 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 data were in agreement with the literature.7 1H NMR (400

MHz, CDCl3): δ 7.77 (d, J = 7.8 Hz, 1H), 7.51 (d J = 7.7 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 6.96 (t,

J = 7.8, 1H), 4.63 (s, 2H), 0.98 (s, 9H), 0.14 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 142.9,

138.6, 128.5, 128.2, 127.4, 95.8, 69.4, 26.0, 18.4, –5.3.

Methyl 5-norbornene-2-carboxylate (25). Cyclopentadiene (0.93 mL, 11 mmol) and methyl

acrylate (0.90 mL, 10 mmol) were combined in CHCl3 (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 literature.8 1H

NMR (400 MHz, CDCl3) endo isomer: 6.18 (dd, J = 5.6, 3.0 Hz, 1H), 5.92 (dd, J = 5.6, 2.8 Hz,

1H), 3.62 (s, 3H), 3.19 (br s, 1H), 2.94 (m, 1H), 2.90 (br s, 1H), 1.90 (m, 1H), 1.39 (m, 2H), 1.26

(d, J = 8.1 Hz, 1H), exo isomer: 6.13 (dd, J = 5.6, 2.9 Hz, 1H), 6.10 (dd, J = 5.6, 3.1 Hz, 1H), 3.68

(s, 3H), 3.03 (br s, 1H), 2.92 (br s, 1H), 2.21 (dd, J = 10.3, 4.6 Hz, 1H), 1.90 (m, 1H), 1.52 (d, 8.4

Hz, 1H), 1.39 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) endo isomer: 175.4, 137.9, 132.5, 51.6,

49.7, 45.8, 43.3, 42.6, 29.4, exo isomer: 176.9, 138.2, 135.9, 51.8, 46.7, 46.5, 43.1, 41.7, 30.5.

4 Procedures for batch kinetic experiments

4.1 Benzoyl chloride + benzyl alcohol

General procedure. Benzoyl chloride (1) and hexadecane (59 μL, 0.2 mmol) were made up to 1.00

mL with toluene. Benzyl alcohol (2) and Bu3N (3) were made up to 1.00 mL with toluene. The

two solutions were combined at room temperature and stirred. 15 μL aliquots were taken at 1, 2,

3, 5, 10, 15, 25 and 40 min which were quenched with 600 μL of 5:1 EtOAc:MeOH and analyzed

by GC-FID.

Reaction 1. 0.5 M 1 (116 μL, 1.0 mmol), 0.5 M 2 (103 μL, 1.0 mmol), 0.6 M 3 (286 μL, 1.2 mmol).

11




4.2 1-Fluoro-4-nitrobenzene + morpholine

General procedure. 1-Fluoro-4-nitrobenzene (5) and 1,3,5-trimethoxybenzene (134 mg, 0.8

mmol) were made up to 1.00 mL with MeCN. Morpholine (6) and DBU (7) were made up to 1.00

mL with MeCN. The two solutions were combined and stirred at 80 °C. 15 μL aliquots were taken

at 2, 4, 6, 10, 15, 30 and 45 min which were quenched by dilution with 700 μL MeCN and analyzed

by GC-FID.





4.3 TBSCl + 2-iodobenzyl alcohol

General procedure. Solutions of 9 and hexadecane were prepared in DCM (electrophile solution).

Solutions of 10, 3 and 11 were prepared in DCM (nucleophile solution). For each reaction 250 μL

of electrophile solution was combined with 250 μL of nucleophile solution and the reaction stirred

at 0 °C. 15 μL aliquots were taken at 2, 4, 6, 10, 15, 25, 35 and 45 min which were quenched with

600 μL of 5:1 EtOAc:MeOH and analyzed by GC-FID. It was essential to use a single stock

solution of 9 to prepare all subsequent electrophile solutions to obtain best results.

Electrophile solution 1: 1 (1.50 g, 10 mmol) and hexadecane (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.

Nucleophile solution 1: 10 (116 mg, 0.50 mmol), 3 (143 μL, 0.6 mmol), 11 (6.6 μL, 0.050 mmol).


12



Reaction 1. 0.28 M 9, 0.25 M 10, 0.3 M 3, 0.025 M 11: 250 μL of electrophile solution 2 + 250

μL of nucleophile solution 1.







Reaction 5. 0.5 M 9, 0.25 M 10, 0.5 M 3, 0.025 M 11: 250 μL of electrophile solution 1 + 250 μL

of nucleophile solution 4.

13

5 Batch kinetics data

Figure S12. Variable time normalization plots for reaction of 1 and 2. Standard conditions: 0.5 M 1, 0.5 M 2, 0.6 M 3

in toluene, room temperature.

0

0.1

0.2

0.3

0.4

0.5

0 10 20 30 40

[4] (M

)

[1]0t

0.5 M 11.0 M 1

0 5 10 15 20 25 30

[1]1t

0.5 M 11.0 M 1

0 5 10 15

[1]2t

0.5 M 11.0 M 1

0

0.1

0.2

0.3

0.4

0.5

0 10 20 30 40

[4] (M

)

[2]0t

0.5 M 21.0 M 2

0 5 10 15 20 25

[2]1t

0.5 M 21.0 M 2

0 5 10 15

[2]2t

0.5 M 21.0 M 2

0

0.1

0.2

0.3

0.4

0.5

0 10 20 30 40

[4] (M

)

[3]0t

0.6 M 31.0 M 3

0 5 10 15 20 25

[3]1t

0.6 M 31.0 M 3

0 5 10 15

[3]2t

0.6 M 31.0 M 3

0

0.1

0.2

0.3

0.4

0.5

0 5 10 15 20 25 30

[4] (M

)

[3]1/2t

0.6 M 31.0 M 3

0

0.1

0.2

0.3

0.4

0 25 50 75

[4] (M

)

[1]1[2]1[3]1/2t

kobs = 6.82 10–3 L3/2mol–3/2s–1

y = 0.00682xR2 = 0.981 standard

excess 1excess 2excess 3

14


in MeCN, 80 °C

0

0.1

0.2

0.3

0.4

0.5

0 10 20 30 40

[8] (M

)

[5]0t

0.5 M 51.0 M 5

0 5 10 15 20 25 30

[5]1t

0.5 M 51.0 M 5

0 5 10 15 20

[5]2t

0.5 M 51.0 M 5

0

0.1

0.2

0.3

0.4

0.5

0 10 20 30 40

[8] (M

)

[6]0t

0.5 M 61.0 M 6

0 5 10 15 20 25 30

[6]1t

0.5 M 61.0 M 6

0 5 10 15

[6]2t

0.5 M 61.0 M 6

0

0.1

0.2

0.3

0.4

0.5

0 10 20 30 40

[8] (M

)

[7]0t

0.5 M 71.0 M 7

0 5 10 15 20 25 30 35

[7]1t

0.5 M 71.0 M 7

0 5 10 15 20 25

[7]2t

0.5 M 71.0 M 7

15

0

0.05

0.1

0.15

0.2

0 10 20

[12] (M

)

[9]0t

0.28 M 90.5 M 9

0 2 4 6 8

[9]1t

0.28 M 90.5 M 9

0 1 2 3

[9]2t

0.28 M 90.5 M 9

0

0.05

0.1

0.15

0.2

0 10 20

[12] (M

)

[10]0t

0.25 M 100.38 M 10

0 2 4 6

[10]1t

0.25 M 100.38 M 10

0 0.5 1

[10]2t

0.25 M 100.38 M 10

0

0.05

0.1

0.15

0 10 20

[12] (M

)

[3]0t

0.3 M 30.5 M 3

0 2 4 6 8 10 12

[3]1t

0.3 M 30.5 M 3

0 2 4

[3]2t

0.3 M 30.5 M 3

0 25 50 75 100 125

[3]–1t

0.3 M 30.5 M 3

16

Figure S14. Variable time normalization plots for reaction of 9 and 10. Standard conditions: 0.28 M 9, 0.25 M 10, 0.5

M 3, 0.025 M 11, DCM, 0 °C.

6 Procedures for flow kinetic experiments

6.1 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 (Figure

S2).

The N2 flow was set to 3 mL/min for 2 min (to quickly 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) and the sampling valve was set to collect a sample. The 2-way valve was closed

(to interrupt the N2 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.

Notes: 1) Valve 1 is actuated before valve 2 to maintain N2 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.

0

0.05

0.1

0.15

0 10 20 30 40

[12] (M

)

t[11]0

0.013 M 110.025 M 11

0 0.2 0.4 0.6

t[11]1

0.013 M 110.025 M 11

0 0.005 0.01 0.015

t[11]2

0.013 M 110.025 M 11

17

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.

This sequence of sample collection + valve actuation was repeated to collect subsequent samples.

To increase the time increment between samples, the flow rate of N2 was decreased to 0.4 mL/min

after the 3rd sample was collected and to 0.2 mL/min after the 6th 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).

Electrophile solution 1: 1 (116 μL, 1.0 mmol), hexadecane (59 μL, 0.2 mmol) made up to 1.00 mL

with toluene.

Electrophile solution 2: 1 (232 μL, 2.0 mmol), hexadecane (59 μL, 0.2 mmol) made up to 1.00 mL

with toluene.

Nucleophile solution 1: 2 (103 μL, 1.0 mmol), 3 (286 μL, 1.2 mmol) made up to 1.00 mL with

toluene.


toluene.


toluene.

Reaction 1. Electrophile solution 1 + nucleophile solution 1: 0.5 M 1, 0.5 M 2, 0.6 M 3.




6.2 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 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 (see

Figure S2). 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.

18

Reaction slugs were formed as in section 6.1 and the initial N2 flow rate was also the same at 0.8

mL/min. 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 two

samples had been collected the N2 flow was set to 0.5 mL/min, then after two more samples had

been collected N2 flow was set to 0.2 mL/min and 4 more samples were collected. This allowed

collection of reaction aliquots at approximately 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).

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.

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.


MeCN.


MeCN.


MeCN.





6.3 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 (Figure

S2). 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 section 6.1 and the initial N2 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 N2 flow was set to 0.4 mL/min and an additional 5 samples

19

were collected. This allowed collection of reaction aliquots at approximately 1:40, 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).

Electrophile solution 1: 9 (1.50 g, 10 mmol) and hexadecane (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.

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.







Reaction 1. Electrophile solution 1 + nucleophile solution 1: 0.28 M 9, 0.25 M 10, 0.3 M 3, 0.025

M 11.


M 11.


M 11.


M 11.


M 11.

6.4 1-Bromoethylbenzene and EtOH

General procedure. A 1.0 M solution of 16 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 18 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 (Figure S2). The reactor coils were submerged in

20

the water bath at desired reaction temperature. The valves placed just above the surface of the ice

water bath.

Reaction slugs were formed as in section 6.1. The initial N2 flow rate was varied depending on the

reaction 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: 1-Bromoethylbenzene (273 μL, 2.0 mmol), 1,3,5-trimethoxybenzene (269

mg, 1.6 mmol) made up to 2.00 mL with EtOH.


mg, 0.8 mmol) made up to 1.00 mL with 4:1 EtOH:t-BuOH.


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.

TosOH solution 2: TosOH (96 mg, 0.5 mmol) made up to 10.00 mL with EtOH.

TosOH solution 3: TosOH (47 mg, 0.25 mmol) made up to 1.00 mL with 4:1 EtOH:t-BuOH.

TosOH solution 4: TosOH (46 mg, 0.25 mmol) made up to 1.00 mL with 10:1 EtOH:t-BuOH.

Reaction 1. Electrophile solution 1 + TosOH solution 1, 40 °C. N2 flow 0.5 mL/min, samples

collected at 3:30, 6:20, 9:30 min then N2 flow decreased to 0.2 mL/min, samples collected at 17:45,

29:00, 40:00, 51:00 min.


collected at 2:15, 5:15, 8:15, 11:15 min then N2 flow decreased to 0.2 mL/min, samples collected

at 16:20, 23:10, 29:00, 34:45, 40:20, 46:00 min.



14:00, 17:45 min then N2 flow decreased to 0.3 mL/min, samples collected at 23:00, 28:30, 34:10,

39:30, 45:10 min.




37:45 min.



10:30, 13:15 min then N2 flow decreased to 0.3 mL/min, samples collected at 18:00, 23:15, 28:15

min.



14:45, 19:00 min then N2 flow decreased to 0.3 mL/min, samples collected at 24:10, 30:15, 36:30

min.



21


29:50 min.




39:50 min.

6.5 TBS protected 2-iodobenzyl alcohol and 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 (S1) and t-BuXPhos (S2) in

THF and aging 10 min (“catalyst solution”). Solutions of 12, 20, 3 and hexandecane were prepared

in THF (“substrate solutions”). The reactor was purged with N2 at 0.8 mL/min for 1 h before

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 (Figure S7).

Reaction slugs were formed as in section 6.1 and the initial N2 flow rate was the same at 0.8

mL/min. Valve 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).

Order in catalyst experiments:

Catalyst solution 1: [PdCl(allyl)]2 (S1, 5.7 mg, 0.016 mmol) and t-BuXPhos (S2,13.6 mg, 0.032

mmol) were made up to 4.00 mL with THF.

Catalyst solution 2: 0.75 mL of catalyst solution 1 was diluted to 1.00 mL with THF.




Substrate solution 1: 12 (52 μL, 70 mg, 0.2 mmol), 20 (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 1. Catalyst solution 2 + substrate solution 1: 0.05 M 12, 0.075 M 20, 0.1 M 3, 0.003 M

Pd(t-BuXPhos)(allyl)Cl (6%).



22





Order in ArI experiments:

Catalyst solution 1: S1 (4.3 mg, 0.012 mmol) and S2 (10.1 mg, 0.024 mmol) were made up to 4.00

mL with THF.

Substrate solution 1: 12 (39 μL, 52 mg, 0.15 mmol), 20 (8.4 μL, 0.075 mmol), 3 (24 μL, 0.1 mmol),






Substrate solution 4: 12 (6.5 μL, 9 mg, 0.025 mmol), 20 (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 5: 12 (3.2 μL, 4 mg, 0.013 mmol), 20 (8.4 μL, 0.075 mmol), 3 (24 μL, 0.1



Pd(t-BuXPhos)(allyl)Cl.









Order in t-BuSH experiments:


mL with THF.









23



Substrate solution 6: 12 (13 μL, 17 mg, 0.05 mmol), 20 (1.0 μL, 0.0094 mmol), 3 (24 μL, 0.1


Reaction 1. Catalyst solution 1 + substrate solution 1: 0.05 M 12, 0.3 M 20, 0.1 M 3, 0.003 M Pd(t-

BuXPhos)(allyl)Cl.











Order in Bu3N experiments:


mL with THF.

















Reaction 4. Catalyst solution 1 + substrate solution 4: 0.05 M 12, 0.075 M 20, 0.025 M 3, 0.003

M Pd(t-BuXPhos)(allyl)Cl.

24

Reaction 5. Catalyst solution 1 + substrate solution 5: 0.05 M 12, 0.075 M 20, 0.013 M 3, 0.003

M Pd(t-BuXPhos)(allyl)Cl.

6.6 Cyclopentadiene and methyl acrylate

23 was freshly distilled immediately before use and stored at –78 °C.

Solutions of 24 with hexadecane were prepared in CHCl3 (“acrylate solutions”):

Acrylate solution 1: 24 (34 μL, 0.38 mmol), hexadecane (22 μL, 0.075 mmol) up to 0.50 mL with

CHCl3.


CHCl3.


CHCl3.

Slugs were loaded into the loading coil (Scheme S8) by taking the desired 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 (Figure S8). The slugs were loaded as follows: 333 μL of dienophile solution

1, 150 μL of H2O, 333 μL of dienophile solution 2, 150 μL of H2O, 167 μL of dienophile solution

3, 50 μL of H2O.

A 2.25 M solution of 23 was prepared by diluting 23 (189 μL, 2.25 mmol) up to 1.00 mL with

CHCl3 (“diene solution”) and 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 (Figure

S9) and 50 μL was 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.

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 24 and 0.75 M in 23. 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.

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 24 and 0.75 M in 23. After the dienophile solution

2 slug completely exited the loading coil the SyrDos flow rate was set back to 200 μL/min again

and the diene pump was stopped.

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

25

mL reaction plug that was 0.5 M in 24 and 1.5 M in 23. After the dienophile solution 3 slug

completely exited the loading coil the SyrDos pump was set to 200 μL/min again and the diene

solution pump was stopped.

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 flushed with H2O. 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 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 flushed with H2O. 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 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 H2O. 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.

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 (counter-clockwise rotation), and the sampling valve to collection. Sampling

and valve actuation were repeated to collect desired samples.

Note. In experiments using N2 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 progressed by

decreasing the N2 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 between sample collection as the reaction progressed therefore the carrier flow rate

was unchanged and collection of sample collection was simply skipped at 50, 1:10, 1:30, 1:50,

2:10, 2:20, 2:40 and 2:50 min. To skip sample collection, the sampling valve was simply not

actuated as the reaction slugs travelled through, and only reactor valves 1 and 2 were actuated

after all three reaction slugs had passed from one reactor coil into the other.

26

7 Flow kinetic data used to determine reaction orders


in toluene, room temperature.

0

0.1

0.2

0.3

0.4

0.5

0 10 20 30 40

[4] (M

)

[1]0t

0.5 M 11.0 M 1

0 5 10 15 20 25

[1]1t

0.5 M 11.0 M 1

0 5 10 15

[1]2t

0.5 M 11.0 M 1

0

0.1

0.2

0.3

0.4

0.5

0 10 20 30 40

[4] (M

)

[2]0t

0.5 M 21.0 M 2

0 5 10 15 20 25

[2]1t

0.5 M 21.0 M 2

0 5 10 15

[2]2t

0.5 M 21.0 M 2

0

0.1

0.2

0.3

0.4

0.5

0 10 20 30 40

[4] (M

)

[3]0t

0.6 M 31.0 M 3

0 5 10 15 20 25

[3]1t

0.6 M 31.0 M 3

0 5 10 15

[3]2t

0.6 M 31.0 M 3

0 5 10 15 20 25 30

[3]1/2t

0.6 M 31.0 M 3

27


in MeCN, 80 °C.

0

0.1

0.2

0.3

0.4

0.5

0 10 20 30 40

[8] (M

)

[5]0t

0.5 M 51.0 M 5

0 5 10 15 20 25 30

[5]1t

0.5 M 51.0 M 5

0 5 10 15 20

[5]2t

0.5 M 51.0 M 5

0

0.1

0.2

0.3

0.4

0.5

0 10 20 30 40

[8] (M

)

[6]0t

0.5 M 61.0 M 6

0 5 10 15 20 25 30

[6]1t

0.5 M 61.0 M 6

0 5 10 15 20

[6]2t

0.5 M 61.0 M 6

0

0.1

0.2

0.3

0.4

0.5

0 10 20 30 40

[8] (M

)

[7]0t

0.5 M 71.0 M 7

0 5 10 15 20 25 30 35

[7]1t

0.5 M 71.0 M 7

0 5 10 15 20 25

[7]2t

0.5 M 71.0 M 7

28

0

0.05

0.1

0.15

0.2

0.25

0 10 20 30

[12] (M

)

[9]0t

0.28 M 90.5 M 9

0 2 4 6 8

[9]1t

0.28 M 90.5 M 9

0 1 2 3

[9]2t

0.28 M 90.5 M 9

0

0.05

0.1

0.15

0.2

0 10 20 30

[12] (M

)

[10]0t

0.25 M 100.38 M 10

0 2 4 6

[10]1t

0.25 M 100.38 M 10

0 0.5 1 1.5

[10]2t

0.25 M 100.38 M 10

0

0.05

0.1

0.15

0.2

0 10 20 30

[12] (M

)

[3]0t

0.3 M 30.5 M 3

0 2 4 6 8 10 12

[3]1t

0.3 M 30.5 M 3

0 2 4

[3]2t

0.3 M 30.5 M 3

0 25 50 75 100 125 150 175

[3]–1t

0.3 M 30.5 M 3

29

Figure S17. Variable time normalization plots for reaction of 9 and 10. Standard conditions: 0.28 M 9, 0.25 M 10, 0.5

M 3, 0.025 M 11 in DCM, 0 °C.

0

0.05

0.1

0.15

0.2

0 10 20 30 40

[12] (M

)

t[11]0

0.013 M 110.025 M 11

0 0.2 0.4 0.6

t[11]1

0.013 M 110.025 M 11

0 0.005 0.01 0.015

t[11]2

0.013 M 110.025 M 11

30

Figure S18. Integrated rate law plots for the pseudo-first order ethanolysis of 16. Conditions: 0.5 M 16, 0.125 M 18

in EtOH, 70 °C.

Figure S19. Plots of ln[16] vs. time. A) Varying [18], B) varying [17], C) varying T.

0

0.1

0.2

0.3

0.4

0.5

0 10 20 30 40

[16]

t (min)

y = -0.054x - 0.761R² = 0.997

-3

-2.5

-2

-1.5

-1

-0.5

0 10 20 30 40

ln[1

6]

t (min)

0

5

10

15

0 10 20 30 40

1/[

16]

t (min)

y = -0.054x - 0.761

y = -0.060x - 0.674

-3

-2.5

-2

-1.5

-1

-0.5

0 10 20 30 40

ln[1

6]

t (min)

25% TosOH

5% TosOH

A

y = -0.054x - 0.761

y = -0.048x - 0.736

y = -0.038x - 0.706

-3

-2.5

-2

-1.5

-1

-0.5

0 10 20 30 40 50

ln[1

6]

t (min)

EtOH

10:1 EtOH:t-BuOH

4:1 EtOH:t-BuOH

B

y = -0.0036x - 0.7053

y = -0.0087x - 0.7373

y = -0.023x - 0.743

y = -0.054x - 0.761

y = -0.12x - 0.82

-3

-2.5

-2

-1.5

-1

-0.5

0 10 20 30 40 50

ln[1

6]

t (min)

40 °C

50 °C

60 °C

70 °C

80 °C

C

31

Figure S20. Initial rate plots. A) Varying concentration of 21, B) varying concentration of 12, C) varying concentration

of 20, D) varying concentration of 3. Standard conditions: 50 mM 12, 75 mM 20, 100 mM 3, 3mM 21 (prepared from

1.5 mM S1, 3 mM S2) in THF, room temperature.

0

0.5

1

1.5

2

2.5

3

1 3 5 7 9

[P] (m

M)

t (min)

A 3 mM 212 mM 211 mM 210.5 mM 21

0

0.5

1

1.5

2

2.5

3

3.5

4

1 3 5 7 9

[22] (m

M)

t (min)

150 mM 12100 mM 1250 mM 1225 mM 1213 mM 12

B

0

0.5

1

1.5

2

2.5

3

3.5

4

1 3 5 7 9

[P] (m

M)

t (min)

C 300 mM 20150 mM 2075 mM 2038 mM 2019 mM 209.4 mM 20

0

0.5

1

1.5

2

2.5

3

3.5

4

1 3 5 7 9

[22] (m

M)

t (min)

150 mM 3100 mM 350 mM 325 mM 313 mM 3

D

32

Figure S21. Variable time normalization plots for reaction of 23 and 24. Standard conditions: 0.75 M 23, 0.5 M 24 in

CHCl3, 70 °C.

8 Calculated reaction pathway for the C–S cross-coupling reaction

Kinetic experiments identified either thiol deprotonation or reductive elimination as the rate

determining steps of the catalytic cycle. To provide further insight, the reaction pathway for the

cross-coupling of PhI with t-BuSH was calculated (Figure S22). All individual elementary steps

exhibited small activation barriers (< 10 kcal/mol), consistent with the experimental observation

of saturation kinetics due to very fast elementary steps. Only oxidative addition (I2 to I3) and

reductive elimination (I8 to I10) were exergonic enough to be considered irreversible, with all

other elementary steps occurring as rapid, reversible equilibria.

The oxidative addition intermediate I3 was found to be the turnover frequency determining

intermediate9 (TDI, i.e., the catalyst resting state), in agreement with the previous 31P NMR

experiments10 and the reaction order of 0 observed for aryl iodide 12. Interestingly, it was found

that cis-trans isomerization of I4 to a trans species after oxidative addition was not favorable, (no

stable trans intermediate could be located) presumably due to the steric bulk of the t-Bu groups on

the phosphine in close proximity to the metal centre even after rotation of the biaryl group to reveal

a vacant coordination site in I4. Exchange of I– for t-BuS– by coordination of t-BuSH,

deprotonation and isomerization was slightly uphill by ~5 kcal/mol, with low activation barriers

throughout. Reductive elimination (TS4) was found to the be turnover frequency limiting

transition state (TDTS, i.e., the rate limiting step). The activation energy (energy separating TDI

0

0.1

0.2

0.3

0.4

0.5

0 50 100 150 200

[25] (M

)

[23]0t

0.75 M 231.5 M 23

0 50 100 150 200

[23]1t

0.75 M 231.5 M 23

0 50 100 150 200

[23]2t

0.75 M 231.5 M 23

0

0.1

0.2

0.3

0.4

0.5

0 50 100 150 200

[25] (M

)

[24]0t

0.5 M 241.0 M 24

0 50 100

[24]1t

0.5 M 241.0 M 24

0 20 40 60 80

[24]2t

0.5 M 241.0 M 24

33

I3 and TSTS TS4) is illustrated by placing two catalytic cycles consecutively in Figure S23. For

the reductive elimination, it could be envisioned to occur with the ligand in the open configuration

TS4, or after rotation of the biaryl group to stabilize the vacant coordination site on Pd (TS6,

Figure S24). The activation barrier for ligand rotation was estimated by performing a potential

energy scan of the ligand dihedral angle and was found to be ~13 kcal/mol. This was greater than

the energy barrier for the reductive elimination with the ligand in an ‘open’ configuration (~10

kcal/mol), suggesting that reductive elimination occurs immediately following cis-trans

isomerization of the thiol group to I8 and then ligand rotation occurs from I9 to lead give I10.

Figure S22. Energy profile of one catalytic cycle for the cross-coupling of PhI with t-BuSH; M06-L/def2-TZVP//M06-

L/def2-SVP level of theory. Only lowest energy pathway is shown.

Figure S23. Energy profile for two consecutive catalytic cycles in the cross-coupling of PhI with t-BuSH with energies

relative to TDI I3; M06-L/def2-TZVP//M06-L/def2-SVP level of theory.

34

Figure S24. Additional computation details regarding the ligand orientation during reductive elimination; M06-

L/def2-TZVP//M06-L/def2-SVP level of theory. The energy of TS5 was estimated from the maximum of a potential

energy surface scan of the ligand dihedral angle.

9 Troubleshooting and limitations

The main limitation of the flow reactor is an inability to handle heterogeneous reaction

mixtures well. Solid handling is an inherent limitation of flow in general, although obtaining good

kinetics from heterogeneous liquid-solid mixtures is also problematic in batch since mass transport

plays a significant role in reaction rate and factors such as particle shape and size, agitation, etc.

can change over the course of the reaction.

Liquid-liquid or gas-liquid biphasic reactions also present a challenging due to inability to

control which phase gets sampled. This could be addressed by incorporating a liquid-liquid or gas-

liquid separator respectively before the sampling valve to send only the desired liquid stream for

sampling, then recombining the two phases after the sampling valve before returning to the

residence coil.

Reactions generating gaseous biproducts are also currently a challenge to handle, again due to

lack of control over which phase gets sampled. A gas-liquid separator installed before the sampling

valve to off-gas the solution before sampling on each cycle could address this problem (no

recombination after the sampling valve needed in this case).

There is also an upper limit to the carrier fluid flow rate in order to maintain integrity of the

reaction slug which sets a lower limit on sampling frequency. This was empirically observed to be

~0.8 mL/min with the current reactor design. Higher flow rates of N2 carrier gas resulted in

excessive breaking of the reaction slug due to shear forces along the coil walls and gave a lower

limit of ~1 sample every 90s. Faster sampling could be achieved by decreasing the volumes of the

residence coils, but this would also begin to set a limit on the volume of the reaction slug, and

therefore the number of samples that could be taken before. Regardless, achieving sampling rates

35

above ~1 sample / minute would be a challenge and therefore this reactor design is likely not

amenable to extremely fast chemistries. However, extremely fast reactions are ideally suited for

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.

36

10 Calibration curves

Figure S25. Calibration curve for benzyl benzoate (4);

0.1 M hexadecane as internal standard.

Figure S26. Calibration curve for 4-(4-nitrophenyl)

morpholine (8); 0.4 M 1,3,5-trimethoxybenzene as

internal standard.

Figure S27. Calibration curve for tert-butyl((2-

iodobenzyl)oxy)dimethylsilane (12); 0.1 M

hexandecane as internal standard.

Figure S28. Calibration curve for 1-bromoethylbenzene

(16); 0.4 M 1,3,5-trimethoxybenzene as internal

standard.

Figure S29. Calibration curve for methyl 5-norbornene-

2-carboxylate (25); 0.1 M hexadecane as internal

standard.

Figure S30. Calibration curve for dicyclopentadiene;

0.1 M hexadecane as internal standard.

y = 0.00640x + 0.16390R² = 0.99774

0

2

4

6

0 200 400 600 800 1000

A/A

instd

C (mM)

y = 0.00285x - 0.09765R² = 0.99914

0

1

2

3

0 200 400 600 800 1000

A/A

instd

C (mM)

y = 0.00782x + 0.06187R² = 0.99930

0

1

2

3

4

5

0 100 200 300 400 500

A/A

instd

C (mM)

y = 0.00336x - 0.05692R² = 0.99989

0

1

2

3

4

0 200 400 600 800 1000

A/A

instd

C (mM)

y = 0.00508x + 0.00831R² = 0.99966

0

1

2

3

0 100 200 300 400 500

A/A

instd

C (mM)

y = 0.00526x + 0.00792R² = 0.99994

0

1

2

3

0 100 200 300 400 500

A/A

instd

C (mM)

37

11 Characterization data of starting and reference materials

Benzyl benzoate (4)

38

4-(4-nitrophenyl)morpholine (8)

39

tert-butyl((2-iodobenzyl)oxy)dimethylsilane (12)

40

methyl 5-norbornene-2-carboxylate (25)

41

12 Energies of calculated structures

Table S1. Energies (in Hartree) for all organic and organometallic compounds and transition states: EDZ and thermal

corrections were calculated at the M06-L/def2-SVP level of theory; ETZ single point energy calculations were

performed on the M06-L/def2-SVP geometries at the M06-L/def2-TZVP level of theory with incorporation of

solvation energy using the continuous polarization model for THF.

Energies Thermal Corrections

(T = 298.15 K, p = 1 atm)

Structure ETZ EDZ Ezpe H G

Organic molecules

toluene -271.6206739 -271.3323151 0.127719 0.134944 0.096017

PhI -529.5707398 -529.3137692 0.089870 0.096724 0.058092

t-BuSH -556.6856135 -556.3831547 0.130282 0.137790 0.100779

Et3N -292.4725907 -292.1551786 0.205427 0.215722 0.171732

Et3N·HI -590.9958862 -590.6486939 0.219175 0.231623 0.179688

t-BuSPh -787.7821525 -787.2365297 0.213448 0.225934 0.176048

Organometallic compounds (L = t-BuXPhos)

I1 -1873.509479 -1871.877435 0.798618 0.843669 0.724982

I2 -2131.462221 -2129.862899 0.761501 0.806118 0.687807

TS1 -2131.452934 -2129.849546 0.760883 0.805454 0.685721

I3 -2131.490235 -2129.885513 0.763967 0.808442 0.690533

I4 -2131.466468 -2129.858705 0.762367 0.685409 0.685409

I5 -2688.171684 -2686.26779 0.895288 0.948866 0.80977

42

TS2 -2980.657771 -2978.437885 1.102390 1.164991 1.009864

I6 -2980.666403 -2978.441724 1.107991 1.170922 1.014437

I7 -2389.639849 -2387.747795 0.885954 0.936322 0.806276

TS3 -2389.641901 -2387.747156 0.885561 0.935170 0.806939

I8 -2389.647233 -2387.751497 0.884953 0.935526 0.804754

TS4 -2389.629697 -2387.736489 0.883936 0.934310 0.803382

I9 -2389.650521 -2387.755725 0.885993 0.936883 0.802996

I10 -2389.68188 -2387.78978 0.884109 0.934892 0.803088

TS5a -2389.625743 -2387.734902 0.886347 0.936484 0.807342

I11 -2389.669625 -2387.778985 0.885753 0.936207 0.805858

43

TS6 -2389.656562 -2387.766682 0.885903 0.935078 0.810177

a Transition state energy estimated from the maximum of a potential energy surface scan of the ligand dihedral angle.

13 Cartesian coordinates of calculated structures

toluene

atom x y z

C -1.198297 1.203598 0.001939 C 0.195028 1.201044 -0.009192 C 0.916457 0.000094 -0.011908 C 0.195145 -1.200986 -0.009188 C -1.198135 -1.203684 0.001935 C -1.901445 -0.000065 0.009055 H -1.739732 2.153231 0.001599 H 0.738993 2.150553 -0.018900 H 0.739208 -2.150443 -0.018891 H -1.739490 -2.153364 0.001585 H -2.993992 -0.000135 0.014947 C 2.413380 0.000054 0.008822 H 2.830925 0.890742 -0.479641 H 2.800196 -0.005870 1.040166 H 2.831093 -0.885036 -0.489641

PhI

atom x y z

C 2.645931 -1.205054 -0.000006 C 1.251437 -1.213546 -0.000003 C 0.561722 -0.000017 -0.000002 C 1.251423 1.213539 -0.000002 C 2.645903 1.205070 -0.000004 C 3.345869 0.000008 -0.000007 H 3.186742 -2.154721 -0.000007 H 0.707542 -2.160060 -0.000002 H 0.707487 2.160029 -0.000001 H 3.186723 2.154731 -0.000005 H 4.438065 0.000031 -0.000009 I -1.555477 0.000000 0.000003

t-BuSH

atom x y z

C -0.356280 -0.004703 -0.000002 C -0.840446 -0.719323 1.252267 H -0.494197 -1.762502 1.284759 H -0.486183 -0.220024 2.163777 H -1.942126 -0.738708 1.280458 C -0.840469 -0.719630 -1.252089 H -1.942149 -0.738890 -1.280343

44

H -0.486081 -0.220675 -2.163734 H -0.494358 -1.762870 -1.284253 C -0.816572 1.447039 -0.000166 H -1.916038 1.492538 0.000029 H -0.459912 1.986159 0.888900 H -0.460229 1.985877 -0.889535 S 1.505987 0.075940 -0.000019 H 1.708083 -1.256247 0.000190

Et3N

atom x y z

C -0.914176 -0.915174 0.699275 C -1.582505 -1.609802 -0.477899 H -2.375816 -2.289178 -0.135887 H -2.048009 -0.892866 -1.171061 H -0.869247 -2.211484 -1.060582 N 0.171780 -0.002392 0.382564 C 1.358368 -0.679169 -0.109512 C 2.623843 0.142501 0.017995 H 3.505315 -0.460345 -0.239037 H 2.633992 1.015261 -0.649883 H 2.747810 0.509694 1.046510 H 1.473324 -1.605004 0.478432 H 1.246025 -1.013797 -1.168096 C -0.210002 1.128213 -0.444152 C -1.367176 1.926848 0.112448 H -1.504701 2.856795 -0.455139 H -2.320610 1.381130 0.067566 H -1.186779 2.195211 1.163419 H 0.666273 1.790007 -0.526779 H -0.437884 0.822078 -1.493941 H -0.510122 -1.671432 1.392633 H -1.672136 -0.369834 1.284966

Et3N·HI

atom x y z

C -1.709059 -0.775108 -1.109422 N -1.323595 0.192910 -0.046105 C -1.573816 1.604789 -0.447419 C -1.018240 2.611454 0.527125 H -1.063551 3.610787 0.077506 H -1.582931 2.655281 1.467561 H 0.036968 2.393918 0.750836 H -1.081735 1.714328 -1.425263 H -2.656839 1.732809 -0.603820 C -1.826427 -0.141256 1.314297 C -1.542032 -1.566236 1.712662 H -1.773306 -1.699092 2.776481 H -2.143056 -2.297368 1.155618 H -0.476870 -1.801686 1.569019 H -1.307748 0.543196 1.998989 H -2.900027 0.108440 1.357470 C -3.193117 -0.939778 -1.303733 H -3.378176 -1.661795 -2.108672

45

H -3.695198 -1.327173 -0.405834 H -3.691285 -0.004646 -1.594306 H -1.206113 -0.425103 -2.022564 H -1.214191 -1.722907 -0.856053 H -0.225535 0.095898 0.001573 I 1.939640 -0.151480 -0.112771

t-BuSPh

atom x y z

C -0.356280 -0.004703 -0.000002 C -0.840446 -0.719323 1.252267 C -0.494197 -1.762502 1.284759 C -0.486183 -0.220024 2.163777 C -1.942126 -0.738708 1.280458 C -0.840469 -0.719630 -1.252089 H -1.942149 -0.738890 -1.280343 H -0.486081 -0.220675 -2.163734 H -0.494358 -1.762870 -1.284253 H -0.816572 1.447039 -0.000166 H -1.916038 1.492538 0.000029 S -0.459912 1.986159 0.888900 C -0.460229 1.985877 -0.889535 C 1.505987 0.075940 -0.000019 H 1.708083 -1.256247 0.000190 H -0.356280 -0.004703 -0.000002 H -0.840446 -0.719323 1.252267 C -0.494197 -1.762502 1.284759 H -0.486183 -0.220024 2.163777 H -1.942126 -0.738708 1.280458 H -0.840469 -0.719630 -1.252089 C -1.942149 -0.738890 -1.280343 H -0.486081 -0.220675 -2.163734 H -0.494358 -1.762870 -1.284253 H -0.816572 1.447039 -0.000166

(I1)

atom x y z

C 3.415283 -0.376078 -1.187923 P 2.003630 -0.054249 0.084654 C 2.660734 -0.455678 1.839741 C 1.778869 1.786576 0.104446 C 0.490463 2.368562 -0.028224 C 0.392713 3.769203 -0.104019 C 1.508477 4.596407 -0.040182 C 2.771394 4.028738 0.105454 C 2.890071 2.644929 0.173530 H 3.886698 2.213711 0.275949 H 3.662678 4.658389 0.158509 H 1.390526 5.680626 -0.106789 H -0.599672 4.211894 -0.230953 C -0.811775 1.628496 -0.110488 C -1.280247 1.138091 -1.357274 C -2.564407 0.593295 -1.435676

46

C -3.419802 0.519863 -0.333431 C -2.942573 1.014306 0.878458 C -1.662929 1.570083 1.013780 H -3.581981 0.976577 1.764123 H -2.918920 0.219888 -2.403059 Pd 0.076148 -1.230539 -0.324290 C 0.009290 -3.966649 -1.912829 C -0.420178 -3.525730 -0.544257 C -1.569041 -2.696283 -0.366252 C -2.079947 -2.481476 0.939487 C -1.514594 -3.113354 2.040183 C -0.413051 -3.966293 1.866165 C 0.130236 -4.150720 0.602680 H 0.993425 -4.811714 0.470543 H 0.030191 -4.472335 2.727655 H -1.931280 -2.947824 3.037009 H -2.955877 -1.840533 1.067516 H -2.152170 -2.377113 -1.238316 H 1.088842 -4.166955 -1.954413 H -0.498522 -4.902306 -2.202271 H -0.226142 -3.221293 -2.684933 C -1.261211 2.118805 2.371375 H -0.167169 2.264095 2.365307 C -0.482669 1.322871 -2.634306 H 0.547904 1.582817 -2.343286 C -4.807592 -0.069717 -0.500918 H -4.671601 -1.057246 -0.984164 C -5.546689 -0.300358 0.806253 H -6.505587 -0.806344 0.627657 H -4.973690 -0.921557 1.509988 H -5.774639 0.648828 1.315489 C -5.652531 0.782371 -1.445787 H -6.636329 0.323997 -1.624391 H -5.824279 1.783128 -1.020373 H -5.170253 0.922733 -2.423006 C -1.598504 1.158266 3.508521 H -1.106820 1.468148 4.442589 H -2.679386 1.133955 3.714879 H -1.284767 0.128697 3.285473 C -1.893997 3.484371 2.627232 H -2.993022 3.416883 2.616689 H -1.597227 3.880947 3.609722 H -1.603291 4.224124 1.868795 C -0.410111 0.062826 -3.485297 H 0.234933 0.216998 -4.363687 H 0.001068 -0.779377 -2.899859 H -1.396802 -0.244442 -3.865809 C -1.035916 2.500094 -3.433748 H -0.436261 2.686641 -4.337172 H -2.071835 2.309473 -3.755730 H -1.043384 3.426119 -2.840884 C 1.433758 -0.363946 2.745078 H 1.715305 -0.581816 3.788867 H 0.994970 0.643838 2.727042 H 0.653451 -1.080011 2.440281 C 3.730115 0.480950 2.392056

47

H 3.359224 1.510227 2.499341 H 4.021849 0.143726 3.400500 H 4.648222 0.510730 1.791219 C 3.151750 -1.901714 1.856183 H 2.397227 -2.583458 1.432618 H 4.094545 -2.046156 1.310207 H 3.333537 -2.216364 2.896889 C 4.854640 -0.154723 -0.730472 H 5.536888 -0.418981 -1.555478 H 5.078887 0.888960 -0.472422 H 5.137640 -0.784981 0.122681 C 3.145321 0.487876 -2.417045 H 2.137817 0.307432 -2.816405 H 3.247347 1.564502 -2.218935 H 3.860952 0.229005 -3.214130 C 3.259321 -1.840734 -1.613351 H 2.257214 -2.025226 -2.030183 H 4.006904 -2.086505 -2.385708 H 3.397353 -2.547179 -0.782484

(I2)

atom x y z

C -1.771647 3.010302 -1.018747 P -1.556771 1.477609 0.120655 C -2.068764 1.964562 1.902486 C -2.864056 0.265615 -0.375224 C -2.530682 -1.098856 -0.578101 C -3.545479 -1.983523 -0.983728 C -4.854914 -1.566096 -1.189102 C -5.182636 -0.226507 -0.996050 C -4.193642 0.665652 -0.595730 H -4.465378 1.713344 -0.453237 H -6.204019 0.125992 -1.157672 H -5.614255 -2.283662 -1.508970 H -3.279229 -3.030342 -1.156754 C -1.167417 -1.716750 -0.448875 C -0.244774 -1.625208 -1.529838 C 0.925414 -2.390884 -1.493169 C 1.220548 -3.269324 -0.447876 C 0.302017 -3.350199 0.597569 C -0.879669 -2.596257 0.622052 H 0.498053 -4.027357 1.433802 H 1.626997 -2.317384 -2.332119 Pd 0.516336 0.376863 0.184425 C 2.464117 1.114794 0.863136 C 2.440141 -0.314459 0.960864 C 2.187707 -0.884912 2.239715 C 2.035115 -0.092185 3.364271 C 2.131116 1.309481 3.261019 C 2.343459 1.910978 2.032925 H 2.420355 2.997892 1.952633 H 2.026291 1.933919 4.152065

48

H 1.856215 -0.557206 4.336946 H 2.152477 -1.974935 2.326902 H 2.843269 -0.943158 0.161250 C -1.824226 -2.792432 1.793921 H -2.605570 -2.016244 1.730407 C -0.582545 -0.873108 -2.803458 H -1.431660 -0.207874 -2.580537 C 2.479236 -4.110721 -0.517148 H 3.287893 -3.437831 -0.860741 C 2.908632 -4.699944 0.815494 H 3.873658 -5.216683 0.719943 H 3.022645 -3.931926 1.594106 H 2.185624 -5.443225 1.185393 C 2.331357 -5.209042 -1.568745 H 3.262039 -5.784695 -1.679889 H 1.534889 -5.914723 -1.286759 H 2.070944 -4.800845 -2.555417 C -1.111990 -2.631325 3.133558 H -1.834414 -2.607448 3.962985 H -0.426145 -3.469693 3.332346 H -0.516783 -1.708136 3.173177 C -2.527616 -4.145341 1.723962 H -1.801454 -4.972064 1.763066 H -3.220173 -4.275961 2.568798 H -3.107456 -4.263632 0.798152 C 0.557236 -0.002109 -3.311582 H 0.252919 0.557440 -4.209115 H 0.876289 0.726718 -2.546882 H 1.444475 -0.590422 -3.591156 C -1.050548 -1.856814 -3.873711 H -1.356680 -1.331298 -4.790440 H -0.247092 -2.559312 -4.145348 H -1.906962 -2.455404 -3.530393 C -1.708333 0.753633 2.759687 H -1.971861 0.942741 3.813616 H -2.259687 -0.142779 2.439191 H -0.631099 0.527510 2.711382 C -3.548380 2.268261 2.114763 H -4.182132 1.392251 1.916826 H -3.711791 2.542250 3.170168 H -3.922659 3.103700 1.510131 C -1.208608 3.143372 2.351078 H -0.140353 2.949799 2.170144 H -1.477155 4.088367 1.858686 H -1.334926 3.299772 3.434837 C -2.873192 4.005189 -0.663197 H -2.854487 4.833173 -1.391059 H -3.882976 3.575245 -0.711170 H -2.743705 4.458342 0.328076 C -2.000650 2.514436 -2.444180 H -1.195219 1.843555 -2.770240 H -2.958764 1.988878 -2.568593 H -2.003529 3.372756 -3.135089 C -0.421443 3.733449 -0.985567 H 0.394129 3.076777 -1.324655 H -0.451108 4.610404 -1.652567

49

H -0.150866 4.092841 0.017715 I 3.412665 2.012611 -0.852682

(TS1)

atom x y z

C -3.336936 -0.854949 -1.589563 P -2.106723 -0.656193 -0.118184 C -3.093943 0.000003 1.390250 C -1.604859 -2.374154 0.366806 C -0.234844 -2.729149 0.499058 C 0.077371 -4.054696 0.853203 C -0.900479 -5.020650 1.064808 C -2.241558 -4.677105 0.920941 C -2.573864 -3.370720 0.578471 H -3.628640 -3.113150 0.470264 H -3.027279 -5.420821 1.073680 H -0.612967 -6.040164 1.333247 H 1.133320 -4.326750 0.945862 C 0.973117 -1.858679 0.264406 C 1.548166 -1.781093 -1.032923 C 2.802912 -1.190459 -1.192687 C 3.541236 -0.681322 -0.119294 C 2.971538 -0.782593 1.148592 C 1.713136 -1.359145 1.362612 H 3.518038 -0.396539 2.014035 H 3.231873 -1.130971 -2.199647 Pd -0.235477 0.517972 -0.499181 C -0.168234 3.530001 0.006666 C -0.475342 3.809061 1.339982 C -1.648354 4.504606 1.635586 C -2.498545 4.925455 0.614779 C -2.171072 4.649728 -0.714235 C -1.004058 3.956207 -1.028459 H -0.758060 3.734005 -2.068733 H -2.831835 4.974092 -1.522091 H -3.415424 5.469184 0.852538 H -1.893509 4.716325 2.679525 H 0.185209 3.477239 2.144080 C 1.182360 -1.411474 2.780789 H 0.128355 -1.730429 2.726697 C 0.874144 -2.388069 -2.246846 H -0.158326 -2.646106 -1.961388 C 4.921075 -0.103903 -0.363816 H 4.844761 0.526051 -1.271219 C 5.433505 0.774133 0.765839 H 6.379175 1.259743 0.486711 H 4.718459 1.565220 1.037040 H 5.634296 0.187745 1.675706 C 5.920428 -1.216462 -0.675800 H 6.913126 -0.808956 -0.918998 H 6.038359 -1.887028 0.189378 H 5.595240 -1.834724 -1.524266

50

C 1.222168 -0.035481 3.439122 H 0.654311 -0.025725 4.381741 H 2.252399 0.268948 3.680420 H 0.801101 0.735455 2.776156 C 1.922140 -2.443368 3.625902 H 2.996208 -2.208871 3.689352 H 1.530210 -2.472777 4.653705 H 1.831988 -3.455570 3.206697 C 0.793657 -1.406577 -3.409220 H 0.209985 -1.825180 -4.243224 H 0.315286 -0.462993 -3.092481 H 1.787677 -1.155755 -3.810382 C 1.564947 -3.684928 -2.658397 H 1.059006 -4.152724 -3.516383 H 2.611910 -3.504589 -2.949054 H 1.574777 -4.417014 -1.837801 C -2.046651 0.330007 2.450245 H -2.534448 0.756500 3.343121 H -1.496458 -0.566100 2.772389 H -1.314988 1.060281 2.071335 C -4.109090 -0.952725 2.015219 H -3.625503 -1.841248 2.445464 H -4.624019 -0.440781 2.845290 H -4.889164 -1.293038 1.322268 C -3.764768 1.308053 0.975238 H -3.055205 1.976074 0.460538 H -4.634856 1.159909 0.320672 H -4.125332 1.840617 1.871005 C -4.776322 -1.248992 -1.270382 H -5.350703 -1.303004 -2.210381 H -4.865362 -2.238336 -0.800372 H -5.293309 -0.520139 -0.632466 C -2.742479 -1.885386 -2.544912 H -1.732241 -1.589859 -2.856324 H -2.689120 -2.895197 -2.111654 H -3.359881 -1.947097 -3.455639 C -3.341504 0.494584 -2.316318 H -2.318559 0.793910 -2.594419 H -3.944659 0.418749 -3.236439 H -3.765909 1.308327 -1.712278 I 1.661499 2.506055 -0.449475

(I3)

atom x y z

C 3.025245 0.997726 -1.712023 P 2.079203 0.777894 -0.048291 C 3.352138 0.471319 1.353439 C 2.540883 0.112908 2.597900 H 3.216635 -0.262645 3.382766 H 2.027212 0.993660 3.009759 H 1.790028 -0.663678 2.403264

51

C 4.256720 1.642962 1.734101 H 3.695466 2.482586 2.164990 H 4.951061 1.297505 2.517225 H 4.876783 2.020758 0.912016 C 4.225033 -0.721409 0.955138 H 3.642446 -1.597750 0.644614 H 4.931901 -0.476159 0.151220 H 4.828304 -1.027640 1.824334 C 1.353548 2.448776 0.243754 C -0.047740 2.630429 0.292840 C -0.546754 3.937039 0.452991 C 0.285542 5.045049 0.541702 C 1.664781 4.867877 0.471719 C 2.180407 3.585508 0.325622 H 3.261266 3.470598 0.259702 H 2.341131 5.723747 0.527195 H -0.142344 6.043224 0.660550 H -1.631588 4.069263 0.503891 C -1.125222 1.585600 0.197727 C -1.908731 1.507172 -0.986734 C -3.151141 0.879548 -0.940443 C -3.676369 0.331578 0.231227 C -2.892539 0.400997 1.382831 C -1.636835 1.008684 1.391491 C -0.876564 1.104380 2.695757 H 0.158798 1.379060 2.441266 C -0.826759 -0.227900 3.432466 H -0.103243 -0.194734 4.260691 H -1.800822 -0.496687 3.868254 H -0.540748 -1.048570 2.755554 C -1.437562 2.210847 3.583594 H -2.486811 2.009387 3.849510 H -0.868182 2.294487 4.521376 H -1.405624 3.190707 3.085423 H -3.262277 -0.040159 2.311650 C -5.051358 -0.299555 0.209254 H -5.105202 -0.879510 -0.730491 C -5.305754 -1.260870 1.357227 H -6.264161 -1.781326 1.221839 H -4.516837 -2.022973 1.432956 H -5.363995 -0.737271 2.324319 C -6.130904 0.779188 0.145587 H -7.133483 0.334619 0.062238 H -6.118840 1.401835 1.053668 H -5.991862 1.451682 -0.712936 H -3.737320 0.801721 -1.862862 C -1.445582 2.098217 -2.302396 H -0.443271 2.527619 -2.142360 C -1.327692 1.014053 -3.369449 H -0.888645 1.411829 -4.296923 H -0.707437 0.170512 -3.024781 H -2.310442 0.590065 -3.626210 C -2.350675 3.235373 -2.763756 H -1.985618 3.673950 -3.704134 H -3.378769 2.885793 -2.943975 H -2.404700 4.042635 -2.019237

52

Pd 0.268782 -0.766695 -0.186980 C 1.337821 -2.467684 0.011583 C 1.466722 -2.997941 1.300664 C 2.266038 -4.120096 1.528572 C 2.923088 -4.744450 0.469683 C 2.742527 -4.256503 -0.823419 C 1.941669 -3.135694 -1.056305 H 1.777491 -2.806602 -2.083426 H 3.213857 -4.761420 -1.671420 H 3.548242 -5.622543 0.647451 H 2.359722 -4.512924 2.544857 H 0.931210 -2.552580 2.143269 I -1.688030 -2.512627 -0.685273 C 4.381912 1.691245 -1.621335 H 4.798565 1.774946 -2.638058 H 4.323154 2.714879 -1.227916 H 5.116810 1.132732 -1.028123 C 2.129631 1.800055 -2.651572 H 1.150843 1.319263 -2.778038 H 1.970504 2.835521 -2.318071 H 2.597678 1.841410 -3.647821 C 3.205985 -0.388074 -2.325584 H 2.230731 -0.845948 -2.540358 H 3.750802 -0.299461 -3.279110 H 3.766116 -1.084754 -1.687789

(I4)

atom x y z

C -0.652818 2.889159 -0.847851 P -0.513979 0.997367 -0.551198 C 0.354787 0.164155 -2.034296 C 0.367457 0.948507 1.097826 C 1.696607 0.705054 1.542280 C 1.999067 0.973934 2.891509 C 1.059849 1.418232 3.812397 C -0.260793 1.560159 3.402996 C -0.585680 1.315575 2.075434 H -1.631751 1.407434 1.772800 H -1.043313 1.848915 4.108106 H 1.352048 1.609857 4.847327 H 3.024790 0.788650 3.222680 C 2.830761 0.068444 0.797343 C 2.931095 -1.345487 0.790136 C 4.031377 -1.938398 0.162551 C 5.053997 -1.189841 -0.420572 C 4.969728 0.200403 -0.335175 C 3.888586 0.844403 0.272925 H 5.778827 0.810575 -0.750821 H 4.103173 -3.029917 0.133618

53

Pd -2.246412 -0.569253 -0.301074 C -3.742525 0.699612 -0.038549 C -4.352026 1.275485 -1.156005 C -5.377791 2.207397 -0.978619 C -5.801080 2.558765 0.303001 C -5.209255 1.954380 1.411060 C -4.184540 1.017505 1.247444 H -3.747710 0.532138 2.124524 H -5.550661 2.202404 2.419886 H -6.601462 3.289946 0.436796 H -5.849048 2.658778 -1.856206 H -4.036532 1.004598 -2.167505 I -3.617683 -2.785585 -0.041906 C 6.219669 -1.861252 -1.112097 H 6.066356 -2.950658 -1.015652 C 3.916583 2.355694 0.403850 H 2.902125 2.682140 0.681442 C 1.911612 -2.229662 1.497447 H 0.943361 -1.697655 1.502643 C 7.548583 -1.520446 -0.447615 H 8.380353 -2.059192 -0.924204 H 7.773180 -0.445543 -0.524101 H 7.548489 -1.779313 0.620367 C 6.245152 -1.526454 -2.599562 H 5.299674 -1.793771 -3.092553 H 6.407293 -0.449753 -2.763391 H 7.055746 -2.060586 -3.116455 C 1.667547 0.778506 -2.496531 H 1.533285 1.780645 -2.929181 H 2.411777 0.839489 -1.693154 H 2.103650 0.149127 -3.289680 C -1.135114 3.137774 -2.275061 H -0.376987 2.890616 -3.029185 H -2.058416 2.587015 -2.507110 H -1.360157 4.209016 -2.392877 C -0.627005 0.099770 -3.213194 H -0.226850 -0.612733 -3.951161 H -1.616651 -0.275254 -2.906224 H -0.765392 1.052130 -3.734895 C 0.573604 -1.278843 -1.582541 H 1.228205 -1.344542 -0.712202 H -0.376264 -1.797338 -1.346790 H 1.043716 -1.857012 -2.394391 C 0.692416 3.571966 -0.623794 H 0.989889 3.537008 0.434402 H 1.504656 3.140883 -1.223242 H 0.611901 4.636138 -0.899070 C -1.670524 3.520766 0.103577 H -1.345641 3.502001 1.151357 H -1.779471 4.582509 -0.168710 H -2.665302 3.062560 0.035922 C 4.854167 2.775193 1.534023 H 5.888452 2.460671 1.324505 H 4.859695 3.867817 1.661358 H 4.566985 2.329453 2.496274 C 4.299000 3.068985 -0.888164

54

H 3.702387 2.732085 -1.748024 H 4.158645 4.155520 -0.789609 H 5.356750 2.910012 -1.146741 C 1.685192 -3.579603 0.825780 H 0.812776 -4.081953 1.266125 H 1.504822 -3.496321 -0.254652 H 2.541278 -4.256912 0.964728 C 2.316935 -2.449904 2.954609 H 2.414277 -1.508987 3.511919 H 1.572866 -3.068707 3.476686 H 3.284247 -2.972436 3.013363

(I5)

atom x y z

C 0.091087 -2.907952 0.280624 P 0.094946 -1.034537 -0.147940 C -0.756176 -0.751669 -1.826423 C -0.836230 -0.364672 1.344709 C -2.208852 -0.124511 1.667478 C -2.542116 0.051753 3.023909 C -1.606920 0.073718 4.051018 C -0.261955 -0.044554 3.727415 C 0.095394 -0.262038 2.402453 H 1.161177 -0.380648 2.171081 H 0.513453 0.019825 4.493690 H -1.928731 0.219289 5.084786 H -3.596595 0.219961 3.260941 C -3.372529 0.115307 0.745819 C -3.545319 1.415159 0.201574 C -4.636808 1.661783 -0.636896 C -5.598523 0.692321 -0.917991 C -5.475704 -0.538209 -0.275866 C -4.399779 -0.841123 0.564753 H -6.251504 -1.296173 -0.427678 H -4.754699 2.652875 -1.084245 C 3.357125 -1.569775 -0.725029 C 3.548549 -1.631492 -2.110783 C 4.274169 -2.678548 -2.686945 C 4.835627 -3.670562 -1.886069 C 4.700288 -3.581490 -0.501041 C 3.983096 -2.532192 0.076279 H 3.943134 -2.458912 1.165662 H 5.173980 -4.325557 0.145676 H 5.398246 -4.492091 -2.335964 H 4.402680 -2.708560 -3.772720 H 3.143698 -0.854044 -2.764552 I 4.680167 0.921052 0.890547 C -6.743256 0.970519 -1.866401 H -6.615528 2.005835 -2.229675 C -4.434046 -2.168934 1.296615 H -3.449277 -2.325021 1.758537

55

C -2.622683 2.565897 0.573303 H -1.609629 2.158312 0.733265 C -8.095014 0.889676 -1.166462 H -8.914719 1.143801 -1.854158 H -8.292456 -0.125301 -0.788439 H -8.151589 1.574914 -0.309100 C -6.691300 0.045074 -3.077170 H -5.726483 0.114635 -3.599708 H -6.828930 -1.007019 -2.783168 H -7.483457 0.287263 -3.800658 C -2.036075 -1.539744 -2.079219 H -1.852806 -2.619287 -2.171606 H -2.796186 -1.379749 -1.304264 H -2.478022 -1.210397 -3.034001 C 0.635037 -3.713536 -0.899435 H -0.059461 -3.725266 -1.750695 H 1.614054 -3.364004 -1.252143 H 0.762027 -4.760858 -0.583332 C 0.271675 -1.067764 -2.916157 H -0.197742 -0.909394 -3.900032 H 1.130523 -0.386237 -2.847618 H 0.661473 -2.092497 -2.897090 C -1.036539 0.743541 -1.921548 H -1.813027 1.063576 -1.223694 H -0.127973 1.333019 -1.725836 H -1.381623 0.992373 -2.938486 C -1.294379 -3.419985 0.647060 H -1.645774 -2.968211 1.584107 H -2.049161 -3.245044 -0.127295 H -1.246088 -4.508337 0.815282 C 0.985582 -3.117016 1.503211 H 0.498185 -2.784604 2.429509 H 1.192810 -4.192567 1.617984 H 1.948309 -2.602056 1.420166 C -5.458594 -2.127122 2.428713 H -6.473123 -1.952566 2.038006 H -5.476743 -3.078404 2.981083 H -5.246540 -1.327438 3.151817 C -4.724157 -3.352132 0.377036 H -4.114833 -3.337499 -0.537925 H -4.532494 -4.305546 0.890991 H -5.777822 -3.370690 0.059490 C -2.516377 3.646512 -0.492797 H -1.722252 4.357134 -0.226720 H -2.287788 3.243285 -1.490391 H -3.444036 4.232060 -0.580016 C -3.066915 3.208220 1.887675 H -3.099709 2.492679 2.718676 H -2.377900 4.015947 2.175894 H -4.072049 3.646340 1.786930 Pd 2.289882 -0.001206 -0.038109 S 1.295943 2.439889 0.405728 H 2.318141 2.635532 1.271344 C 2.021820 3.482208 -1.018908 C 0.863189 4.285283 -1.587822 H 1.221943 4.897158 -2.429981

56

H 0.058270 3.641624 -1.970931 H 0.430341 4.964543 -0.840981 C 2.614694 2.575457 -2.085091 H 3.475833 2.004679 -1.709562 H 1.873473 1.862438 -2.478166 H 2.959866 3.190131 -2.932062 C 3.080261 4.401359 -0.434167 H 2.666166 5.060044 0.342330 H 3.915882 3.829752 -0.004772 H 3.486278 5.041854 -1.232652

(TS2)

atom x y z

C 0.669672 2.958571 1.358559 P 0.447939 1.450502 0.177530 C 1.448535 1.753624 -1.418219 C 1.122832 0.098858 1.306342 C 2.404185 -0.487544 1.547710 C 2.573147 -1.242373 2.724114 C 1.553716 -1.486572 3.635909 C 0.285118 -0.995227 3.357734 C 0.091799 -0.229542 2.213063 H -0.912666 0.163062 2.009453 H -0.554660 -1.190174 4.029970 H 1.748818 -2.074269 4.536045 H 3.561469 -1.675337 2.902862 C 3.610272 -0.520835 0.652247 C 3.661140 -1.498299 -0.378112 C 4.779958 -1.550333 -1.208579 C 5.881796 -0.706386 -1.040968 C 5.865926 0.152883 0.053226 C 4.766292 0.245689 0.917436 H 6.740420 0.775538 0.259748 H 4.804074 -2.283222 -2.021455 C -2.581470 2.809781 -0.277282 C -2.576040 3.459924 -1.518948 C -3.022188 4.778147 -1.646771 C -3.507611 5.468189 -0.537982 C -3.584358 4.808071 0.687795 C -3.143462 3.489223 0.811863 H -3.269828 2.984296 1.772759 H -4.010353 5.315753 1.558326 H -3.851778 6.500938 -0.634425 H -2.995118 5.262186 -2.627587 H -2.231805 2.938734 -2.416437 I -4.545786 0.293818 -0.086153 C 7.010371 -0.746773 -2.048387 H 7.193071 -1.813706 -2.275783 C 4.915124 1.122698 2.146268

57

H 3.920596 1.245475 2.597012 C 2.570310 -2.546788 -0.530235 H 1.609565 -2.100200 -0.217071 C 8.313837 -0.149502 -1.547458 H 9.119453 -0.302066 -2.279074 H 8.229985 0.936965 -1.390891 H 8.637245 -0.597966 -0.597208 C 6.569614 -0.075901 -3.348640 H 5.649570 -0.524386 -3.750165 H 6.366814 0.994114 -3.185562 H 7.346359 -0.152036 -4.123743 C 2.829535 2.377157 -1.247868 H 2.792191 3.401542 -0.852537 H 3.490148 1.778500 -0.607703 H 3.314701 2.437975 -2.236210 C 0.417178 4.260960 0.598639 H 1.208989 4.480975 -0.130108 H -0.548928 4.278038 0.079170 H 0.410641 5.093751 1.319370 C 0.582721 2.641731 -2.313760 H 1.126787 2.835302 -3.251889 H -0.352789 2.127812 -2.573405 H 0.315993 3.611788 -1.877942 C 1.579707 0.415703 -2.134965 H 2.258739 -0.262056 -1.614126 H 0.609290 -0.088916 -2.236629 H 1.990195 0.580412 -3.145218 C 2.050944 3.006344 1.996257 H 2.204308 2.153487 2.671237 H 2.871320 3.027493 1.270667 H 2.135951 3.918404 2.610022 C -0.344139 2.827260 2.497190 H -0.020825 2.096293 3.250368 H -0.438830 3.796585 3.011644 H -1.342156 2.540707 2.148764 C 5.797234 0.431868 3.184880 H 6.810589 0.258926 2.790526 H 5.896108 1.046888 4.091709 H 5.395069 -0.544944 3.487538 C 5.469260 2.509920 1.834462 H 4.965706 2.983999 0.979774 H 5.359235 3.179950 2.699807 H 6.543153 2.476526 1.596390 C 2.383080 -3.053022 -1.952121 H 1.475942 -3.671064 -2.014786 H 2.275875 -2.235335 -2.678728 H 3.222683 -3.684084 -2.282555 C 2.862381 -3.729537 0.393290 H 2.920353 -3.437964 1.450231 H 2.079589 -4.497212 0.304775 H 3.820294 -4.204598 0.129195 Pd -1.887940 0.899173 -0.269219 S -1.232006 -1.552137 -0.886521 H -2.108793 -2.625492 -0.015736 C -1.934864 -1.806001 -2.623734 C -0.900095 -2.576092 -3.432184

58

H -1.270425 -2.743800 -4.457221 H 0.050858 -2.030217 -3.505043 H -0.687281 -3.562474 -2.993875 C -2.193081 -0.454825 -3.275772 H -2.966814 0.116974 -2.742926 H -1.280359 0.158717 -3.323354 H -2.539704 -0.604163 -4.311970 C -3.227443 -2.600901 -2.542439 H -3.058686 -3.600128 -2.111864 H -3.980520 -2.074183 -1.939465 H -3.645466 -2.748535 -3.551863 N -2.489093 -3.500318 0.953799 C -1.229981 -4.246042 1.162892 H -0.450868 -3.488630 1.359697 H -1.312974 -4.864547 2.074655 C -3.614691 -4.394268 0.611511 H -3.381902 -4.845195 -0.364091 H -3.635095 -5.235605 1.332595 C -2.774999 -2.575479 2.070548 H -1.905118 -1.904930 2.127650 H -3.607965 -1.929977 1.752924 C -0.832321 -5.095798 -0.019795 H 0.161592 -5.529078 0.149485 H -1.517686 -5.935980 -0.192481 H -0.778036 -4.491043 -0.937709 C -4.957847 -3.712496 0.546112 H -5.695286 -4.395122 0.104868 H -5.336758 -3.420564 1.535034 H -4.924235 -2.802643 -0.070111 C -3.048676 -3.224638 3.406694 H -2.183247 -3.775914 3.802391 H -3.302931 -2.454070 4.146551 H -3.899810 -3.920258 3.367636

(I6)

atom x y z

C 0.699330 2.852627 1.444687 P 0.461487 1.409103 0.186537 C 1.483804 1.787481 -1.380656 C 1.110565 -0.004525 1.258836 C 2.379713 -0.620779 1.484404 C 2.519536 -1.453722 2.612208 C 1.486097 -1.732008 3.497202 C 0.231274 -1.193857 3.239063 C 0.063921 -0.364564 2.135771 H -0.928419 0.062033 1.940163 H -0.615679 -1.400818 3.899779 H 1.660137 -2.374998 4.363405 H 3.497665 -1.914738 2.775927 C 3.608203 -0.593861 0.619281 C 3.683958 -1.487432 -0.482010

59

C 4.823360 -1.475748 -1.288060 C 5.921033 -0.652185 -1.026825 C 5.879163 0.118695 0.131375 C 4.759290 0.146547 0.972897 H 6.749215 0.720783 0.407335 H 4.866385 -2.138425 -2.158291 C -2.543546 2.832466 -0.213228 C -2.530413 3.529629 -1.430004 C -2.981413 4.849614 -1.517546 C -3.478903 5.499610 -0.389904 C -3.561905 4.796961 0.811666 C -3.115970 3.476443 0.893094 H -3.247329 2.940166 1.836707 H -3.995648 5.273384 1.696150 H -3.825831 6.534078 -0.453276 H -2.947477 5.367537 -2.480823 H -2.174807 3.042131 -2.342386 I -4.541702 0.309794 -0.097161 C 7.074887 -0.601466 -2.003875 H 7.174913 -1.616785 -2.429848 C 4.885890 0.917490 2.273446 H 3.882683 1.013070 2.711005 C 2.599201 -2.519267 -0.745321 H 1.624414 -2.091624 -0.447330 C 8.405798 -0.230686 -1.370097 H 9.224896 -0.324493 -2.096840 H 8.414020 0.812455 -1.018635 H 8.646324 -0.871711 -0.509933 C 6.736606 0.343439 -3.155791 H 5.798787 0.059013 -3.654493 H 6.612784 1.375033 -2.790674 H 7.532647 0.352746 -3.914894 C 2.867874 2.392673 -1.169047 H 2.838419 3.398017 -0.727164 H 3.519359 1.758385 -0.553899 H 3.360184 2.493755 -2.150727 C 0.467196 4.197839 0.756394 H 1.262558 4.446867 0.041247 H -0.498248 4.256246 0.238255 H 0.470380 4.990070 1.521603 C 0.625659 2.728692 -2.229220 H 1.187677 2.997249 -3.137800 H -0.296017 2.222322 -2.546623 H 0.333155 3.659677 -1.729788 C 1.618856 0.493810 -2.173548 H 2.346302 -0.182238 -1.720309 H 0.662196 -0.040968 -2.252620 H 1.977631 0.726433 -3.190153 C 2.079513 2.841903 2.086005 H 2.200033 1.971488 2.744758 H 2.901785 2.843612 1.362601 H 2.197535 3.738517 2.717019 C -0.320059 2.683043 2.572508 H -0.035755 1.879830 3.265660 H -0.364121 3.612715 3.161906 H -1.330729 2.477850 2.203370

60

C 5.738697 0.134616 3.270903 H 6.758976 -0.015336 2.884935 H 5.822511 0.672850 4.226952 H 5.322728 -0.859678 3.484351 C 5.463451 2.318569 2.091600 H 4.993624 2.866781 1.262910 H 5.333349 2.917634 3.004728 H 6.543902 2.288359 1.885096 C 2.474718 -2.938317 -2.202655 H 1.565191 -3.539354 -2.342117 H 2.408698 -2.080564 -2.886600 H 3.322473 -3.560449 -2.529510 C 2.855718 -3.762467 0.107730 H 2.818870 -3.556617 1.186103 H 2.112250 -4.543483 -0.109520 H 3.847234 -4.188691 -0.112540 Pd -1.860458 0.910969 -0.285729 S -1.199834 -1.487524 -0.956357 H -2.371078 -2.748473 0.144188 C -1.898429 -1.678947 -2.696281 C -0.874142 -2.441781 -3.526130 H -1.249032 -2.594967 -4.552547 H 0.079985 -1.900663 -3.595332 H -0.664627 -3.435065 -3.100810 C -2.146668 -0.313983 -3.325147 H -2.916374 0.253942 -2.781636 H -1.228242 0.291916 -3.353937 H -2.493524 -0.434303 -4.365855 C -3.200725 -2.465508 -2.650460 H -3.042478 -3.478237 -2.243928 H -3.954947 -1.948541 -2.039398 H -3.616810 -2.588859 -3.665126 N -2.634289 -3.434712 0.951102 C -1.351164 -4.148528 1.231236 H -0.620631 -3.355656 1.460749 H -1.494797 -4.747901 2.143160 C -3.719823 -4.357147 0.508084 H -3.392595 -4.770688 -0.455297 H -3.748792 -5.199982 1.219513 C -3.019377 -2.531455 2.075298 H -2.165086 -1.851999 2.196573 H -3.836278 -1.896999 1.701068 C -0.863213 -4.992123 0.083134 H 0.121520 -5.402950 0.337257 H -1.516972 -5.846621 -0.135638 H -0.745173 -4.380535 -0.824152 C -5.063813 -3.694431 0.361886 H -5.750437 -4.376365 -0.154907 H -5.520561 -3.439514 1.327388 H -4.997751 -2.766603 -0.225624 C -3.370303 -3.232123 3.360586 H -2.524050 -3.772428 3.807999 H -3.695125 -2.485255 4.096173 H -4.202302 -3.941556 3.243055

61

(I7)

atom x y z

C 0.938650 -2.733833 0.373502 P 0.735633 -0.862783 -0.035545 C -0.027209 -0.659878 -1.775452 C -0.308808 -0.318712 1.419917 C -1.708576 -0.154622 1.634429 C -2.154051 -0.027685 2.964073 C -1.302679 -0.000490 4.060569 C 0.067844 -0.050334 3.841360 C 0.538179 -0.200934 2.543701 H 1.619449 -0.225198 2.383308 H 0.776711 0.033230 4.667646 H -1.709196 0.105392 5.068993 H -3.228554 0.102043 3.120580 C -2.810034 0.041628 0.632648 C -3.009180 1.337905 0.089328 C -4.098721 1.553090 -0.760301 C -5.013324 0.548198 -1.076092 C -4.837959 -0.697581 -0.475176 C -3.772778 -0.965516 0.390191 H -5.564451 -1.492440 -0.675158 H -4.244122 2.545884 -1.196566 C 4.029431 -1.006208 -0.559234 C 4.413024 -1.290648 -1.880051 C 5.614121 -1.947363 -2.162163 C 6.461007 -2.344656 -1.128876 C 6.104346 -2.064860 0.189558 C 4.902123 -1.409757 0.467821 H 4.654238 -1.200205 1.515166 H 6.763509 -2.359876 1.011243 H 7.396051 -2.865471 -1.349681 H 5.887902 -2.148763 -3.202116 H 3.781999 -0.988590 -2.720589 C -6.152288 0.798235 -2.039698 H -6.128504 1.872729 -2.294095 C -3.736635 -2.318924 1.076279 H -2.754501 -2.424497 1.559626 C -2.085786 2.493302 0.434638 H -1.067954 2.088510 0.561742 C -7.510998 0.499576 -1.417477 H -8.328097 0.742131 -2.112413 H -7.612510 -0.566172 -1.161274 H -7.673116 1.075548 -0.495581 C -5.953710 0.012293 -3.331983 H -4.988755 0.245401 -3.804622 H -5.971638 -1.072675 -3.144500 H -6.747348 0.231683 -4.061369 C -1.188129 -1.602294 -2.078361 H -0.893951 -2.660086 -2.117104 H -2.012819 -1.492292 -1.361998 H -1.596409 -1.348819 -3.070199 C 1.546362 -3.492357 -0.804147

62

H 0.886424 -3.534016 -1.680045 H 2.517836 -3.080406 -1.111147 H 1.723551 -4.533717 -0.493469 C 1.105635 -0.872883 -2.784026 H 0.678210 -0.839753 -3.798624 H 1.843671 -0.059900 -2.709568 H 1.640780 -1.823173 -2.680860 C -0.488938 0.783851 -1.947157 H -1.482184 0.944155 -1.522330 H 0.207740 1.507109 -1.494249 H -0.562257 1.006146 -3.023560 C -0.402529 -3.352862 0.754682 H -0.782080 -2.937053 1.698777 H -1.176491 -3.230670 -0.012224 H -0.268813 -4.435550 0.910315 C 1.878231 -2.889580 1.567988 H 1.444059 -2.509418 2.501389 H 2.070878 -3.962781 1.723017 H 2.846618 -2.402746 1.402266 C -4.792183 -2.390984 2.177968 H -5.805487 -2.273320 1.763554 H -4.757968 -3.360424 2.697207 H -4.657305 -1.605701 2.934175 C -3.910198 -3.486933 0.110561 H -3.236837 -3.421428 -0.756375 H -3.711937 -4.444039 0.615463 H -4.936272 -3.543362 -0.283420 C -1.990006 3.565447 -0.641815 H -1.159821 4.246196 -0.406435 H -1.802564 3.152217 -1.643267 H -2.901792 4.180118 -0.702130 C -2.476386 3.148346 1.758355 H -2.499476 2.436818 2.593566 H -1.752630 3.934461 2.019551 H -3.472219 3.614687 1.690276 Pd 2.637643 0.387727 -0.029721 S 1.605800 2.399937 0.807335 C 2.839707 3.516286 -0.049001 C 2.165037 4.253786 -1.197197 H 2.879575 4.912264 -1.720702 H 1.749239 3.552398 -1.936238 H 1.338860 4.880977 -0.834703 C 3.974296 2.650331 -0.586370 H 4.435109 2.032440 0.209351 H 3.632901 1.996662 -1.413596 H 4.797031 3.250532 -1.012156 C 3.373362 4.504976 0.976196 H 2.560311 5.103002 1.411246 H 3.884505 3.990505 1.801644 H 4.090533 5.202467 0.510094

(TS3)

63

atom x y z

C 0.919813 -2.880743 -0.417690 P 0.719910 -0.967116 -0.282950 C -0.079088 -0.305808 -1.889022 C -0.262179 -0.855635 1.306151 C -1.646352 -0.736163 1.614049 C -2.045561 -0.988086 2.940596 C -1.156241 -1.283497 3.964981 C 0.205837 -1.279179 3.687968 C 0.627471 -1.063190 2.383383 H 1.702560 -1.049798 2.179011 H 0.943813 -1.436525 4.477134 H -1.524400 -1.463313 4.977582 H -3.110670 -0.891268 3.169068 C -2.752326 -0.215211 0.747800 C -2.895830 1.194126 0.624347 C -3.985242 1.694801 -0.087430 C -4.943548 0.868374 -0.682475 C -4.814819 -0.505459 -0.497656 C -3.752018 -1.062952 0.226880 H -5.570995 -1.177203 -0.913749 H -4.092130 2.778313 -0.199768 C 3.942167 -0.872037 -0.404855 C 4.407268 -0.944189 -1.726354 C 5.661058 -1.493613 -2.009944 C 6.460304 -1.996719 -0.985044 C 6.001906 -1.940979 0.331329 C 4.751356 -1.390785 0.618937 H 4.414829 -1.356007 1.660883 H 6.621273 -2.328715 1.145161 H 7.437193 -2.431240 -1.209999 H 6.011841 -1.527307 -3.045482 H 3.804205 -0.554739 -2.552160 C -6.034953 1.488008 -1.528383 H -6.355678 2.407387 -1.004368 C -3.759072 -2.560605 0.472812 H -2.772101 -2.838032 0.872718 C -1.896020 2.155791 1.245788 H -0.902018 1.678648 1.207077 C -7.257811 0.605235 -1.708988 H -8.059194 1.148649 -2.228628 H -7.032348 -0.283755 -2.318091 H -7.660851 0.254831 -0.748100 C -5.464814 1.912598 -2.880943 H -4.612918 2.598195 -2.767895 H -5.107143 1.036884 -3.445063 H -6.223280 2.418100 -3.496849 C -1.221877 -1.144810 -2.450684 H -0.910460 -2.138768 -2.799306 H -2.039242 -1.264982 -1.726590 H -1.647723 -0.620163 -3.321559 C 1.543414 -3.255532 -1.760279 H 0.892261 -3.042701 -2.617206 H 2.512312 -2.760074 -1.918170 H 1.732639 -4.340122 -1.769521 C 1.055911 -0.193940 -2.914434

64

H 0.636288 0.188003 -3.858224 H 1.817176 0.525265 -2.574195 H 1.563021 -1.138816 -3.139954 C -0.585220 1.111914 -1.634840 H -1.607543 1.111996 -1.248017 H 0.059443 1.672274 -0.941302 H -0.601611 1.665705 -2.587218 C -0.427861 -3.575669 -0.243542 H -0.808804 -3.454140 0.780647 H -1.199656 -3.230058 -0.940782 H -0.298954 -4.657143 -0.411115 C 1.845894 -3.399041 0.681544 H 1.420452 -3.285821 1.686470 H 1.993907 -4.478923 0.523990 H 2.835513 -2.927523 0.658261 C -4.796605 -2.925580 1.532626 H -5.811760 -2.657302 1.201202 H -4.791391 -4.006498 1.737381 H -4.617750 -2.406325 2.484168 C -3.994457 -3.382387 -0.790553 H -3.327271 -3.091628 -1.614695 H -3.833788 -4.452866 -0.594658 H -5.025872 -3.280453 -1.160694 C -1.769435 3.483081 0.509348 H -0.878933 4.018353 0.870206 H -1.663267 3.359499 -0.578409 H -2.636423 4.139444 0.683563 C -2.205125 2.428971 2.716269 H -2.247351 1.513646 3.320304 H -1.428276 3.074156 3.151996 H -3.172366 2.944664 2.825615 Pd 2.490241 0.401937 0.137241 S 1.899890 2.445865 1.185432 C 2.600048 3.718365 0.000105 C 2.454839 5.080275 0.665966 H 2.876735 5.872636 0.025161 H 1.399571 5.324647 0.852906 H 2.980231 5.112536 1.630653 C 1.840613 3.694524 -1.316933 H 1.942353 2.716484 -1.813520 H 0.767715 3.890076 -1.174974 H 2.234731 4.460607 -2.006321 C 4.071435 3.409805 -0.251417 H 4.646474 3.383636 0.684671 H 4.192650 2.428026 -0.741018 H 4.527726 4.169024 -0.910445

(I8)

atom x y z

C 0.852317 -2.826624 0.602042

65

P 0.669185 -1.011091 0.004356 C -0.136900 -0.973681 -1.719191 C -0.348414 -0.272474 1.400697 C -1.727608 0.012854 1.630213 C -2.121813 0.353791 2.938403 C -1.234771 0.483366 3.999268 C 0.122114 0.312161 3.756232 C 0.537238 -0.051875 2.481578 H 1.611324 -0.171922 2.301963 H 0.861818 0.460753 4.545874 H -1.600440 0.755426 4.992126 H -3.183063 0.560718 3.103673 C -2.841412 0.154803 0.632461 C -3.020338 1.413052 0.003530 C -4.099495 1.588352 -0.866780 C -5.028221 0.577834 -1.117292 C -4.876192 -0.625907 -0.428882 C -3.816650 -0.851789 0.454418 H -5.618121 -1.418472 -0.573656 H -4.227409 2.551145 -1.371064 C 4.011262 -0.859463 -0.563875 C 4.324590 -1.196590 -1.884300 C 5.320213 -2.140930 -2.150012 C 6.024691 -2.742493 -1.108406 C 5.747022 -2.369864 0.205878 C 4.755247 -1.424595 0.478775 H 4.575507 -1.122638 1.514174 H 6.312853 -2.807547 1.033225 H 6.802130 -3.480283 -1.320242 H 5.550879 -2.396478 -3.188167 H 3.812876 -0.716608 -2.720588 C -6.171936 0.784981 -2.084942 H -6.063215 1.803393 -2.498369 C -3.787239 -2.147533 1.242433 H -2.784515 -2.240141 1.686208 C -2.094325 2.587200 0.285319 H -1.112978 2.172273 0.574074 C -7.523782 0.712417 -1.383638 H -8.346896 0.914019 -2.084576 H -7.699625 -0.286113 -0.954600 H -7.596844 1.438975 -0.562341 C -6.101270 -0.197323 -3.248965 H -5.138590 -0.134552 -3.776106 H -6.218310 -1.236467 -2.904446 H -6.898240 -0.006493 -3.982401 C -1.336650 -1.888997 -1.923551 H -1.069655 -2.955032 -1.891289 H -2.130879 -1.706265 -1.188490 H -1.774160 -1.702753 -2.918421 C 1.494059 -3.659427 -0.506162 H 0.836076 -3.795295 -1.374384 H 2.449872 -3.234480 -0.848190 H 1.710630 -4.664844 -0.112395 C 0.956713 -1.290338 -2.745717 H 0.500816 -1.294854 -3.748439 H 1.726891 -0.507043 -2.737643

66

H 1.460836 -2.253335 -2.610420 C -0.539609 0.474147 -1.979354 H -1.412728 0.770152 -1.395396 H 0.287615 1.172998 -1.768563 H -0.800953 0.596770 -3.042753 C -0.480174 -3.434371 1.021106 H -0.877908 -2.940574 1.919848 H -1.246406 -3.390439 0.237613 H -0.334825 -4.496581 1.277460 C 1.787761 -2.860392 1.810887 H 1.339459 -2.411134 2.706622 H 2.003112 -3.911701 2.059301 H 2.747798 -2.367495 1.609543 C -4.789299 -2.094886 2.393712 H -5.817086 -1.976770 2.016760 H -4.759423 -3.019996 2.988168 H -4.592876 -1.256041 3.075356 C -4.036962 -3.385852 0.388329 H -3.394703 -3.422046 -0.503237 H -3.852358 -4.301802 0.968684 H -5.078984 -3.438639 0.037988 C -1.866935 3.505742 -0.909470 H -1.064365 4.224572 -0.689744 H -1.582898 2.961564 -1.820705 H -2.760388 4.102670 -1.146747 C -2.609362 3.408502 1.466692 H -2.720575 2.809010 2.379459 H -1.923850 4.238024 1.696275 H -3.593217 3.846007 1.236089 Pd 2.572731 0.447878 -0.105231 S 4.182671 2.149104 -0.187326 C 2.892129 3.485957 0.011191 C 3.515906 4.633885 0.789637 H 2.797763 5.463450 0.907952 H 3.838152 4.313606 1.789923 H 4.398858 5.029741 0.267807 C 1.704909 2.918897 0.786583 H 1.183642 2.101777 0.231792 H 1.994733 2.546402 1.779329 H 0.912583 3.677112 0.928817 C 2.430055 3.964793 -1.359501 H 3.273629 4.344356 -1.951795 H 1.971485 3.146506 -1.935652 H 1.687789 4.777725 -1.268847

(TS4)

atom x y z

C 0.627791 -2.705777 -0.018388 P 0.460252 -0.788652 -0.008116 C -0.202030 -0.183748 -1.690454

67

C -0.689596 -0.555039 1.460458 C -2.092020 -0.381986 1.648306 C -2.610755 -0.533289 2.948419 C -1.821508 -0.785910 4.063082 C -0.442168 -0.833574 3.902430 C 0.094601 -0.707036 2.626778 H 1.184468 -0.726355 2.511638 H 0.222260 -0.960570 4.760052 H -2.279468 -0.895145 5.048921 H -3.689731 -0.405353 3.075826 C -3.118202 0.097841 0.664126 C -3.263451 1.495021 0.467658 C -4.274053 1.956435 -0.381103 C -5.170045 1.095764 -1.015591 C -5.054560 -0.268418 -0.750171 C -4.060388 -0.783266 0.087111 H -5.769101 -0.962318 -1.205552 H -4.377057 3.032292 -0.552565 C 4.276790 -0.524465 -0.408543 C 4.400380 -0.591441 -1.807297 C 4.974374 -1.712431 -2.407362 C 5.460388 -2.771002 -1.640578 C 5.376761 -2.688591 -0.248526 C 4.811993 -1.574597 0.364919 H 4.774396 -1.516359 1.456357 H 5.761345 -3.500907 0.374775 H 5.911109 -3.642915 -2.119393 H 5.036390 -1.752772 -3.498792 H 4.024997 0.212094 -2.440882 C -6.220163 1.623937 -1.967608 H -6.182297 2.726270 -1.908313 C -4.067078 -2.269468 0.392280 H -3.105005 -2.513167 0.867480 C -2.390351 2.506903 1.198608 H -1.410975 2.034040 1.389956 C -7.627314 1.186972 -1.580302 H -8.378563 1.631631 -2.248928 H -7.744553 0.094559 -1.646863 H -7.877349 1.480982 -0.551227 C -5.896049 1.226752 -3.404733 H -4.894057 1.566358 -3.703794 H -5.920657 0.132868 -3.528804 H -6.621324 1.653703 -4.112980 C -1.385253 -0.946121 -2.269978 H -1.128263 -1.979587 -2.544549 H -2.241681 -0.972094 -1.584811 H -1.728694 -0.450234 -3.193172 C 1.350353 -3.133658 -1.293589 H 0.735532 -3.013322 -2.195485 H 2.297973 -2.590760 -1.434240 H 1.600763 -4.203899 -1.221246 C 0.966931 -0.196663 -2.681791 H 0.625525 0.251961 -3.628689 H 1.802681 0.411064 -2.303913 H 1.362031 -1.191150 -2.915321 C -0.562180 1.285697 -1.495619

68

H -1.456381 1.411424 -0.882310 H 0.267204 1.847281 -1.032664 H -0.770296 1.748791 -2.473883 C -0.709924 -3.422232 0.102085 H -1.178556 -3.236740 1.080265 H -1.425054 -3.137328 -0.680492 H -0.557476 -4.511307 0.022834 C 1.507618 -3.119537 1.162452 H 1.010141 -2.987601 2.132351 H 1.743706 -4.191969 1.070822 H 2.459975 -2.568282 1.176680 C -5.167202 -2.606091 1.396487 H -6.161467 -2.363711 0.989687 H -5.163981 -3.678118 1.643436 H -5.054434 -2.048672 2.336588 C -4.205908 -3.142374 -0.850263 H -3.486349 -2.872139 -1.636301 H -4.044663 -4.201601 -0.601163 H -5.210879 -3.071965 -1.293294 C -2.131022 3.786010 0.411190 H -1.358913 4.389473 0.909482 H -1.790874 3.593268 -0.615633 H -3.029052 4.418887 0.347475 C -3.001350 2.860913 2.554137 H -3.133684 1.982047 3.198055 H -2.364795 3.575391 3.096583 H -3.989699 3.328489 2.424171 Pd 2.525224 0.274623 0.418869 S 4.574963 1.320168 0.746315 C 4.299710 2.966812 -0.135692 C 5.586756 3.751756 0.077391 H 5.493555 4.756733 -0.364917 H 5.811605 3.879863 1.145750 H 6.446513 3.253233 -0.390505 C 3.122340 3.676465 0.518705 H 2.189967 3.109239 0.369047 H 3.267415 3.795351 1.601353 H 2.990148 4.681225 0.081558 C 4.033577 2.762184 -1.614690 H 4.869908 2.257611 -2.117152 H 3.117930 2.169510 -1.771862 H 3.887518 3.738668 -2.104769

(I9)

atom x y z

C 0.659598 -1.790642 1.294231 P 0.274771 -0.348330 0.068258 C -0.579359 -1.053624 -1.486201 C -0.812529 0.755982 1.150162 C -2.208113 0.977209 1.347371

69

C -2.607813 1.771655 2.440545 C -1.715784 2.383338 3.311127 C -0.353795 2.245770 3.069264 C 0.067370 1.461438 2.003752 H 1.141810 1.383320 1.795736 H 0.383496 2.753701 3.695691 H -2.084345 2.989618 4.142016 H -3.681504 1.926739 2.582302 C -3.359758 0.564753 0.476083 C -3.743281 1.399246 -0.603825 C -4.846547 1.034880 -1.382667 C -5.616079 -0.095646 -1.108085 C -5.278187 -0.848986 0.015667 C -4.178125 -0.535575 0.818570 H -5.892156 -1.716381 0.280484 H -5.129872 1.660272 -2.235051 C 5.045977 -0.833500 -0.644598 C 5.288997 -1.773654 -1.655486 C 5.573347 -3.098334 -1.328690 C 5.650637 -3.495741 0.005181 C 5.434507 -2.555003 1.013766 C 5.122324 -1.236509 0.695986 H 4.915816 -0.522863 1.494449 H 5.487892 -2.853564 2.063903 H 5.879212 -4.533083 0.259027 H 5.745860 -3.823379 -2.127798 H 5.240405 -1.460988 -2.701194 C -6.768482 -0.493210 -2.002953 H -6.878691 0.305149 -2.758701 C -3.936294 -1.365596 2.063849 H -2.912527 -1.155784 2.405588 C -3.037927 2.718886 -0.886575 H -1.990842 2.623410 -0.548786 C -8.084718 -0.594326 -1.242235 H -8.919685 -0.820167 -1.921456 H -8.056421 -1.396872 -0.489418 H -8.323361 0.340288 -0.715401 C -6.457059 -1.790023 -2.743837 H -5.522248 -1.714136 -3.317621 H -6.341736 -2.630419 -2.041583 H -7.262270 -2.055887 -3.444601 C -1.729992 -2.027625 -1.269519 H -1.395372 -2.972953 -0.816366 H -2.530187 -1.611248 -0.645639 H -2.184251 -2.287465 -2.240803 C 1.351802 -2.904663 0.511949 H 0.660713 -3.457402 -0.137997 H 2.180911 -2.515735 -0.102420 H 1.780480 -3.636274 1.216292 C 0.489797 -1.718112 -2.364170 H 0.078010 -1.846637 -3.378406 H 1.396040 -1.093287 -2.441651 H 0.794414 -2.711518 -2.016223 C -1.053792 0.178952 -2.249471 H -1.814479 0.732511 -1.695386 H -0.216372 0.862609 -2.461702

70

H -1.501238 -0.122760 -3.210851 C -0.562145 -2.330994 2.019602 H -0.979029 -1.582424 2.709305 H -1.359150 -2.650659 1.336949 H -0.283545 -3.206606 2.629970 C 1.651883 -1.280205 2.340339 H 1.200522 -0.557171 3.033550 H 2.006198 -2.129527 2.948185 H 2.525308 -0.804247 1.864953 C -4.883934 -0.942569 3.184121 H -5.934477 -1.098622 2.892571 H -4.703374 -1.528364 4.097933 H -4.769752 0.119046 3.442531 C -4.051733 -2.866365 1.818566 H -3.486368 -3.191456 0.933188 H -3.675648 -3.433727 2.682698 H -5.096567 -3.177658 1.666862 C -3.013519 3.110502 -2.359148 H -2.356105 3.978077 -2.511600 H -2.652384 2.302125 -3.009370 H -4.009959 3.405267 -2.721783 C -3.678946 3.844613 -0.074723 H -3.647988 3.652488 1.005428 H -3.165278 4.800519 -0.255677 H -4.734992 3.975766 -0.357979 Pd 2.277942 0.565199 -0.515893 S 4.560389 0.803289 -1.176241 C 5.488779 2.053160 -0.092941 C 6.923220 1.598422 0.097762 H 7.487690 2.375158 0.637203 H 6.992873 0.673860 0.687175 H 7.425969 1.423922 -0.863624 C 4.771889 2.274310 1.229771 H 3.716043 2.540449 1.067447 H 4.790648 1.389800 1.879563 H 5.258117 3.094951 1.782726 C 5.422678 3.322836 -0.932139 H 5.947495 3.208147 -1.890356 H 4.382647 3.610345 -1.145401 H 5.891106 4.154596 -0.384236

(I10)

atom x y z

C 1.703012 -2.371246 -2.002227 P 1.373399 -1.789823 -0.204972 C 1.338558 -3.339709 0.948039 C 2.935588 -0.895505 0.256116 C 2.935723 0.493202 0.552897 C 4.133286 1.083616 0.995954 C 5.314305 0.363637 1.131421

71

C 5.323029 -0.992479 0.817613 C 4.146053 -1.598420 0.391561 H 4.167803 -2.663511 0.160559 H 6.239073 -1.581068 0.908797 H 6.222455 0.860662 1.481385 H 4.119185 2.149005 1.244248 C 1.774430 1.435733 0.436740 C 1.689152 2.301519 -0.676474 C 0.694507 3.284943 -0.695884 C -0.210346 3.460407 0.350454 C -0.101807 2.603152 1.446399 C 0.867796 1.597132 1.512932 H -0.787414 2.722632 2.290838 H 0.630488 3.957751 -1.558833 C -3.890186 -0.834857 0.373612 C -5.122741 -0.501822 0.947033 C -6.011801 -1.509473 1.319776 C -5.675152 -2.848406 1.124837 C -4.445504 -3.181751 0.554561 C -3.552674 -2.180310 0.181315 H -2.570914 -2.410883 -0.250837 H -4.175603 -4.230455 0.405507 H -6.370909 -3.635764 1.424639 H -6.970615 -1.245803 1.772802 H -5.375591 0.549361 1.107714 C -1.202635 4.604575 0.315995 H -1.344790 4.868413 -0.748966 C 1.008630 0.787255 2.787607 H 1.644523 -0.081739 2.551776 C 2.681612 2.253583 -1.826208 H 3.223674 1.294017 -1.765567 C -0.619122 5.832535 1.011873 H -1.304142 6.691894 0.955037 H -0.434067 5.625483 2.077459 H 0.339663 6.134563 0.567173 C -2.566568 4.254307 0.893407 H -2.992900 3.349424 0.435664 H -2.515290 4.069900 1.977311 H -3.277794 5.080584 0.747587 C 2.225608 -4.526599 0.578340 H 1.980855 -4.953693 -0.403683 H 3.300151 -4.301739 0.594038 H 2.071130 -5.331887 1.315686 C 0.607610 -3.359479 -2.398250 H 0.718796 -4.339692 -1.913150 H -0.394315 -2.969171 -2.153367 H 0.641302 -3.535161 -3.486035 C -0.115963 -3.822307 0.972288 H -0.206763 -4.689668 1.647726 H -0.791446 -3.031674 1.333692 H -0.478017 -4.135841 -0.017393 C 1.687034 -2.867074 2.357700 H 2.725266 -2.516179 2.448545 H 1.021493 -2.051890 2.677037 H 1.552654 -3.696367 3.070857 C 3.078634 -2.960805 -2.297532

72

H 3.881779 -2.226144 -2.145017 H 3.316981 -3.853422 -1.704696 H 3.123954 -3.261940 -3.357355 C 1.543780 -1.108992 -2.847592 H 2.296811 -0.353307 -2.581298 H 1.675412 -1.343427 -3.917395 H 0.549404 -0.653492 -2.706445 C 1.735209 1.604541 3.852904 H 1.154028 2.497594 4.131973 H 1.897123 1.014950 4.767804 H 2.717876 1.950658 3.500514 C -0.314192 0.247291 3.314075 H -0.827327 -0.359193 2.546528 H -0.152731 -0.387160 4.199020 H -1.003964 1.049960 3.618765 C 2.011279 2.322966 -3.194689 H 2.739906 2.128965 -3.995976 H 1.198818 1.590915 -3.298033 H 1.584328 3.318070 -3.391934 C 3.720686 3.365281 -1.696043 H 4.277693 3.301783 -0.751207 H 4.452233 3.325216 -2.517086 H 3.241509 4.356431 -1.727861 Pd -0.515014 -0.563708 -0.085621 S -2.730071 0.457746 -0.047085 C -3.144272 0.798377 -1.869221 C -4.545678 1.374647 -1.951200 H -4.789923 1.617283 -2.997644 H -5.304652 0.660746 -1.598637 H -4.641186 2.298018 -1.361959 C -3.012373 -0.479083 -2.674659 H -2.002143 -0.906081 -2.566991 H -3.741349 -1.242008 -2.364734 H -3.191283 -0.267454 -3.741265 C -2.094576 1.813459 -2.289190 H -2.164819 2.742801 -1.705281 H -1.077495 1.409766 -2.151244 H -2.227702 2.069891 -3.351977

(TS5*)

* structure from the maximum of potential energy surface scan of dihedral angle used to estimate activation barrier for ligand rotation

atom x y z

C -0.412700 -3.592974 0.023411 P 0.346109 -1.829074 0.324447 C 1.003061 -1.862729 2.121581 C 1.829085 -1.790832 -0.830901 C 2.839221 -0.774435 -0.795055 C 4.080946 -1.031290 -1.396139

73

C 4.345102 -2.192337 -2.111280 C 3.312332 -3.102197 -2.297106 C 2.095023 -2.903600 -1.648539 H 1.338084 -3.666692 -1.792153 H 3.449038 -3.986847 -2.923121 H 5.322315 -2.345947 -2.574298 H 4.832622 -0.240739 -1.373999 C 2.534174 0.647167 -0.448884 C 1.473015 1.296819 -1.153289 C 1.100616 2.577757 -0.739214 C 1.767773 3.280868 0.268502 C 2.906747 2.694097 0.808610 C 3.314253 1.400468 0.461862 H 3.507969 3.250822 1.531724 H 0.267860 3.078876 -1.236533 C -2.747590 -0.391428 1.024118 C -2.545775 0.579018 2.012397 C -3.420551 0.668232 3.098392 C -4.503802 -0.203335 3.205155 C -4.713509 -1.159969 2.212356 C -3.850887 -1.245835 1.117215 H -4.054768 -1.971694 0.326085 H -5.570694 -1.836414 2.274215 H -5.187462 -0.130741 4.054329 H -3.248145 1.427696 3.866432 H -1.693707 1.264708 1.949394 C 1.237612 4.627114 0.711975 H 0.940389 5.167519 -0.206083 C 4.623715 0.908058 1.062175 H 4.691167 -0.183124 0.915730 C 0.832315 0.726158 -2.428749 H 0.232859 -0.178821 -2.169137 C 2.256230 5.484252 1.443567 H 1.848202 6.483307 1.650902 H 2.533486 5.046704 2.415194 H 3.180675 5.616456 0.863362 C -0.023810 4.441070 1.553420 H -0.796489 3.877415 1.012348 H 0.201857 3.885160 2.477184 H -0.457988 5.408812 1.844902 C 1.713437 -3.166429 2.467158 H 1.047884 -4.038119 2.463103 H 2.554266 -3.370698 1.787451 H 2.131798 -3.087584 3.483618 C -1.489150 -3.855452 1.079274 H -1.069194 -4.102929 2.062756 H -2.185373 -3.015850 1.197050 H -2.080883 -4.729657 0.763103 C -0.174295 -1.609334 3.067479 H 0.181828 -1.717389 4.104438 H -0.552446 -0.586522 2.956442 H -1.030604 -2.279797 2.945406 C 1.978301 -0.720681 2.344157 H 2.913133 -0.862888 1.788509 H 1.550631 0.257403 2.079697 H 2.236193 -0.690440 3.415129

74

C 0.558554 -4.803048 0.051749 H 0.490380 -5.386985 -0.878037 H 1.616894 -4.557315 0.185385 H 0.293861 -5.492182 0.866377 C -1.155278 -3.518761 -1.322849 H -0.540168 -3.180519 -2.168851 H -1.546280 -4.516141 -1.580388 H -2.016548 -2.834301 -1.263556 C 5.804414 1.552241 0.332528 H 5.811576 2.640652 0.497189 H 6.763513 1.157549 0.700117 H 5.772810 1.401689 -0.755512 C 4.764663 1.177976 2.558109 H 3.899924 0.831779 3.137789 H 5.657483 0.674582 2.956582 H 4.891249 2.249965 2.769625 C -0.117064 1.698439 -3.112977 H -0.574874 1.216053 -3.987009 H -0.949674 2.009065 -2.473218 H 0.420370 2.593249 -3.464286 C 1.865708 0.282604 -3.471355 H 2.357035 -0.670422 -3.249679 H 1.376702 0.162450 -4.447987 H 2.650781 1.045386 -3.592602 Pd -1.472005 -0.446593 -0.507956 S -3.177028 0.287599 -1.886982 C -3.991456 1.909505 -1.418667 C -4.491091 2.494469 -2.735714 H -5.014383 3.447889 -2.553581 H -3.662634 2.689322 -3.431935 H -5.197499 1.816822 -3.236136 C -3.009798 2.865547 -0.760774 H -2.554319 2.416269 0.132785 H -2.201132 3.161034 -1.444518 H -3.526415 3.788665 -0.446355 C -5.167924 1.647446 -0.486872 H -5.857173 0.903408 -0.910028 H -4.838262 1.280378 0.494396 H -5.734413 2.579644 -0.319669

(I11)

atom x y z

C 3.492351 -0.153222 1.113750 P 2.148087 -0.530243 -0.205935 C 2.957326 -0.487414 -1.954987 C 1.704299 -2.315291 -0.018207 C 0.353939 -2.723372 0.088506 C 0.070839 -4.102787 0.098111 C 1.064568 -5.067292 -0.003600 C 2.393261 -4.665775 -0.110757 C 2.696848 -3.309401 -0.117344

75

H 3.740260 -3.017426 -0.225429 H 3.193937 -5.403737 -0.197785 H 0.801788 -6.127690 0.000804 H -0.975572 -4.409981 0.186590 C -0.870503 -1.860428 0.207088 C -1.312365 -1.449565 1.497038 C -2.622694 -1.012984 1.660970 C -3.537114 -0.961778 0.605597 C -3.091239 -1.363241 -0.650942 C -1.787567 -1.810299 -0.872550 H -3.770389 -1.306709 -1.505734 H -2.947026 -0.678137 2.651502 C 0.968253 2.584689 0.365856 C 1.576683 3.404829 -0.592363 C 2.200433 4.600106 -0.223294 C 2.216680 5.008546 1.108478 C 1.581987 4.217292 2.065119 C 0.953910 3.026015 1.697039 H 0.436502 2.446412 2.465463 H 1.558738 4.532989 3.111990 H 2.705277 5.942568 1.396211 H 2.672860 5.216669 -0.993571 H 1.575673 3.133296 -1.648173 C -4.944015 -0.471958 0.871779 H -4.827876 0.483968 1.416512 C -1.394876 -2.198327 -2.282957 H -0.342595 -2.525699 -2.261845 C -0.408507 -1.547472 2.706145 H 0.624232 -1.605800 2.329743 C -5.692192 -1.439192 1.786757 H -6.688158 -1.051061 2.045865 H -5.834132 -2.414330 1.295434 H -5.153699 -1.623117 2.726938 C -5.745907 -0.188803 -0.384793 H -5.220153 0.507294 -1.052851 H -5.953366 -1.109256 -0.952875 H -6.718049 0.258926 -0.135100 C 4.403236 -0.965102 -2.045582 H 5.102668 -0.348553 -1.466819 H 4.533881 -2.013606 -1.746035 H 4.726783 -0.903028 -3.097431 C 4.145260 1.186009 0.764064 H 4.778803 1.130425 -0.131519 H 3.413714 1.991081 0.618583 H 4.799659 1.490364 1.596070 C 2.868385 0.951113 -2.457466 H 3.308267 1.019047 -3.465468 H 1.817701 1.270269 -2.528954 H 3.395813 1.669707 -1.816027 C 2.096899 -1.346288 -2.877770 H 2.137653 -2.417720 -2.635125 H 1.047135 -1.024980 -2.853599 H 2.447182 -1.227011 -3.915369 C 4.582773 -1.204881 1.311152 H 4.185137 -2.147644 1.709552 H 5.164233 -1.425091 0.407128

76

H 5.296252 -0.824725 2.060143 C 2.761450 -0.007980 2.448467 H 2.416641 -0.980442 2.827705 H 3.452590 0.404008 3.201081 H 1.896455 0.666630 2.386051 C -2.216465 -3.366523 -2.814925 H -3.288307 -3.121615 -2.863258 H -1.899872 -3.641965 -3.831712 H -2.113307 -4.258849 -2.180895 C -1.489161 -0.984327 -3.202736 H -0.916477 -0.132487 -2.799272 H -1.111672 -1.209980 -4.211816 H -2.530125 -0.639405 -3.306947 C -0.496465 -0.316097 3.596332 H 0.312965 -0.308378 4.341379 H -0.428001 0.607337 3.000162 H -1.443857 -0.272561 4.154193 C -0.678566 -2.826050 3.493535 H -0.547085 -3.724726 2.873248 H 0.000275 -2.913186 4.355143 H -1.709675 -2.839228 3.879886 Pd 0.144162 0.782335 -0.038411 S -1.946375 1.818065 0.148840 C -2.242329 3.216999 -1.053488 C -3.747827 3.209814 -1.303519 H -4.030710 4.055286 -1.952567 H -4.064724 2.282559 -1.803197 H -4.318224 3.302024 -0.367180 C -1.514300 2.973770 -2.365465 H -0.430481 2.882615 -2.214276 H -1.865657 2.050439 -2.847306 H -1.688152 3.807205 -3.067700 C -1.835695 4.547082 -0.431478 H -2.358101 4.713802 0.521195 H -0.758143 4.596041 -0.230250 H -2.089785 5.381889 -1.107343

(TS6)

atom x y z

C 3.400781 -0.384941 1.038835 P 2.031970 -0.681803 -0.273514 C 2.845668 -0.626953 -2.017440 C 1.513498 -2.441463 -0.046117 C 0.164786 -2.779021 0.232790 C -0.156747 -4.134004 0.432133 C 0.790661 -5.145813 0.327843 C 2.105008 -4.819005 0.004468 C 2.449361 -3.483977 -0.173347 H 3.481616 -3.245038 -0.430303 H 2.862124 -5.598465 -0.107912

77

H 0.498985 -6.187253 0.483696 H -1.196868 -4.387672 0.658266 C -1.016165 -1.849839 0.280162 C -1.482437 -1.332933 1.515238 C -2.731563 -0.719235 1.571163 C -3.562601 -0.593835 0.454173 C -3.076489 -1.080683 -0.757717 C -1.830908 -1.713804 -0.867281 H -3.694596 -1.005964 -1.656633 H -3.076235 -0.318280 2.529464 C 0.839394 2.762385 0.435949 C 1.495010 3.442536 -0.608395 C 2.552400 4.313106 -0.339852 C 2.973798 4.549279 0.968024 C 2.307045 3.904733 2.015051 C 1.249428 3.040452 1.758631 H 0.718033 2.579138 2.596186 H 2.606824 4.086441 3.051300 H 3.799659 5.234184 1.171445 H 3.057877 4.805951 -1.175931 H 1.204558 3.269490 -1.646792 C -4.941250 0.018670 0.611250 H -4.783888 1.046099 0.994107 C -1.449666 -2.319511 -2.204536 H -0.393789 -2.628151 -2.145120 C -0.673994 -1.479856 2.786219 H 0.352387 -1.740065 2.483046 C -5.758446 -0.732682 1.660776 H -6.734834 -0.252316 1.820100 H -5.946596 -1.769704 1.342310 H -5.251574 -0.776882 2.634077 C -5.729117 0.115067 -0.684426 H -5.197439 0.670823 -1.469766 H -5.957876 -0.883441 -1.089182 H -6.689218 0.623567 -0.518728 C 4.286108 -1.117190 -2.129908 H 4.996745 -0.521136 -1.543695 H 4.407678 -2.172807 -1.850172 H 4.604224 -1.038861 -3.182581 C 4.053459 0.959459 0.713320 H 4.723124 0.907549 -0.156039 H 3.312739 1.750004 0.529119 H 4.665491 1.285909 1.569301 C 2.767569 0.828310 -2.482399 H 3.194516 0.919605 -3.494694 H 1.720389 1.165733 -2.523199 H 3.307703 1.526491 -1.827976 C 1.975819 -1.458951 -2.953708 H 2.001030 -2.533799 -2.721547 H 0.931375 -1.123673 -2.923909 H 2.327229 -1.334916 -3.990662 C 4.474754 -1.458773 1.192240 H 4.067063 -2.400832 1.583789 H 5.027338 -1.677056 0.270305 H 5.215092 -1.108136 1.929812 C 2.681951 -0.266806 2.381031

78

H 2.265494 -1.233197 2.701776 H 3.397848 0.050582 3.156763 H 1.868345 0.472258 2.350802 C -2.268554 -3.576187 -2.486477 H -3.343738 -3.346617 -2.546577 H -1.974570 -4.036218 -3.441683 H -2.138903 -4.332209 -1.698909 C -1.570640 -1.320167 -3.348563 H -1.026616 -0.388505 -3.130036 H -1.165661 -1.737696 -4.282513 H -2.617181 -1.044099 -3.549431 C -0.601282 -0.181418 3.578662 H 0.147448 -0.249021 4.381960 H -0.332033 0.664865 2.926997 H -1.561546 0.067347 4.055492 C -1.200302 -2.624920 3.646204 H -1.183860 -3.582947 3.106642 H -0.598763 -2.746220 4.559487 H -2.240613 -2.439309 3.956442 Pd 0.214678 0.798757 0.012890 S -1.354946 2.462888 0.478587 C -2.029735 3.249918 -1.084702 C -3.538309 3.239180 -0.871796 H -4.043530 3.704853 -1.733903 H -3.916790 2.214124 -0.767342 H -3.827202 3.801568 0.027857 C -1.675670 2.413443 -2.302015 H -0.587967 2.341302 -2.453496 H -2.062386 1.389113 -2.191351 H -2.114249 2.853262 -3.214138 C -1.546856 4.686949 -1.212378 H -1.809873 5.274545 -0.322035 H -0.461116 4.759660 -1.346614 H -2.023625 5.164907 -2.083912

79

14 References

1 Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone,

V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.;

Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;

Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd,

J.; Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A. P.;

Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.;

Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli,

C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;

Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Rev.

c.0.1; Gaussian, Inc.: Wallingford, CT, USA, 2009. 2 a) Zhao, Y.; Truhlar, D. G. A New Local Density Functional for Main-Group Thermochemistry, Transition Metal

Bonding, Thermochemical Kinetics, and Noncovalent Interactions. J. Chem. Phys. 2006, 125, 194101-1194101-18;

b) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical

Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic

Testing of Four M06-Class Functionals and 12 Other Functionals. Theor. Chem. Acc. 2008, 120, 215241. 3 Weigend, F.; Ahlrichs, R. Balanced Basis Sets of Split Valence, Triple Zeta Valence and Quadruple Zeta Valence

Quality for H to Rn: Design and Assesment of Accuracy. PCCP 2005, 7, 32973305. 4 Andrae, D.; Haussermann, U.; Dolg, M.; Stoll, H.; Preuss, H. Energy-Adjusted Ab Initio Pseudopotentials for the

2nd and 3rd Row Transition-Elements. Theor. Chim. Acta 1990, 77, 123141. 5 a) Miertus, S.; Scrocco, E.; Tomasi, J. Electrostatic Interaction of a Solute with a Continuum - a Direct Utilization

of Ab Initio Molecular Potentials for the Prevision of Solvent Effects. Chem. Phys. 1981, 55, 117129; b) Miertus,

S.; Tomasi, J. Approximate Evaluations of the Electrostatic Free-Energy and Internal Energy Changes in Solution

Processes. Chem. Phys. 1982, 65, 239245; c) Barone, V.; Cossi, M.; Tomasi, J. Geometry Optimization of Molecular

Structures in Solution by the Polarizable Continuum Model. J. Comput. Chem. 1998, 19, 404417; d) Cossi, M.;

Scalmani, G.; Rega, N.; Barone, V. New Developments in the Polarizable Continuum Model for Quantum Mechanical

and Classical Calculations on Molecules in Solution. J. Chem. Phys. 2002, 117, 4354. 6 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, 12871292. 7 K. Kashani, S.; Sullivan, R. J.; Andersen, M.; Newman, S. G. Overcoming Solid Handling Issues in Continuous

Flow Substitution Reactions Through Ionic Liquid Formation. Green Chem. 2018, 20, 17481753. 8 Meng, D.; Li, D.; Ollevier, T. Recyclable Iron(II) Caffeine-Derived Ionic Salt Catalyst in the Diels–Alder Reaction

of Cyclopentadiene and α,β-Unsaturated N-Acyl-oxazolidinones in Dimethyl Carbonate. RSC Advances 2019, 9,

2195621963. 9 Kozuch, S.; Shaik, S. How to Conceptualize Catalytic Cycles? The Energetic Span Model. Acc. Chem. Res. 2011,

44, 101−110. 10

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, 64616466.

download fileview on ChemRxivSupporting Information.pdf (3.97 MiB)



Documents

Reaction Cycling for Efficient Kinetic Analysis in Flow