Difluorocarbene Generation from TMSCF3: Kinetics and Mechanism of NaI-Mediated and Si-Induced Anionic Chain Reactions

DOI: 10.1021/jacs.0c06751

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Journal of the American Chemical Society p. 14649 - 14663 (2020)

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Authors:

García-Domínguez, Andrés

West, Thomas H.

Primozic, Johann J.

Grant, Katie M.

Johnston, Craig P.

Cumming, Grant G.

Leach, Andrew G.

Lloyd-Jones, Guy C.

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Article abstract of DOI:10.1021/jacs.0c06751

The mechanism of CF2 transfer from TMSCF3 (1), mediated by TBAT (2-12 mol %) or by NaI (5-20 mol %), has been investigated by in situ/stopped-flow 19F NMR spectroscopic analysis of the kinetics of alkene difluorocyclopropanation and competing TFE/c-C3F6/homologous perfluoroanion generation, 13C/2H KIEs, LFERs, CF2 transfer efficiency and selectivity, the effect of inhibitors, and density functional theory (DFT) calculations. The reactions evolve with profoundly different kinetics, undergoing autoinhibition (TBAT) or quasi-stochastic autoacceleration (NaI) and cogenerating perfluoroalkene side products. An overarching mechanism involving direct and indirect fluoride transfer from a CF3 anionoid to TMSCF3 (1) has been elucidated. It allows rationalization of why the NaI-mediated process is more effective for less-reactive alkenes and alkynes, why a large excess of TMSCF3 (1) is required in all cases, and why slow-addition protocols can be of benefit. Issues relating to exothermicity, toxicity, and scale-up are also noted.

Full text of DOI:10.1021/jacs.0c06751

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Article

Difluorocarbene Generation from TMSCF3: Kinetics and Mechanism

of NaI-Mediated, and Si-Induced, Anionic Chain Reactions

Andrés García-Domínguez, Thomas H. West, Johann J. Primozic, Katie M. Grant,

Craig P. Johnston, Grant G. Cumming, Andrew G. Leach, and Guy C. Lloyd-Jones

J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 27 Jul 2020

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Page 1 of 13

Journal of the American Chemical Society

Difluorocarbene Generation from TMSCF₃: Kinetics and Mechanism

of NaI-Mediated, and Si-Induced, Anionic Chain Reactions

Andrés García-Domínguez,^†Thomas H. West,^†Johann J. Primozic,^†Katie M. Grant,^†Craig P. Johnston,^†

†

Grant G. Cumming,^†Andrew G. Leach,^‡and Guy C. Lloyd-Jones*^,

^†EaStChem, University of Edinburgh, Joseph Black Building, David Brewster Road, Edinburgh, EH9 3FJ, UK

^‡School of Health Sciences, Stopford Building, The University of Manchester, Oxford Road, Manchester M13 9PT, UK

ABSTRACT: The mechanism of CF₂-transfer from TMSCF₃(1), mediated by TBAT (2–12 mol%) or by NaI (5–20 mol%), has been

investigated by in situ / stopped-flow ¹⁹F NMR spectroscopic analysis of the kinetics of alkene difluorocyclopropanation, and com-

peting TFE / c-C₃F₆/ homologous perfluoroanion generation, ¹³C/²H KIEs, LFERs, CF₂-transfer efficiency and selectivity, the effect

of inhibitors, and density functional theory (DFT) calculations. The reactions evolve with profoundly different kinetics, undergoing

auto-inhibition (TBAT) or stochastic auto-acceleration (NaI), and co-generating perfluoroalkene side products. An overarching mech-

anism involving direct and indirect fluoride transfer from a CF₃-anionoid to TMSCF₃(1) has been elucidated. It allows rationalization

of why the NaI-mediated process is more effective for less-reactive alkenes and alkynes, why a large excess of TMSCF₃(1) is required

in all cases, and why slow-addition protocols can be of benefit. Issues relating to exothermicity, toxicity, and scale-up are also noted.

INTRODUCTION

Scheme 1. Prakash-Hu difluorocyclopropanation.^a10,12

The unique properties of cyclopropanes leads to useful effects on

their fluorination,¹with the application of difluorocyclopropanes

being especially prominent.^1-2The latter are most commonly pre-

pared by alkene-difluorocyclopropanation,^1-3nominally via in situ

capture of singlet CF₂,⁴and over the last 50 years, a very broad

range of reagents have been developed for this process.^5-10How-

ever, many of these reagents have limitations, inter alia, toxicity,

the use of strong bases, or the need for high-temperatures. The latter

aspect is of critical importance for alkynes, where the primary

difluorocyclopropene product can undergo further difluorocyclo-

propanation and other reactions.¹¹Thus, there has been much inter-

est in the development of new reagents,⁹and major advances have

been independently made by Dilman and co-workers,^3c,9fgh,tand by

Prakash and Hu and co-workers,^8c,10in the use of TMSCF₂X spe-

cies (X = F, Cl, Br, I) for CF₂-transfer under mild conditions.

TMSCF₃(1)

(2-7 equiv.)

A or B

R’

A: 5 mol % TBAT, THF, RT.^b

B: 5-200 mol % NaI, THF, 65 °C.^c

^a.TBAT = [Bu₄N]⁺[Ph₃SiF₂]^–. ^b.–50 °C to RT. ^c.Alkyne at 110 °C.

Despite the major synthetic developments outlined above, the ki-

netic and mechanistic details of CF₂-transfer from TMSCF₃(1), not

just to alkenes and alkynes,^10,12but to a wide range of other spe-

cies,¹³remains largely unexplored.^3,12m

RESULTS AND DISCUSSION

The Prakash-Hu difluorocyclopropanation, Scheme 1, employing

commercially-available TMSCF₃(1), and in particular the use of

NaI in THF (conditions B),¹⁰is now widely-applied,¹²e.g. in the

extensive studies of Grygorenko and co-workers,^12i,m,n,pand

Mykhailiuk and co-workers,^12h,land in a difluorocyclopropanation

flow-reactor developed by Charette and co-workers.^12bConditions

analogous to B, Scheme 1, but omitting the alkene, have also been

applied by Hu and co-workers for the preparation of tetrafluoroeth-

ylene (TFE), and its reactive dissolution in a second vessel.^13hThis

allows a range of -CF₂CF₂- containing species to be generated from

TMSCF₃(1), without direct, and potentially hazardous, manipula-

tion of TFE.¹⁴

We recently confirmed that CF₃-transfer from TMSCF₃(1) to ke-

tones and aldehydes involves liberation of a transient CF₃-anionoid,

rather than direct CF₃-transfer from a trifluoromethyl siliconate

[Me₃Si(X)CF₃]^–(2_X; X = alkoxy or CF₃).^16-18Herein we describe a

detailed study of the mechanism of CF₂-transfer from TMSCF₃(1)

to alkenes and alkynes, under the Prakash-Hu difluorocyclopropa-

nation conditions, Scheme 1.¹⁰Extensive in situ ¹⁹F NMR spectro-

scopic investigation has allowed us to analyse the reaction kinetics,

the selectivity, and the side reactions that lead to the requirement

for a large excess of the TMSCF₃(1) reagent. As with our study on

CF₃-transfer,¹⁶concurrent analysis of numerous intermediates and

processes using density functional theory (DFT) has been crucial

in informing and constraining the investigation.

Thus, TMSCF₃(1), a reagent that has been employed for over 30

years for the nucleophilic transfer of CF₃,¹⁵has recently undergone

a major renaissance, as a 'CF₂-surrogate'.^10,12,13There are consider-

able similarities between the conditions employed for CF₃-transfer

from 1 to electrophiles,^15cversus those employed for CF₂-transfer

to alkenes/ynes.^10,12However, a prominent disparity is the large ex-

cess of TMSCF₃(2-7 equivalents) used for CF₂-transfer. Indeed,

this issue has prompted Grygorenko and co-workers to develop a

'slow-addition protocol' allowing substantial improvement in the

efficiency and substrate diversity of the difluorocyclopropanation

process.^12m,p

1. Prior Studies. Common to most proposals for the mechanism

of the Prakash-Hu difluorocyclopropanation^10,12is the assumption

that i) the process involves generation of free CF₂from 1, which

then adds to the alkene,^10,12and ii) that the CF₂arises from direct

loss of fluoride (k_a) from a transient CF₃-anionoid,^19,20Mechanisms

I, II, Scheme 2. In the absence of alkene, the CF₂is suggested to

spontaneously dimerize to give TFE.^13hFluoride ions have been

proposed^10,13b,fto have two distinct roles in these reactions. Non-

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metallic fluorides, such as [Bu₄N]⁺[Ph₃SiF₂]^–('TBAT'), are sug-

8, generated in low yield (12%) from alkyne 5, under the TBAT-

gested^10,13bto initiate a fluoride-mediated chain reaction (Mecha-

nism I). Conversely, metal iodides, such as NaI, are suggested^10,13b,f

to displace a CF₃-anionoid from TMSCF₃(1), with the TMSI co-

product trapping the nascent fluoride from the CF₂generation

(Mechanism II), thus inhibiting Mechanism I. Intriguingly, the pos-

sibility of an a-elimination at silicon²¹(k_aSi), Mechanism III, X =

CF₃, F, I) has not been discussed, despite the indirect role of sili-

conates [Me₃Si(X)CF₃]^–(2_X)¹⁷in CF₃-anionoid transfer.^16-18

Scheme 2. Mechanisms I and II, previously proposed^10,13b,ffor CF₂-

generation from TMSCF₃(1), and mechanism III involving a-elim-

ination in a siliconate (2_X, X = CF₃, F, I)^.See text for full discussion.

mediated conditions, underwent partial decomposition to unidenti-

fied products. In contrast, 8 was quantitatively-generated, and sta-

ble, under NaI-mediated conditions, see section S3.3 in the SI. The

same difluorocyclopropane products (6, 7) were obtained from 3i

and E/Z-4 on thermalization with the zwitterionic CF₂-source

Ph₃PCF₂CO₂.²²The relative reactivities (k_rel) of alkenes 3i, E-4, and

Z-4, and the LFER correlation for a-methylstyrenes (3i-vii, r⁺= –

0.6),²³were independent of the reagent (1 / Ph₃PCF₂CO₂), and ini-

tiator (TBAT / NaI), Table 1,²⁴within experimental error.

Scheme 3. Experimental^aand calculated^bKIEs for rapid addition

of transient singlet CF₂to 3i, at 300 K.²⁵

TMSCF₃(1)

1.5 M

CF₃

CF₂

[TBAT] 18 mM

THF; PhCl 27 °C

–TMSF

(1)

3i, Ar = p-F-C₆H₄

D₄-Ar

(0.6 M)

CD₂

Mechanism I

F^–

TMSF

[α-¹³C₁]-3i

[β-¹³C₁]-3i

[CF₃]^–

[β-D₂]-3i [aryl-D₄]-3i

(1)

CF₂

k_arylH/k_arylDcalc. 0.966

F^–

TMSF

Mechanism II

(exp. 0.975; 0.974)

F^–

I^–

TMSI

[CF₃]^–

CF₂

(1)

k_H/k_Dcalc. 0.832

(exp. 0.891; 0.822)

¹³C

calc. 1.003

_C/k

¹³C

calc. 1.032

_C/k

Mechanism III

(exp. 1.006; 1.001)

(exp. 1.035; 1.032)

CF₃

calc. ∆G₃₀₀^‡= 7.8 kcal mol^-1

Si^–

CF₂

^aExperimental (exp.) values in THF; and in PhCl, as solvent.^{25 b}Cal-

culated (calc.) values by DFT, at the M06/6-31+G* level in Gauss-

ian09 employing IEF-PCM single points to account for solvation,

and goodvibes, kinisot and PyQuiver to compute free energy cor-

rections and KIEs, see sections S1.6 and S6.2 in the SI.²⁶

CF₂

Si^–

(2_X; X = CF₃, F, I)

Table 1. Difluorocyclopropanation of alkenes 3i, and E/Z-4 and al-

kyne 5 in THF. The k_reland r⁺values are independent of the

method: 1 + TBAT (conditions A); 1 + NaI (conditions B),¹⁰or

thermalization of Ph₃PCF₂CO₂.²²

Kinetic isotope effects for the reaction of p-F-a-methylstyrene 3i

with TMSCF₃(1) initiated by TBAT were obtained by a series of

competitions of ¹³C- and H-labelled a-methylstyrenes 3i against

Alkene/yne

Product

aryl-D₄-3i, monitored by ¹⁹F NMR spectroscopy (aryl-Dd_F= 0.5

ppm).²⁵The resulting primary and secondary kinetic isotope ef-

fects, Scheme 3, were consistent with those predicted by DFT cal-

culations,^16,26for the rapid addition of singlet CF₂to 3i, see section

S6.2 in the SI.^4,27The concerted asynchronous cycloaddition of CF₂

is also consistent with the LFER correlation (r⁺–0.64, Table 1),

and with E-4 being about 5-fold more reactive than Z-4.

k_rel.(21 °C)^ak_rel.(65 °C)^a

(±)-6i

1.00

p-F-C₆H₄

E-4

Z-4

trans-(±)-7 0.05

0.08

0.02

0.22

Overall, the preliminary studies above strongly support the conclu-

sion that TMSCF₃(1) functions as an indirect²⁸source of free sin-

glet CF₂.⁴However, as is evident from Figure 1, the two sets of

conditions, Scheme 1,¹⁰evolve with profoundly different kinetics.

Whilst we ultimately show that the two processes are mechanisti-

cally related, vide infra, we discuss data for the two systems sepa-

rately below, beginning with TBAT-initiation.¹⁰

cis-(±)-7

0.01

0.17

! (21 °C)

! (65 °C)

3i-vii

–0.64

(–0.74)^b

–0.61

(–0.63)^b

(±)-6i-vii

3. TBAT mediated CF₂Generation from TMSCF₃. The ki-

netics of reaction of 3i with TMSCF₃(1) initiated by TBAT in THF

were analysed in detail by in situ ¹⁹F NMR spectroscopy. The pro-

cess afforded simple and reproducible temporal-concentration pro-

files, in which 1 and 3i are consumed, and TMSF and 6i are gener-

ated, Figure 1A. Although the decay in [1] correlates directly with

the growth in [TMSF], the difluorocyclopropanation product [6i]

does not. Competing side-reactions consume excess 1, still gener-

ating TMSF, but not 6i, vide infra, making the productive fraction-

ation, f = v_6i/v_TMSF, a useful mechanistic parameter.

p-X-C₆H₄

X = F(i); H (ii); Ph (iii); Me (iv) MeO (v); CF₃(vi); Br (vii)

^aRelative rates (k_rel) are for competitive first-order CF₂capture by

the alkene/yne, not to overall rates of reaction. ^bValues in parenthe-

sis by DFT.²⁶See sections S3.7, S3.8 and S6.2 in the SI.

2. Singlet CF₂as the Reactive Intermediate. We began by

studying the reaction of TMSCF₃(1) with alkenes 3i, and E/Z-4 and

alkyne 5, Table 1. All underwent difluorocyclopropanation, to var-

ying degrees of conversion, in the presence of TMSCF₃(1, 1.5 M)

and 1-5 mol % TBAT, or NaI. Reactions of E/Z-4 proceeded stere-

ospecifically, and with >98 % retention. The difluorocyclopropene

excess TMSCF₃+ 3i ® excess TMSF + 6i

f = v_6i/v_TMSF

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The side reactions that reduce the productive fractionation, f < 1,

Figure 1. Examples of reaction of alkene 3i (0.6 M) with 1 (1.5 M),

mediated by TBAT (Graphs A, 18 mM) and by NaI (Graphs B, 32

also cause inhibition, vide infra, resulting in progressive deviation

from the initially pseudo zero-order kinetics (eqn. 1).

mM), analyzed in situ by ¹⁹F NMR spectroscopy.

3.2 Analysis of Siliconate 2_CF3.Variable temperature ¹⁹F NMR

spectroscopic analysis of the reaction of TBAT with a large excess

of TMSCF₃(1) and alkene (3i) confirms that the TBAT is immedi-

ately consumed, to quantitatively generate siliconate 2_CF3(d_F–63.0

pm),¹⁸plus TMSF (d_F–157.1 pm), Ph₃SiF (d_F–169.7 pm), and

Ph₃SiCF₃(d_F–58.4 pm).²⁹Under the conditions employed for the

preliminary kinetic analyses at 300 K, Figure 2, the signal for 2_CF3

is not evident in the ¹⁹F NMR spectrum due to extensive line-broad-

ening caused by rapid, endergonic, equilibrium (1/K_C) with 1 and

the corresponding CF₃-anionoid, Scheme 4.^16,17

TMSCF₃(1)

1.5 M, THF

p-F-C₆H₄

TMSF

0.6 M

Conditions:

A 18 mM TBAT, 27 °C

B, 32 mM NaI, 65 °C

p-F-C₆H₄

(±)-6i

conc. / M

TMSF

f₀≈ 0.85

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0

TMSF

f₀≥ 0.99

Scheme 4. Complexation (K_C) of CF₃-anionoid with 1 to generate

siliconate 2_CF3, and competing CF₂generation versus electrophilic

capture of CF₃-anionoid. k_–Cby SF-¹⁹F-NMR¹⁶line-shape, see SI.

E⁺

E–CF₃

[Bu₄N]⁺

CF₃

Si^–

500

1000

1500

2000

4000

6000

TFE

K_C(1)

0.040

0.035

0.030

0.025

0.020

0.015

0.010

0.005

0.000

0.16

0.14

0.12

0.10

0.08

0.06

0.04

0.02

0.00

[CF₃]^–[Bu₄N]⁺

CF₃

k_–C

CF₃H

k_–C≈ 4×10³s^-1(27 °C)

)

CF₃

CF₂

c-C₃F₆

–

[C₁₁F₂₃

]

9, 0.3 M

CF₃H

OTMS

CF₃

Ar = p-F-C₆H₄

TMSCF₂CF₃

(initial)

500

1000

1500

2000

4000

6000

TMSCF₃(1), 1.5 M

d[10]

t / s

> 10

[TBAT], 6 mM

THF, 27°C

d [6i]

3.1 Empirical Rate Law and Fractionation, f. Systematic var-

iation of the reactant concentrations led to empirical relationships

(equations 1 and 2) for the initial rate (v₀) and fractionation (f₀) for

conditions A, Figure 2.

3i, 0.3 M

In the absence of an alkene, siliconate 2_CF3is relatively unstable

(t_0.5~1 min at 13 °C), decomposing to TMSF, plus a mixture of

perfluorinated species, including TFE, TMSCF₂CF₃, CF₃H (see

section 6), and complex anions, vide infra.¹⁸The rate of decompo-

sition of 2_CF3is substantially attenuated by the presence of alkene

(3i) which captures the CF₂(to generate 6i).³⁰Variable temperature

stopped-flow ¹⁹F NMR spectroscopy (VT-SF-¹⁹F NMR)¹⁶allowed

the siliconate 2_CF3, and the generation of TMSF, and transfer of

CF₂, to be studied in detail between 2 and 22 °C, see section S1.9

in the SI. Simulation of the ¹⁹F NMR line-width data of siliconate

2_CF3indicates that CF₃-anionoid dissociation (k_-C, Scheme 4) is

–d[1]

d[TMSF]

k_obs[TBAT]₀

(eqn. 1)

v₀

≈

d[6i]

f₀d[TMSF]

(eqn. 2)

f₀

≈

K_f[[TBAT]₀

[1]₀[3i]₀

1 +

Figure 2. Initial rates (v₀/M s^-1) of TMSF / 6i generation in the

TBAT-initiated reaction of 3i with 1.^aCircles: experimental data.

Lines: best-fit using k_obs= 6.7 ´ 10^-2s^-1, K_f= 8.3 M, eq. 1 and 2.

rapid (DG₃₀₀^‡= 13 kcal mol^-1; DS^‡= 23 cal K^-1mol^-1). In contrast,

TMSCF₃(1)

‡

0 to 0.75 M

the overall rate of TMSF generation has a higher barrier (DG₂₉₈

0 to 1.8 M

19 kcal mol^-1; DS^‡= 18 cal K^-1mol^-1), consistent with the empirical

THF, 27 °C

TMSF

rate law for cyclopropanation, k_obs= 6.7 ´ 10^-2s^-1, Figure 2.

p-F-C₆H₄

TBAT

0 to 34 mM

Addition of competitive electrophilic species (E⁺), that trap or di-

vert the CF₃-anionoid,^16,17inhibit or terminate CF₂-transfer from 1

to p-F-a-methylstyrene 3i, see SI. For example, addition of CO₂

(13 mol%) results in generation of [CF₃CO₂]^–and complete cessa-

tion of CF₂generation. Analogously, hindered ketone 9 is con-

verted to CF₃-addition product 10, in advance of the difluorocyclo-

propanation product 6i being generated; section S3.8G in the SI.

(±)-6i

v₀/ M s^-1

₀/ M s^-1

v₀/ M s^-1

0.0025

0.0020

0.0015

0.0010

0.0005

0.0000

0.0012

0.0010

0.0008

0.0006

0.0004

0.0002

0.0000

0.0014

0.0012

0.0010

0.0008

0.0006

0.0004

0.0002

0.0000

TMSF

3.3 Mechanism of CF₂-generation; TBAT. The experiments

outlined above support the conclusion that CF₂generation from 1

under conditions A (TBAT), involves the CF₃-anionoid / siliconate

2_CF3equilibrium, Scheme 4. Prior mechanistic proposals have in-

voked direct a-elimination (k_a) from the CF₃-anionoid to yield CF₂

+ F^–; in other words, a chain-reaction in which the CF₃-anionoid

and F^–are the chain carriers (Mechanism I).^10,13bHowever, as was

analogously shown for the nucleophilic transfer of CF₃from 1 to

electrophiles,¹⁶exergonic complexation (K_C) of the CF₃-anionoid

will result in the TMSCF₃(1) acting as a powerful inhibitor in the

kinetics of CF₂generation (eqn. 3), which is not observed: see equa-

tion 1, and left hand graph in Figure 2.

0.0

1.0

[1]₀/ M

2.0

0.0

0.5

[3i]₀/ M

1.0

0.02

[TBAT]₀/ M

0.04

a. Conditions: THF, 27 °C. Unless stated, [1]₀= 1.5 M; [3i]₀= 0.6 M;

[TBAT]₀= 0.018 M. Data by in situ ¹⁹F NMR spectroscopic analysis. Val-

ues for [1]₀corrected for initial consumption of reagent by trace H₂O, as

estimated from [CF₃H]₀.

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[TBAT]₀

d[6i]

reactivity of the alkene/yne (k_ene), or the lower the initial concen-

tration of 1, the more rapid the onset of inhibition.

(eqn. 3)

(Mech I)

f₀k_α[CF₃]

≈

1 + K_C[1]

Scheme 6. Energies (DG₃₀₀/ kcal mol^-1) calculated by DFT²⁶for

perfluoroalkene homologations see section S6.3 in the SI, leading

to anion sequestration in 11.^32,34Values are discrete, not global.

d[6i]

f₀k_F[TBAT]₀[1]

1 + K_C[1]

f₀k_F[CF₃][1]

(eqn. 4)

(Mech IV)

≈

–

Moreover, DFT calculations indicate a prohibitively high barrier

(DG₃₀₀^‡≥ 27.6 kcal mol^-1; k_obs≤ 10^-7s^-1) for two-step liberation of

CF₂, starting from the dominant anion, i.e. siliconate 2_CF3, and pro-

ceeding via a-elimination (k_a; Mechanism I). An analogous pro-

cess in which the siliconate 2_CF3, rather than the CF₃-anionoid, un-

dergoes a-elimination (k_aSi; Mechanism III, Scheme 2) was also

considered. Whilst the process would be consistent with the empir-

ical rate-law (eqn. 1), DFT calculations in search of a TS for an

intramolecular a-elimination at silicon in 2_CF3, (k_aSi), failed. In-

stead the DFT optimizations diverted to a process in which silane

1 acts as an intermolecular acceptor of fluoride, from the CF₃-

anionoid (k_F, Mechanism IV, Scheme 5). A low barrier is calculated

for this elementary step (DG₃₀₀^‡= 13.4 kcal mol^-1). The predicted

kinetics (eqn. 4; section S5.1 in the SI) are consistent with the em-

pirical rate law (eqn. 1), when K_Cis large. The overall barrier cal-

culated for two-step CF₂-generation from 2_CF3, agrees well with ex-

periment (k_F/K_C, DG₃₀₀^‡= 19.1 kcal mol^-1; k_obs» 7 ´ 10^-2s^-1).

perfluoroalkene homologation

TMSF + CF₃

TMSCF₃

–

+ CF₃

–

[C_n+1F_2n+3

]

C_nF_2n

C_n+1F_2n+2

C₃F₆

CF₂

C₂F₄

C₉F₁₈

(12)

C₄F₈

–TMSF

cat. CF₃

–TMSF

–146.0 kcal.mol^-1

over 5 steps,

average per step

–29.2 kcal.mol^-1

–

cat. CF₃

–56.5 kcal mol^-1

cat. CF₃

–52.9 kcal mol^-1

–49.9 kcal mol^-1

F₃C

CF₃

F₃C

–TMSF

cat. CF₃

–TMSF

cat. CF₃

–

CF₃

F₃C

–

CF₃

–16.3 kcal mol^-1

–24.6 kcal mol^-1

C₉F₁₈

C₁₀F₂₀

C₁₁F₂₂

–

–26.3 kcal mol^-1

+CF₃

Scheme 5. Mechanism IV: silyl-induced CF₂-generation (k_F). En-

ergies (DG₃₀₀/ kcal mol^-1) by DFT.²⁶

F₃C

–

CF₃

[C₁₁F₂₃

]

F₃C

k_F/ k_C≈ 10^–5

Mechanism IV

CF₃

k_C

k_F

silyl-induced

In situ ¹⁹F NMR spectroscopic studies and DFT calculations, see

sections S1.8C and S6.3 in the SI, suggest the major decomposition

product (~50%) of siliconate 2_CF3is the tertiary perfluorocarbanion

[C₁₁F₂₃]^–, 11, Scheme 6.³²This species accumulates during the

difluorocyclopropanation of styrene 3i, Fig. 1A, as the reaction be-

comes progressively inhibited. DFT calculations indicate that per-

fluoroalkene 12,³³a known trimer of perfluoropropene,^34aand its

homologue 13, Scheme 6, are relatively free from steric strain. In

contrast, 14 (and isomer) is highly strained, making fluoride elimi-

nation from 11, [C₁₁F₂₃]^–, disfavored (DG₃₀₀+10.0 kcal mol^-1).

Figure 3. Selected simulations (see section S5.2 in the SI) using a

simplified mechanism IV. I: TBAT 34 mM, [3i]₀0.6 M; II: TBAT

15mM, [3i]₀0.6 M; III: TBAT 18 mM, [3i]₀0.3 M. k_–C= 4 ´10³s^-

¹, K_C= 1.2 ´10⁴M^-1, k_CF3/k_ene= 9 ´10⁴, k_T= 0.016 (± 0.004) M s^-1.

TMSCF₃(1)

CF₂-generation (k_F) via

intermolecular F-transfer

from CF₃^–to TMSCF₃(1)

^-Me

Me Si

CF₃

(1–f)

–

[C_nF_2n+1

]

CF₃

Si^–Me

[CF₃]^–

CF₃

_F(1)

_C(1)

CF₂

k_–C

(2_F)

CF₃

calc. ∆G₃₀₀^‡k_F

13.4 kcal mol^-1

(2_CF

)

k_ene3i

calc. ∆G₃₀₀(1/K_C)

5.6 kcal mol^-1

Equation 5 allows the CF₃-anionoid dissociation rate (k_-C, deter-

mined by VT-SF-¹⁹F NMR, see section S1.9 in the SI) to be used

to estimate the ratio of fluoride transfer to 1 (k_F) versus Si-com-

plexation (k_C). Whilst the ratio doubles across the temperature

range studied (2-22 °C), CF₂is generated only once in every ap-

proximately 10⁵reactions of 1 with the CF₃-anionoid (k_F/k_C= 1±0.4

1.5 M

´10^-5). At 27 °C the k_F/k_Cratio corresponds to DDG₃₀₀= 7 kcal

‡

[TBAT]

(±)-6i

mol^-1, consistent with Si-complexation of the CF₃-anionoid (k_C) be-

ing close to diffusion-controlled. The low k_F/k_Cratio (10^-5) results

in an excess of CF₃-anionoid being present during generation of

CF₂, and thus competing side reactions (k_CF₃) which lead to

TMSCF₂CF₃and TFE, both of which accumulate in low concen-

trations (2-10 mM). Equation 6, see section S5.2 in the SI, incorpo-

rates the parameters that influence the efficiency of CF₂capture by

alkene, i.e. k_ene[3i], and the concentration of the CF₃-anionoid, i.e.

K_C,[2_CF3] and [1], thus accounting for the empirical fractionation, f

(eqn. 2, when K_f» k_CF3/K_Ck_ene).³¹

15-34 mM

THF, 27 °C

3i, Ar = p-F-C₆H₄

(0.3-0.6 M)

TMSF

(Mech IV)

CF₃

TMSCF₃

1 k_C

[CF₃]^–

Si^–

CF₃

Me 2_F

CF₃

CF₂

k_F

k_–C

CF₃

[CF₃]^–

(cat)

k_T

TFE

CF₃

k_ene

k_F

d[TMSF]

–

[C_nF_2n+1

conc. / M

]

(Mech IV)

[TBAT]₀k_–C

(eqn. 5)

≈

k_C

conc. / M

TMSF

III

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.0

1.0

0.8

0.6

0.4

0.2

0.0

(eqn. 6)

TMSF

≈

k_CF[2_CF

]

TMSF

1 +

K_C[1]_tk_ene[3i]_t

3.4 Chain-Termination: the [C₁₁F₂₃]^–anion, 11. Difluorocy-

clopropanation under conditions A suffers progressive inhibition,

with reactions sometimes stalling prior to complete consumption of

alkene/yne, despite a large excess of TMSCF₃(1). The lower the

500 1000 1500

500

1000

t / s

1500

500 1000 1500

t / s

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satellites) apart from 1, TMSF, alkene 3i, product 6i, and the inter-

Thus, beginning with C₂F₄(TFE), a series of CF₃-anion additions,

1,2-shifts, and then F^–eliminations via TMSCF₃,³⁴see section S6.3

in the SI, results in the generation of a carbanion (11) that is suffi-

ciently stabilized,³⁵to terminate reaction involving 1. Inclusion of

a simplified pathway for chain-termination (k_T, TFE, Figure 3) in

an anionic chain-reaction based on Mechanism IV, afforded a basic

but functional model for the simulation (Figure 3) of the temporal

evolution of the TBAT-initiated Prakash-Hu difluorocyclopropa-

nation¹⁰of 3i; conditions A.

nal standard (PhF), were traces of CF₃H (see section 6).

4.2 Intermediacy of NaCF₃. A variety of electrophilic additives,

e.g CO₂, which again generated [CF₃CO₂]^–, inhibited difluorocy-

clopropanation, section S2.3 in the SI. However, in contrast to the

TBAT-initiated process, Scheme 4, co-reaction of alkene 3i and ke-

tone 9 resulted in difluorocyclopropanation without any significant

CF₃-transfer to 9, indicative of a much lower concentration of CF₃-

anionoid. With the more reactive aldehyde 15, the CF₃-addition

product 16 is co-generated, Figure 4.

4. NaI mediated CF₂Generation from TMSCF₃. In contrast

to TBAT, difluorocyclopropanation under conditions B (NaI)¹⁰ef-

fects complete conversion of alkenes E/Z-4, and alkyne 5 (see sec-

tion S3.2 and S3.3 in the SI, and k_rel, Table 1), and proceeds without

progressive inhibition. Exploration of the NaI-mediated reaction of

1 with 3i, using a wide range of alternative activators, additives,

and inhibitors, see section S1.10 in the SI, indicated that both the

sodium and the iodide, are essential components for efficient reac-

tion. For example, whilst an in situ combination of [Hex₄N][I] (5.2

mol %) with NaBAr₄(5 mol %), was as equally effective as NaI,

neither component was effective in isolation, and addition of 15-

crown-5 to the NaI-mediated reaction resulted in powerful inhibi-

tion. LiI and KI were much less effective than NaI, affording ≤ 10%

difluorocyclopropane 6i, over 2 days at 65 °C - conditions under

which NaI effects 100 % conversion of 3i to 6i in minutes to hours.

Other nucleophilic / reducing species, M⁺X^–(M = Bu₄N, Li, Na,

K), including MOtBu, MOAr, MO₂CR, MOTMS, TEMPO-M, and

M-naphthalenide, induced TMSF-generation from 1, displaying a

wide range of efficiencies for CF₂-transfer to 3i (f = 0.01 to 0.95).

However, most reactions underwent progressive inhibition, all gen-

erated TFE, and none displayed auto-acceleration, vide infra. At-

tempts to induce electrochemically-mediated TMSF + CF₂genera-

tion from 1 were only moderately effective: reactions initially dis-

played high productive fractionation, but quickly stalled, with side

products and decomposition of 6i, evident, see section S1.10K in

the SI.

4.1 In Situ ¹⁹F NMR Analysis. Attempts to establish an empiri-

cal rate law for the NaI mediated reaction of 3i with 1 were

thwarted by large kinetic variations between and within runs, See

Figure 1B, and sections S2.2DE in the SI. All of the reactions stud-

ied underwent one or more short periods of acute auto-accelera-

tion³⁶with the rate of TMSF generation increasing by a factor 10²-

10³(v_max» 2 ´ 10^-2[1]_tMs^-1). Whilst the occurrence and duration

of these periods varied substantially between runs, in general the

lower the initial concentration, or reactivity (k_ene, Table 1), of the

alkene/yne, the earlier the onset of auto-acceleration, see section

S3.8 in the SI.

Analysis of [3i]_t/[15]_tas a function of net conversion, revealed that

throughout reaction, i.e. before, during, and after auto-acceleration,

the two processes {3i + CF₂; Scheme 3}, and {15 + NaCF₃}¹⁷are

competitive and synchronized. Moreover, the relative reactivity of

3i to 15 (k_rel) is found to vary in proportion to the [NaI] concentra-

tion, see section S3.8I in the SI, with higher concentrations of NaI

increasing the relative-rate of consumption of 3i over 15. The first-

order dependency of this partitioning on all three components (i.e.

3i, 15 and NaI) is indicative that the two competing reactive inter-

mediates, CF₂and NaCF₃, are in equilibrium, with NaI biasing this

equilibrium in favor of the CF₂, see section S5.3 in the SI, and equa-

tion 7, K_rel» 1.7 ´ 10¹M^-1.

k_ene[3i] [CF₂]

–d[3i]/dt

–d[15]/dt

[3i]

k_rel

_rel≈ K_rel[NaI]

(eqn. 7)

[15]

k_ald[15] [NaCF₃]

Figure 4. Difluorocyclopropanation of 3i versus CF₃-addition to

15, mediated by NaI, analyzed by in situ ¹⁹F NMR spectroscopy.

The CF₂I-addition product 17 is only detected in the absence of 3i.

Lines through data are solely a guide to the eye.

15, 0.3 M

OTMS

CF₃

OTMS

Ar = p-F-C₆H₄

CF₂I

TMSCF₃(1), 1.5 M

[NaI], 16-64 mM

THF, 65 °C

+ TMSF

3i, 0.3 M

[3i, 15] / M

[TMSF] / M

[NaI]₀= 16 mM; k_rel= 0.3

3i (alkene)

0.35

0.30

0.25

0.20

0.15

0.10

0.05

0.00

1.2

TMSF

1.0

0.8

0.6

0.4

0.2

0.0

Preceding auto-acceleration is a phase of slow generation of 6i +

TMSF with very high efficiency (f ≥ 0.99 under all conditions ex-

amined) and no evident correlation of the rate (3±2 ´ 10^-5M s^-1)

with [NaI]₀, [3i]_t, or [1]_t. During the final auto-acceleration, the pro-

ductive fractionation is substantially reduced (f ≤ 0.1; see sections

S2.2CD in the SI), initially through generation of TFE, to a maxi-

mum concentration of 0.25±0.1 M, before being depleted by con-

version to perfluorocyclopropane (c-C₃F₆),¹²ⁱand a plethora of

other minor species, including CF₃I and further CF₃H.

In situ ¹⁹F NMR spectroscopy during the periods of auto-accelera-

tion suggests that the process causes chemical or physicochemical

inhomogeneity within the NMR sample,³⁶resulting in broad and

asymmetric ¹⁹F NMR signals in all of the reaction components, in-

cluding the internal standard, section S2.5B in the SI. This line-

broadening hinders identification of transient species generated

during acute periods of auto-acceleration. As auto-acceleration at-

tenuates, the ¹⁹F NMR signals return to normal (sharp, symmet-

ric).³⁶Prior to auto-acceleration, the only species detected by in situ

¹⁹F NMR spectroscopy (> 0.05 mol%; as referenced against ¹³C-

15 (ArCHO)

500

1000

1500

2000

2500

t / s

In the absence of alkene 3i, traces of the CF₂I-addition^9hproduct 17

(0.9 %) were also generated,³⁷and reactions conducted in the ab-

sence of both 3i and 15 rapidly underwent auto-acceleration, again

generating TFE (0.25±0.1 M), and white precipitates containing

NaF. Detailed in situ analyses of this process, see Figure 5 and sec-

tion S2.5 in the SI, revealed that low concentrations of a transient

species, tentatively identified as TMSCF₂CF₂CF₂I, 18,³⁸are gener-

ated immediately after TFE begins to appear. The concentration of

18 (Figure 5B) correlates with the degree of auto-acceleration,

reaching a maximum concentration at the point of maximum rate

of TMSCF₃1 consumption (Figure 5C). The decay in TFE, and 18,

correlate with the growth of c-C₃F₆.

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Page 6 of 13

Figure 5. Auto-accelerating decomposition of TMSCF₃(1) medi- TMSCF₂I are both powerful inhibitors of the NaI-mediated reac-

ated by NaI in THF at 65 °C, in the absence of exogenous alkene.

Analysis by in situ ¹⁹F NMR spectroscopy. Lines through data are

solely a guide to the eye. -d[1]/dt: was estimated from the first-de-

rivative of truncated polynomial fitted between 85-210 s.

tion of 1 with 3i, see sections S2.3EJ in the SI. In addition, no

TMSI, or THF ring-opened co-products,⁴¹are detected by in situ

²⁹Si and ¹H NMR spectroscopy. Moreover, there is no direct corre-

lation between [NaI]₀and rate, or an induction period after addition

of the NaI.

TMSF

(18)

TMSCF₂CF₂CF₂I

NaI, 100 mM

THF, 65 °C

TMSCF₃(1)

Initiation must therefore be effected by traces of unidentified si-

laphilic species generated in situ from the NaI, by oxidation,⁴²re-

action with decomposition products of the TMSCF₃,¹⁶co-reaction

with the Lewis basic THF solvent, or already present in the NaI

from manufacture.⁴³Traces of white flocculate are observed in the

reactions of 1 mediated by NaI (3.5 mol%), in the presence and

absence of alkene 3i. The precipitates become much more volumi-

nous in the final phases of reaction. Analysis of the precipitate (¹⁹F

NMR in D₂O) obtained after 12-16 % conversion of 3i, showed it

contains NaF (0.005-0.02 mol%); see section S2.2D in the SI. After

full auto-acceleration, 1.9 mol % NaF had been precipitated. How-

ever, the reactions of 1 with 3i are not initiated by powdered NaF,

or accelerated by exogenous NaF in the presence of NaI, see section

S1.10I in the SI. In other words, microcrystalline NaF is insoluble

and inert under the reaction conditions. Despite extensive efforts,

we have not yet been able to identify the primary initiation route(s).

1.5 M

c-C₃F₆

TFE

[c-C₃F₆] / M

[18] / M

conc. / M

0.02

0.10

(18)

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0.0

c-C₃F₆

TMSCF₃(1)

TMS(CF₂)₃I

TMSF

0.01

0.00

0.05

0.00

200

400

t / s

-d[1]/dt (M s^-1

0.015

)

v_maxꢀ0.015 M s^-1

TFE

0.010

0.005

0.000

t / s

Thus, the primary role of the NaI appears to be to mediate efficient

difluorocyclopropanation, vide infra, via an anionic chain reaction

proceeding at very low concentrations of chain-carrier.³⁹Our anal-

ysis of the role of NaI in mediating the desired difluorocyclopropa-

nation thus centres on the a-elimination step (k_a, upper section of

Scheme 7). Although calculations show this process to be rapid, it

is also endergonic, see section S6.4B in the SI, with CF₂+ NaF

(monomeric) reverting to NaCF₃at diffusion-control.³⁹However,

the equilibrium concentration of CF₂can be raised by coupling the

endergonic a-elimination (K_a) to an exergonic complexation with

NaI⁴⁴(K_NaI), see Scheme 8.

t / s

200

400

200

400

4.3. Mechanism of CF₂generation; NaI. The above analysis

(section 4.2) supports the intermediacy of a CF₃-anionoid in an an-

ionic chain reaction that generates CF₂from TMSCF₃(1), as has

previously been suggested.^10,13b,fHowever, unlike TBAT initiation,

TMSCF₃is not predicted to inhibit the chain reaction by siliconate

2_CF3generation (calc. K_C≤ 10^-5; Scheme 7), due to a stronger, but

still predominantly ionic, interaction of Na⁺with the CF₃anionoid;

see section S6.4B in the SI. Moreover, the interaction of the CF₃

anionoid with Na⁺raises the barrier of silyl-induced elimination via

F^–anion transfer (compare k_F, mechanism IV, Scheme 5) to DG₃₃₈

‡

Scheme 8. Mechanism V: NaI-mediated chain-reaction for the gen-

eration of CF₂from TMSCF₃(1) with auto-acceleration via chain-

branching. NaF_solidprecipitation increases substantially during

auto-acceleration. Primary initiation is by trace unidentified si-

laphilic species (see text). Additional chain-branching processes

are also possible. Na-intermediates are primarily bound through

ion-pair interactions, see section S6.4B in the SI, not covalent

bonds. Energies (DG₃₃₈/ kcal mol^-1) calculated by DFT.²⁶

= +21.4 kcal mol^-1; substantially above the barrier for direct a-

elimination, k_a, Scheme 7. Indeed, on first-inspection, if the reac-

tion proceeds via an a-elimination pathway (NaCF₃® CF₂+ NaF,

calc. k_a~ 10⁴s^-1), just micromolar concentrations³⁹of NaCF₃are

required to sustain the fastest rates of TMSF-generation observed

(v_max» 2 ´10^-2[1]; see section S2.5B in the SI).³⁹

Scheme 7. Upper section: disfavored Si-complexation (K_C) of

NaCF₃, and rapid, reversible a-elimination (k_a). Lower: Highly en-

dergonic routes to NaCF₃from NaI and 1. Interaction of NaI with

1 at Si is repulsive, see section S6.4B in the SI. Energies by DFT.²⁶

TMSF

TMSCF₃(1)

Mechanism V

∆G₃₃₈+9.1 kcal mol^-1

initiation

termination

NaF_solid

(1)

TMSCF₃

primary-chain

TMSCF₃(1)

Na⁺

solv.

k_α> 10⁴s^-1

CF₃

Si^–

K_C

NaX

NaI

∆G₃₃₈(K_αK_NaI

)

CF₂+ NaF

+1.3 kcal mol^-1

NaIꢀNaF

CF₂

∆G₃₃₈(1/K_α)

Na⁺

–11.5 kcal mol^-1

Na-C interaction

predominantly ionic

∆G₃₃₈(1/K_C)

–9.6 kcal mol^-1

CF₃

NaI + NaCF₃

k_ene

(2_CF

)

(18)

TMS(CF₂)₃I

chain

branching

∆G₃₃₈

2.5 kcal mol^-1

∆G₃₃₈

NaI

+3.8 kcal mol^-1

∆G₃₃₈+ 36.4 kcal mol^-1

TMSCF₃(1)

TMSI

NaCF₃

Na(CF₂)₃I

NaCF₂I

TFE

TMSCF₂I

NaI

NaCF₂I

TMSF

∆G₃₃₈+28.9 kcal mol^-1

∆G₃₃₈

–4.0 kcal mol^-1

CF₂

NaCF₃

CF₂

Na⁺

C_nF_2n

NaI + c-C₃F₆

NaI + TFE

CF₃

repulsive

interaction:

(2_I) and TS

not located

CF₂I

Si^–

∆G₃₃₈–30.2 kcal mol^-1

∆G₃₃₈

+31.4 kcal mol^-1

∆G₃₃₈

+21.7 kcal mol^-1

CF₃

Analogous dinuclear NaX·NaX complexes (X = F, Cl, Br, I) have

been characterized in the gas phase,^44band related synergistic al-

kali-metal effects are known.⁴⁵Whilst the stoichiometry of com-

plexation (K_NaI, to generate NaF·(NaI)_x) has not been evaluated di-

rectly, the first-order correlation of [NaI] with k_rel(equation 7) in

I^–

However, initiation of the anionic chain by direct reaction of 1 with

NaI to generate NaCF₃(Mechanism II)^10,13b,fis calculated to be

strongly disfavored, Scheme 7. Indeed, exogenous TMSI and

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In contrast, co-reactions of TESCF₃(19) and TMSCF₃(1) mediated

the competition of alkene 3i with aldehyde 15, Figure 4, suggests

that x is close to unity. Chain propagation, by direct or dissociative

reaction of NaF·NaI with 1, regenerates transient NaCF₃in mi-

cromolar concentrations, Scheme 8, allowing efficient difluorocy-

clopropanation of the alkene/yne (f ≥ 0.99). NaI thus serves at least

three roles: i) it indirectly generates chain-carrier, ii) it biases the

endergonic equilibrium with CF₂, i.e. (K_aK_NaI), and in doing so at-

tenuates the undesired reaction of CF₂with NaCF₃, and iii) it stabi-

by NaI, proceeded selectively (k_TMS/ k_TES~ 30, see S3.9BC in the

SI) in both the presence and absence of alkene 3i. This is consistent

with siliconates (2, 20) being disfavored in the presence of Na⁺,

allowing the selective reaction of the more fluorophilic reagent 1.

6. Fluoroform (CF₃H) Generation. There have been conflicting

reports in the literature about whether a CF₃anionoid is able to

deprotonate THF to generate CF₃H.^17a,cIn all of the reactions ex-

plored herein, CF₃H was detected, see e.g. Fig 1. However, CF₃H

is generated in two distinct phases. Under the standard conditions,

Table 1, approximately 0.4 mol% CF₃H is generated immediately

after the reaction is assembled. This arises from protonation of the

CF₃anionoid^16,17by residual H₂O (20 ppm, KF-titration) in the

THF, as confirmed by ²H labelling. Further CF₃H (up to 18 mM, 1-

1.2 % of 1) is generated in the later stages of the reaction, either

progressively (TBAT) or in a final 'burst' (NaI, see Figure 1B). The

source of H-atom in this distinct second stage of CF₃H generation

is the THF, as confirmed by ²H labelling, section S2.4A in the SI.

Calculations indicate that deprotonation of THF by the CF₃ani-

onoid is highly endergonic. However, abstraction of an H-atom by

a CF₃radical⁴⁸is favorable,⁴⁹and the calculated KIEs are consistent

with those determined experimentally, Scheme 10, see sections

S2.4B and S6.7 in the SI.^49g

lizes the NaF chain-carrier by inhibiting generation of NaF_solid

4.4. Chain-Branching; Auto-acceleration by NaI. In compe-

tition with CF₂-capture by the alkene (k_ene) is the mildly endergonic

(DG₃₃₈= 2.5 kcal mol^-1) reversible addition of NaI to CF₂to gener-

ate NaCF₂I,^9hresulting in generation of 17, when an aldehyde is

present, Figure 4. Although silylation of NaCF₂I is disfavored

(NaCF₂I + 1 ® NaCF₃+ TMSCF₂I, DG₃₃₈= 16.0 kcal mol^-1) pri-

marily because of the steric clash between iodine and the TMS in

the resulting TMSCF₂I,^9hreaction of NaCF₂I with CF₂will gener-

ate TFE (DG₃₃₈= –59.5 kcal mol^-1); in other words, NaI can cata-

lyze the dimerization of CF₂.⁴⁶Subsequent exergonic reaction of

the TFE with NaCF₂I (or with NaI, followed by CF₂), will generate

I(CF₂)₃Na. This can either cyclize, generating c-C₃F₆, or be revers-

ibly silylated by 1 to generate 18 and NaCF₃. The latter process

facilitates indirect chain-branching, i.e. increases [NaCF₃], thus ac-

celerating the chain reaction, and facilitating competing side reac-

tions such as capture of CF₂by NaCF₃to generate further TFE and

NaF. A number of processes will attenuate branching, or the chain

reaction itself, including the reverse reaction of NaCF₃with 18 to

regenerate 1 + I(CF₂)₃Na (and c-C₃F₆), CF₂-capture by alkene, CF₂-

capture by TFE to generate c-C₃F₆,¹²ⁱaggregation of (NaF)_nleading

to precipitation of inert, microcrystalline, NaF_solid, and trapping or

oxidation of NaCF₃by perfluoroalkenes, vide infra, generated from

TFE. A characteristic of branched chain-reactions is their sensitiv-

ity to small changes in the concentrations of components, hetero-

geneity, and trace inhibitors, in some cases leading to fluctuations

in active species and irreproducible kinetics,⁴⁷as is observed in the

current system,³⁶Figure 1B, see also sections S2.2D and S2.5B in

the SI.

Scheme 10. CF₃H generation from THF; C_nF_2n= higher perfluoro-

alkene, e.g. 2,3-(CF₃)₂C₄F₆, as indicated. Energies (DG₃₃₈/ kcal

mol^-1) calculated by DFT.²⁶KIEs at 300 K: exp. 7.2 exp., calc. 7.4.

calc. ∆G₃₃₈

+36.5 kcal mol^-1

–

e.g.

CF₃

CF₃H/D

F₃C

CF₃

C_nF_2n

d₈-THF,

d₀-THF

–

[C_nF_2n

]

calc. ∆G₃₃₈

-12.6 kcal mol^-1

calc. ∆G₃₃₈

+2.1 kcal mol^-1

CF₃H/D

CF₃

‡

calc. ∆G₃₃₈

+10.5 kcal mol^-1

KIE calc. 6.0

KIE exp. 6.2

Computational exploration of single-electron-transfer to perfluoro-

alkenes, see SI, indicates that higher C_nF_2nspecies, e.g. Scheme 6,

can readily generate a CF₃radical^48,49from the CF₃anionoid, thus

accounting for the differing phases of CF₃H evolution under con-

ditions A, and B. In contrast to THF, reactions conducted in MeCN

develop CF₃H throughout their evolution, and comparison of ex-

perimental and calculated KIEs with two alternative tunnelling ap-

proximations, see SI, indicate that this is via deprotonation.⁵⁰

5. TESCF₃versus TMSCF₃. Reactions involving the more ste-

rically hindered reagent TESCF₃(19) were briefly explored, see

section S3.9 in the SI. Under TBAT-initiation, in the presence of

alkene 3i, mixtures of TESCF₃(19) and TMSCF₃(1) co-evolved

TMSF, TESF, and product 6i, with very little apparent selectivity

for reaction of 1 over 19. This initially confusing result is different

to our previous studies of TBAT-initiated CF₃-transfer to ketones

and aldehydes,¹⁶where TMSCF₃(1) reacted in advance of TESCF₃

(19). The result can be understood by the intermediacy of fluoro-

siliconates (2_F/ 20_F) in mechanism IV, which allow equilibration of

TMSF/TESCF₃with TMSCF₃/TESF, calc. DG₃₀₀–0.2 kcal mol^-1,

Scheme 9.

CONCLUSIONS

We have investigated the mechanism by which the commercially-

available reagent TMCF₃(1), widely-applied for CF₃-transfer,^16-18

can also function as source of CF₂.^10-13Despite co-generation of

TMSF, and thus a strong Si-F bond, the liberation of CF₂from

TMSCF₃is endergonic (DG₃₀₀+ 11.8 kcal mol^-1; 1M standard state

in THF). However, by coupling this to a process that captures the

CF₂, a thermodynamically-favorable, and usually exothermic, re-

action can be established. Thus, in the presence of a suitable initia-

tor / mediator, TMSCF₃can be a highly-effective reagent for

difluorocyclopropanation^10-13of alkenes/ynes, equation 8.

Scheme 9. Differing outcomes of co-reaction of TESCF₃(19) and

TMSCF₃(1) under conditions A (TBAT) versus B (NaI), with equi-

libration via siliconates (2_F, 20_F) under conditions A.

TMSCF₃(1)

TESCF₃

(19)

∆G₃₀₀

–26.3 kcal mol^-1

TMSF

+ TMSF, TESF

THF

∆H₃₀₀

(eqn. 8)

TMSCF₃

conditions A / B

k_TMS

–26.9 kcal mol^-1

initiator

(Ar = p-F-C₆H₄)

k_TMS

∼ = 1.0

= 30 ± 5

B, NaI:

A, TBAT:

k_TES

2 × TMSF

∆G₃₀₀

–37.3 kcal mol^-1

cat.

TMSCF₃(1)

TMSF

TESCF₃(19)

2 × TMSCF₃

(eqn. 9)

CF₂=CF₂

calc. ∆G₃₀₀

–0.2 kcal mol^-1

∆H₃₀₀

–26.1 kcal mol^-1

initiator

TESF

Two general sets of conditions have been described for this: TBAT-

initiation (conditions A) and NaI-initiation (conditions B), in

THF,^10-13Scheme 1. Both require an excess of TMSCF₃(1) over

cat. = [R₃Si(F)CF₃]^–2_F(R = Me) and 20_F(R = Et)

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Page 8 of 13

the alkene/yne CF₂-acceptor.^10,11c,12The NaI-mediated method has

erations, via chain branching, Scheme 8. Under nearly all condi-

also been widely applied for CF₂-transfer to a range of other spe-

cies, and also for the in situ generation of TFE, equation 9.¹³

tions this leads to rapid and near-complete consumption of the

TMSCF₃(1), and co-generation of TFE. Counterintuitively, less re-

active alkenes/ynes (k_ene, Scheme 8, k_rel, Table 1), can (phenome-

nologically) undergo more rapid difluorocyclopropanation by 1 /

NaI, due to the earlier onset of auto-acceleration, provided that the

alkene/yne is sufficiently more-reactive towards CF₂(k_ene) than the

accumulating TFE (DG₃₃₈^‡= 12.2 kcal mol^-1). These counteracting

effects, may account for the apparently anomalous alkene reactivi-

ties noted in previous studies.^12mIn the case of alkyne 5, the barrier

to the first CF₂addition to generate 8 (DG₃₃₈^‡= 12.0 kcal mol^-1) is

lower than for TFE, whilst that for second addition (DG₃₃₈^‡= 17.4

kcal mol^-1) is higher. The overall result is that double-addition¹¹of

CF₂is avoided, i.e. the difluorocyclopropene 8 (Table 1) is selec-

tively generated, see section S3.3 in the SI

Analysis of ¹³C/²H KIEs, LFERs, and alkene competition experi-

ments, confirms that both sets of conditions (A and B) liberate free,

transient, singlet CF₂(Scheme 3). The transient intermediate CF₂

adds to most alkenes and alkynes via a concerted cycloaddition

transition state, Scheme 3. 1-Phenylpropyne is more reactive⁵¹than

beta-methyl styrene towards CF₂, Table 1. Trans beta-methyl sty-

rene is more reactive than its cis isomer, due to destabilizing steric

interactions between cis-substituents that are enhanced on approach

to the state; see section S6.2 in the SI for further discussion.

The mechanisms by which carbene CF₂is generated from TMSCF₃

(1) have been investigated in detail using in situ / stopped-flow ¹⁹

NMR spectroscopy, kinetics and simulation of the difluorocyclo-

propanation of a-methylstyrene 3i, analysis of CF₂-transfer effi-

ciency, the effect of inhibitors, and density functional theory (DFT)

calculations. Having eliminated a wide range of mechanistic possi-

bilities, including radical chain reactions, cationic chain reactions,

and direct anion-induced liberation of CF₂from TMSCF₃, see sec-

tions S1.4, S2.3 and S6.8 in the SI, we conclude that both sets of

conditions proceed via anionic chain reactions, in which a CF₃-

anionoid is a key intermediate, albeit present at very much lower

concentrations under the NaI-mediated conditions.

In all cases, the productive fractionation (f) of TMSCF₃into the

difluorocyclopropanation product, is substantially attenuated dur-

ing NaI-mediated auto-acceleration, and an excess of 1 is still re-

quired. As shown by Grygorenko and co-workers,^12m,the slow ad-

dition of a large excess of 1 (up to 10 equiv.) can be used to achieve

good conversion of a range of electron-deficient alkenes. Slow-ad-

dition can increase the productive fractionation, f, by curtailing, or

attenuating, auto-acceleration, and allowing TFE to dissipate or de-

cay. For example, sequential additions of TMSCF₃(1) to methyl

acrylate results in a series of auto-accelerations, and TFE accumu-

lation / partial depletions, with somewhat improved levels of

difluorocyclopropanation as compared to addition of 1 in a single

portion, see section S3.4 in the SI.

Both processes require a fluoride-acceptor to enable efficient gen-

eration of highly-reactive CF₂from the CF₃-anionoid, Scheme 11.

When loosely ion-paired, e.g. with Bu₄N⁺, the CF₃-anionoid under-

goes silyl-induced fluoride elimination by TMSCF₃1 (k_F; Mecha-

nism IV, Scheme 5). With the more closely associated cation, Na⁺,

an NaI-assisted a-elimination (K_aK_NaI; Mechanism V, Scheme 8)

predominates. Key to efficient alkene/yne difluorocyclopropana-

tion is minimizing the competing reaction of the CF₃-anionoid with

the CF₂.

Finally, we note two important practical aspects relating to the CF₂-

generating reactions investigated herein. Firstly, the conditions al-

ways co-generate a range of perfluoroalkenes, e.g. Scheme 6, many

of which are volatile and toxic.⁵²Secondly, the kinetics of reactions

mediated by NaI can undergo acute and unpredictable auto-accel-

eration, e.g. Figure 1B, resulting in rapid generation of TMSF (b.p

19 °C),⁵³and highly-exothermic capture of CF₂; equations 8 and 9.

Appropriate caution^12m.pshould be exercised in any reactions that

generate transient singlet CF₂from TMSCF₃(1), or analogous rea-

gents, especially on scale-up.⁵⁴In this regard, the application of

continuous flow technology may be advantageous,^12bas may addi-

tives that can trigger and/or control auto-acceleration.

Scheme 11. Pathways to CF₂from CF₃-anionoids, generated in situ

in anionic chain reactions involving TMSCF₃(1) where M+ =

Bu₄N⁺(TBAT initiation), or Na⁺(NaI-mediation). Autoinhibition

and auto-acceleration not shown; see Schemes 5 and 8 for more

detailed chain reaction mechanisms (IV and V).

M⁺= Bu₄N⁺

^-Me

______________________

ASSOCIATED CONTENT

Supporting Information: Additional discussion, experimental

procedures, further kinetic data and analysis, characterization data

and NMR spectra, and full computational details. This material is

available free of charge via the Internet at http://pubs.acs.org.

Mechanism IV

_F[1][MCF₃]

Me Si

_C(1)

CF₃

M⁺

M⁺= Bu₄N⁺

CF₃

Si^–Me

k_ene3i

CF₂

M⁺

M⁺= Na⁺

CF₃

[2_CF]^–[M]⁺

Mechanism V

NaI [MI][MCF₃]

KαK

M⁺

M⁺= Na⁺

M⁺

AUTHOR INFORMATION

Corresponding Author

The TBAT-initiated process (M⁺= Bu₄N⁺) proceeds with very re-

producible kinetics, but undergoes progressive inhibition via per-

fluoroalkene homologation, see Scheme 6 and section S6.3 in the

SI, eventually leading to [C₁₁F₂₃]^–, 11, and analogous species that

are inert for F-anion transfer to 1. Higher concentrations of 1 in-

crease the efficiency of CF₂-transfer, f, equation 6, by reducing the

concentration (via K_C) of the CF₃-anionoid that leads to non-pro-

ductive consumption of 1. The TBAT procedure is only suitable for

alkenes/ynes that have sufficient reactivity (k_ene) towards singlet

CF₂to compete with the CF₃-anionoid and avoid extensive inhibi-

tion.

guy.lloyd-jones@ed.ac.uk

Notes The authors declare no competing financial interest.

Funding Sources A.G.D. thanks the SNSF for a postdoctoral

fellowship (P2ZHP2_181497). C.P.J. thanks the EC for an In-

ternational Outgoing Fellowship (PIOF-GA-2013-627695). J.P.

thanks the Bayer Science & Education Foundation, the

Deutschlandstipendium and the Erasmus+ Traineeships Pro-

gram. The research leading to these results has received funding

from the European Research Council under the European Un-

ion's Seventh Framework Programme (FP7/2007-2013) / ERC

grant agreements n° [340163] and [838616].

In contrast to TBAT, the NaI-mediated process displays non-repro-

ducible kinetics, see Figs. 1B and 5, and sections S2.2D and S2.5

in the SI, indicative of fluctuations in low concentrations of active

species, with variable delays before one or more acute auto-accel-

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Journal of the American Chemical Society

Morimoto, Y.; Amii, H. Sodium Bromodifluoroacetate: A

ACKNOWLEDGMENT

Difluorocarbene Source for the Synthesis of Gem -Difluorocyclo-

propanes. Synthesis 2010, 2080–2084.

We thank Dr Bela Bode (St Andrews) and Prof John Murphy

(Strathclyde) for valuable discussions regarding radicals, and the

characteristics of SET processes, and Prof. Dean Toste (Berkeley)

for suggesting we test electrochemically-mediated CF₂generation

from 1. The authors would like to acknowledge the assistance given

by Research IT and the use of the Computational Shared Facility at

The University of Manchester. We are very grateful to one of the

reviewers for sharing with us their unpublished observations on the

scale-up of NaI-mediated CF₂transfer from TMSCF₃(1).⁵⁴

(7) From difluorohalocarbons: (a) Fritz, H. P.; Wolfang, K. Die

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C. Conversion of Olefins to Dihalocyclopropanes with Sodium Hy-

droxide and Haloforms. Tetrahedron Lett. 1965, 6, 1749–1752; (c)

Dolbier, W. R.; Wotowicz, H.; Burkholder, C. R. New Zinc Diflu-

orocarbenoid Reagent. J. Org. Chem. 1990, 55, 5420–5422

(8) (a) Burton, D. J.; Naae, D. G. Bromodifluoro-

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(28) Although there was no detectable product (6i) on heating 1

with 3i in THF (67 °C, 72 h.) in the absence of exogenous initiator,

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ated, see SI. The transition state barrier for gas-phase unimolecular

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27 kcal mol^-1(DFT calc. 23.0 kcal mol^-1). A substantially higher

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dicative of a half-life of >3 months at 140 °C.

(35) As noted by Smart and Farnham, ref. 34c, tertiary per-

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(36) Reactions were monitored using an NMR spectrometer fit-

ted with a cryoprobe; these are known to be sensitive to changes in

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itation becomes more extensive during auto-acceleration and may

be the cause of, or augment, the line-broadening.

(37) Reactions conducted in MeCN gave greater proportions of

CF₃-anionoid and CF₂I-anionoid addition products, see SI.

(38) Iodo-addition product 18 is a transient species, and was

only detected in some runs, notably when the initial NaI concentra-

tion was high, and the alkene concentration low or zero. Other iodo-

adducts may also be generated through other pathways to facilitate

conversion of NaI into NaCF₃and thus effect auto-acceleration.

(39) Calculations (see section S.6.4B in the SI) suggest NaCF₃

® CF₂+ NaF is barrierless, but endergonic (DG₃₃₈= 11.5 kcal mol^-

¹); thus the rate of reversible elimination is estimated to be k_a~ 10⁴

to 10⁶s^-1, based on an additional 2.5±1 kcal mol^-1for solvent reor-

ganization. To sustain supply of CF₂at sufficient rate to correlate

with the maximum rates observed, (v_max» 2 ´ 10^-2[1] Ms^-1), would

require [NaCF₃] ~ 2 µM when k_a» 10⁴.

(40) For discussion of MF/carbenoid interactions see: Waerder,

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(41) TMSI reacts with THF to generate 4-iodobutoxy-TMS: (a)

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(43) The kinetic studies described herein were conducted using

NaI "99.999% trace metals basis" from Sigma-Aldrich (409286)

that is "prepared by reacting acidic iodides with sodium hydroxide

(NaOH) to form NaI salts". We found aqueous solutions of these

samples to be very slightly basic (pH raised by about 0.5 units).

(29) Ph₃SiF also undergoes reversible conversion to Ph₃SiCF₃;

[Ph₃SiX]_tot, corresponds to [TBAT]₀.

(30) Tests based on the initial stoichiometry-ratio of 3i /

TMSCF₃(1) are consistent with this: reactions run to exhaustion of

alkene 3i, with excess 1, did not re-initiate on addition of further 3i.

In contrast, reactions run to exhaustion of TMSCF₃(1), with excess

alkene 3i, re-initiated on addition of further 1.

(31) The analysis suggests that maintaining low concentrations

of siliconate 2_CF3will increase the productive fractionation, f, and

attenuate auto-inhibition (k_CF₃). This was tested by syringe-pump

addition of a TBAT solution (total 2.6 mol%) to a mixture of

TMSCF₃(1; 1.5 M) + styrene E-4 (0.7 M) in THF over a period of

10 hours at 21 °C. The conversion of E-4 to trans-7 increased from

23% to 62% compared to addition of TBAT in a single portion.

(32) a) The ¹⁹F NMR signals for 11 are identical to those previ-

ously assigned to an isomeric structure (see ref. 32b), which we

found failed to optimize in DFT calculations, and to be less con-

sistent with the ¹⁹F NMR data, see SI. (b) Tyrra, W.; Kremlev,M.

M.; Naumann, D.; Scherer, H.; Schmidt, H.; Hoge, B.; Pantenburg,

I. Yagupolskii, Y L. How Trimethyl(trifluoromethyl)silane Reacts

with Itself in the Presence of Naked Fluoride—A One-Pot Synthe-

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bis(trifluoromethyl)pentenide. Chem. Eur. J. 2005, 11, 6514–6518.

(33) In CsF-initiated oligomerization of TFE in various glymes,

pentamers, i.e. C₁₀F₂₀, were found to dominate the product distri-

butions - see Graham, D. P.; Fluoride Ion Initiated Reactions of

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(53) Sisti, N. J. Fluorotrimethylsilane. Encyclopedia of Reagents

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iodide in pure tetrahydrofuran and aqueous binary mixtures of tet-

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(54) One of the reviewers of this manuscript noted that NaI me-

diated CF₂-transfer reactions of TMSCF₃can proceed "violently

upon scale-up", consistent with the acute auto-acceleration of the

exothermic processes described herein. Grygorgenko and co-work-

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because of their highly exothermic (reference 12p) and vigorous

(reference 12m) nature.

(45) (a) Too, P. C.; Chan, G. H.; Tnay, Y. L.; Hirao, H.; Chiba,

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101, 2–9; (g) see also: Robertson, S. D.; Uzelac, M.; Mulvey, R.

E. Alkali-Metal-Mediated Synergistic Effects in Polar Main Group

Organometallic Chemistry. Chem. Rev. 2019, 119, 8332–8405.

(46) All Na-containing initiators tested, tended to give rise to

TFE (0.2-0.3 M) - see SI.

GRAPHICAL ABSTRACT

0.6

anionic-chain reactions

0.5

auto-acceleration

singlet-CF₂

0.4

kinetic variability

perfluoroalkene homologation

0.3

0.2

Me₃SiCF₃

5–20 mol % NaI

0.1

THF, 65 °C

5000

Time (s)

10000

(47) Singer, K. Application of the Theory of Stochastic Pro-

cesses to the Study of Irreproducible Chemical Reactions and Nu-

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Difluorocarbene Generation from TMSCF3: Kinetics and Mechanism of NaI-Mediated and Si-Induced Anionic Chain Reactions

DOI: 10.1021/jacs.0c06751

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