SUPPORTING INFORMATION - The Royal Society of … INFORMATION Seeing Through Solvent Effects using Molecular Balances Ioulia K. Mati, Catherine Adam, and Scott L. Cockroft* EaStCHEM

S1

SUPPORTING INFORMATION

Seeing Through Solvent Effects using Molecular Balances

Ioulia K. Mati, Catherine Adam, and Scott L. Cockroft*

EaStCHEM School of Chemistry, University of Edinburgh, King’s Buildings, West Mains

Road, Edinburgh, EH9 3JJ, UK

E-mail: [email protected]

Contents

-Determination of experimental (Gexp) free energies

-Linear regression to obtain modelled free energies (G model)

-Linear regression to obtain modelled free energies including a solvophobic term (ss)

-Computational methods and data

-Crystallographic data

-NMR Chemical Shift Data

-Measurement of the barrier to rotation by EXSY NMR

-Conformer assignment by NMR

-Synthetic Methods and Compound Characterisation

-Additional references

Electronic Supplementary Material (ESI) for Chemical ScienceThis journal is © The Royal Society of Chemistry 2013

S2

Determination of experimental free energies (Gexp)

All molecular balances were fully characterised in CDCl3 by 1H and

13C-NMR and the O- and

H-conformers identified using 2D NMR methods as detailed in the Conformer Assignment

section below. The ratios of the 19

F-NMR peak integrations were used to calculate the free

energy difference between the two conformers, Gexp. In accordance with other studies,1

experimental NMR measurements of K have a standard deviation of 5%, which corresponds

to an error of 0.12 kJ mol–1

in Gexp. Gexp values are reported in Table S1.


S3

Table S1: Measured (Gexp), predicted G model) and errors (G) in fitted free energies

for balances 1-11 in all solvents examined. Errors in Gexp are ±0.12 kJ mol–1

.

Compound Solvent Gexp* /kJ mol-1

G model /kJ mol-1

G/kJ mol-1

1 (p-NEt2) Chloroform* -1.57 -1.45 0.46

Acetone* -1.53 -1.67 0.46

Acetonitrile* -0.99 -1.58 0.46

Benzene* -1.39 -2.05 0.46

Ethyl acetate -2.15 -1.69 0.46

Hexane -2.75 -2.17 0.46

THF -2.09 -2.01 0.46

DCM -1.11 -1.62 0.46

Ethanol -1.53 -0.98 0.46

Methanol* -1.07 -0.98 0.46

DMSO* -0.81 -1.14 0.46

Diethyl ether -2.40 -2.04 0.46

Carbon tetrachloride -1.92 -1.93 0.46

2 (p-OMe) Chloroform* -0.78 -0.78 0.23

Acetone -0.71 -0.82 0.23


Benzene* -0.75 -1.11 0.23


Hexane -1.48 -1.20 0.23

THF -1.07 -1.02 0.23

DCM -0.58 -0.87 0.23

Ethanol* -0.68 -0.43 0.23

Methanol -0.52 -0.43 0.23

DMSO* -0.37 -0.47 0.23



3 (p-H) Chloroform* -1.14 -1.01 0.18

Acetone* -0.85 -0.89 0.18


Benzene* -0.68 -1.04 0.18


Hexane -1.14 -1.10 0.18

THF -0.88 -0.92 0.18

DCM -0.81 -1.02 0.18

Ethanol -0.81 -0.82 0.18

Methanol* -0.81 -0.82 0.18

DMSO* -0.75 -0.74 0.18



4 (p-Ph) Chloroform* -0.68 -0.69 0.15

Acetone* -0.58 -0.61 0.15


Benzene* -0.46 -0.70 0.15


Hexane insoluble - -

THF -0.65 -0.63 0.15

DCM* -0.58 -0.70 0.15

Ethanol -0.55 -0.59 0.15

R² = 0.8088

R² = 0.8384

R² = 0.7453

-2.00

-1.50

-1.00

-0.50

0.00

0.50

1.00

1.50

2.00

-2.00 -1.00 0.00 1.00 2.00

R² = 0.8368

R² = 0.8207

R² = 0.7456

-1.50

-1.00

-0.50

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

-2.00 0.00 2.00 4.00

R² = 0.3892

R² = 0.3648

R² = 0.2457

4.00

4.10

4.20

4.30

4.40

4.50

4.60

4.00 4.20 4.40 4.60


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G model /kJ mol-1

G/kJ mol-1

1 (p-NEt2) Chloroform* -1.57 -1.45 0.46

Acetone* -1.53 -1.67 0.46


Benzene* -1.39 -2.05 0.46

Methanol* -0.62 -0.59 0.15

DMSO* -0.58 -0.54 0.15



5 (p-Br) Chloroform* 0.08 0.06 0.12

Acetone* 0.05 0.11 0.12

Acetonitrile* -0.15 0.08 0.12

Benzene* 0.08 0.23 0.12

Ethyl acetate 0.18 0.11 0.12

Hexane 0.37 0.27 0.12

THF 0.23 0.21 0.12

DCM 0.08 0.11 0.12

Ethanol -0.05 -0.09 0.12

Methanol* -0.08 -0.09 0.12

DMSO* -0.10 -0.06 0.12

Diethyl ether 0.37 0.21 0.12

Carbon tetrachloride 0.21 0.20 0.12

6 (p-CN) Chloroform* 1.03 0.94 0.41

Acetone 0.29 0.41 0.41

Acetonitrile* -0.15 0.45 0.41

Benzene* 0.78 1.17 0.41


Hexane Insoluble - -

THF 0.68 0.63 0.41

DCM 0.71 1.02 0.41

Ethanol* 0.37 0.03 0.41

Methanol 0.15 0.03 0.41

DMSO* -0.55 -0.34 0.41



7 (p-NO2) Chloroform* 1.39 1.22 0.53

Acetone 0.46 0.69 0.53

Acetonitrile 0.02 0.72 0.53

Benzene* 1.07 1.59 0.53



THF 0.88 0.99 0.53

DCM 0.99 1.35 0.53

Ethanol* 0.58 0.15 0.53

Methanol 0.18 0.15 0.53

DMSO* -0.37 -0.21 0.53



8 (o-OMe) Chloroform* -0.75 -0.62 0.39

Acetone -0.81 -0.87 0.39

Acetonitrile -0.13 -0.76 0.39

Benzene* -0.78 -1.37 0.39


Hexane -1.87 -1.53 0.39


S5


G model /kJ mol-1

G/kJ mol-1

1 (p-NEt2) Chloroform* -1.57 -1.45 0.46

Acetone* -1.53 -1.67 0.46


Benzene* -1.39 -2.05 0.46

THF -1.44 -1.31 0.39

DCM -0.55 -0.83 0.39

Ethanol -0.49 0.00 0.39

Methanol -0.02 0.00 0.39

DMSO* 0.08 -0.18 0.39



9 (o-Me) Chloroform* -0.15 -0.14 0.42

Acetone 0.55 0.32 0.42


Benzene* -0.15 -0.76 0.42

Ethyl acetate -0.05 0.22 0.42

Hexane -1.35 -1.15 0.42

THF -0.13 -0.13 0.42

DCM -0.29 -0.33 0.42

Ethanol 0.78 1.17 0.42

Methanol 1.18 1.17 0.42

DMSO* 1.48 1.48 0.42



10 (di o-Me) Chloroform* 0.49 0.53 0.53

Acetone 1.53 1.28 0.53

Acetonitrile* 2.33 1.28 0.53

Benzene* 0.55 -0.25 0.53


Hexane -1.22 -0.80 0.53

THF 0.68 0.69 0.53

DCM 0.49 0.28 0.53

Ethanol 1.87 2.37 0.53

Methanol 2.40 2.37 0.53

DMSO* 2.82 2.88 0.53

Diethyl ether -0.18 0.51 0.53


11 (o-NO2) Chloroform* 3.99 3.97 0.29

Acetone 4.25 4.12 0.29


Benzene* Overlapping peaks - -



THF 4.11 4.02 0.29

DCM 4.39 3.93 0.29

Ethanol 4.11 4.29 0.29

Methanol 4.11 4.29 0.29

DMSO* 4.54 4.39 0.29




S6

Linear regression to obtain modelled free energies (G model)

Multiple linear regression was performed in Origin v8.5.1 for each data set for each balance

in all solvents (using the constants listed in Table S2) to obtain the values of E and

quoted in the main text. Errors in G model (G) were calculated as follows:

√( ) ( ) ( )

where E and are the fitting errors in and as output by Origin.

G model values are reported in Table S1.

Table S2: s and s values used in linear regressions

Solvent s s

Chloroform 2.2 0.9

Acetone 1.5 5.8

Acetonitrile 1.7 5.1

Benzene 1.1 2.1

Ethyl acetate 1.5 5.3

Hexane 1.0 0.6

THF 0.9 5.9

DCM 1.9 1.1

Ethanol 2.7 5.3

Methanol 2.7 5.3

DMSO 2.2 8.7

Diethyl ether 0.9 5.3

Carbon Tetrachloride 1.4 0.6


S7

Linear regression to obtain modelled free energies including a solvophobic term (ss)

As noted in the references of the main text, experimental data was also fitted to a model

including an additional solvophobic term: G = E + s + s + ss

The correlation between the predicted free energies when the model included the solvophobic

term (Gpredicted) and experimental (Gexp) free energy values (Figure S1) has a gradient of

y = x. The coefficients and errors from the fitting are listed in Table S3. Values of ,

and are all equal (within error) between the models fitted with and without the

solvophobic term (Figure S2).

Table S3: Fitting results from Origin for the model including the solvophobic term (see equation

above).

Compound E

/ kJ mol-1

E

/ kJ mol-1

ss

/ kJ mol-1

ss

/ kJ mol-1

(1) p-NEt2 -2.86 0.90 0.06 0.54 0.64 0.19 -0.01 0.11

(2) p-OMe -1.75 0.44 0.08 0.26 0.46 0.09 -0.03 0.05

(3) H -1.10 0.36 0.01 0.21 0.01 0.08 0.01 0.04

(4) p-Ph -0.89 0.39 0.05 0.21 0.10 0.08 -0.01 0.04

(5) p-Br 0.44 0.23 -0.01 0.14 -0.16 0.05 0.00 0.03

(6) p-CN 1.52 1.02 -0.08 0.57 -0.15 0.20 -0.05 0.11

(7) p-NO2 2.06 1.34 -0.08 0.74 -0.25 0.27 -0.06 0.14

(8) o-OMe -2.13 0.76 0.01 0.45 0.64 0.16 0.02 0.09

(9) o-Me -2.01 0.83 0.20 0.50 0.76 0.18 0.01 0.10

(10) di o-Me -2.20 1.05 0.34 0.63 1.15 0.22 -0.03 0.13

(11) o-NO2 2.85 0.85 0.19 0.45 0.55 0.16 -0.07 0.08


S8

Figure S1: Correlation of experimental (Gexp) free energy measurements with equivalent values

predicted (Gpredicted) using a model that included the solvophobic term.

Figure S2: Correlation of a) b) and c) when calculated including (x-axis) and excluding

(y-axis) the solvophobic term (ss) in the solvation model. Dotted lines represent a 1:1 relationship.


S9

Figure S3: Average Gexp determined in 13 different solvents (Gave) plotted against a) gas-phase

conformational free energies GDFT calculated using B3LYP/6-31G* b) meta Hammett substituent

constants for the para-X substituents and c) the electrostatic potentials on the molecular surface over

the carbon atoms positioned meta to the para X-substituent calculated using B3LYP/6-31G*

(obtained as described in the computation methods and data section below). Data for the para-

substituted balances 1-7 are indicated with black circles, and the ortho-substituted balances 8-11 by

hollow circles.


S10

Computational methods and data

Calculations were performed using Spartan ’08 with DFT/B3LYP/6-31G* to obtain the

minimised geometries. Electrostatic potential values (ESPmeta) were obtained using simple

aromatic rings as shown in Figure S4. The ESP values were measured over both meta

positions relative to the X substituent on each face of the molecule, and the mean ESP values

reported (Table S4). Errors in ESPs were based on the standard deviation of the four ESP

measurements taken over both meta carbons on each side of the ring. Electrostatic potentials

of the formyl oxygen atoms (ESPoxygen) was obtained from the minimised structures shown in

Figures S5-S11.

Figure S4. DFT/B3LYP/6-31G* electrostatic surface potentials (ESPs) used to model the

electrostatic properties of the molecular balance where X = NO2. The ESPs over the meta

positions were taken at the 0.002 electron/Bohr3

isosurface on each face of the molecule as

indicated.


S11

Minimised geometries and ESPs of molecular balances

Figure S5: DFT/B3LYP/6-31G* ESP surfaces of the O- and H-conformers for the p-NEt2 balance (1)

Figure S6: DFT/B3LYP/6-31G* ESP surfaces of the O- and H-conformers for the p-H balance (3)

Figure S7: DFT/B3LYP/6-31G* ESP surfaces of the O- and H-conformers for the p- NO2 balance (7)


S12

Figure S8: DFT/B3LYP/6-31G* ESP surfaces of the O- and H-conformers for the o-OMe balance (8)

Figure S9: DFT/B3LYP/6-31G* ESP surfaces of the O- and H-conformers for the o-Me balance (9)

Figure S10: DFT/B3LYP/6-31G* ESP surfaces of the O- and H-conformers for the di o-Me balance

(10)


S13

Figure S11: DFT/B3LYP/6-31G* ESP surfaces of the O- and H-conformers for the o-NO2 balance

(11)


S14

Table S4: meta-Hammett constants, ESPmeta and average Gexp for each balance in all solvents

examined. SD = standard deviation across all solvents examined.

Compound

Hammett

constant, m ESPmeta

/ kJ mol-1

SD* ESPmeta

/ kJ mol-1

Average Gexp

/ kJ mol-1

SD* av Gexp

/ kJ mol-1

(1) p-NEt2 -0.23 -92.30 +4.80 -1.64 +0.39 (2) p-OMe +0.12 -76.90 +3.50 -0.84 +0.25 (3) H 0 -70.90 +0.60 -0.94 +0.11 (4) p-Ph +0.06 -66.90 +2.57 -0.64 +0.05

(5) p-Br +0.39 -40.60 +3.10 +0.10 +0.12 (6) p-CN +0.56 -14.40 +1.50 +0.57 +0.48 (7) p-NO2 +0.71 -7.40 +0.70 +0.85 +0.57 (8) o-OMe - - - -0.84 +0.50 (9) o-Me - - - +0.09 +0.78 (10) di o-Me - - - +0.92 +1.08 (11) o-NO2 - - - +4.09 +0.16

*SD is standard deviation

Table S5: DFT/B3LYP/6-31G* minimised conformer energies and max ESP (ESPoxygen) for each

balance 1 to 11

Compound

Energy H conformer

/kJ mol-1

Energy O conformer

/kJ mol-1

GDFT (H-O)

/kJ mol-1

ESPoxygen H conformer

/kJ mol-1

ESPoxygen O conformer

/kJ mol-1

(1) p-NEt2 -2477995.06 -2477991.35 -3.71 -198.22 -204.23 (2) p-OMe -2220496.48 -2220494.45 -2.03 -188.84 -192.46 (3) H -1919817.02 -1919816.13 -0.89 -183.83 -183.82 (4) p-Ph -2526459.38 -2526458.93 -0.45 -183.10 -181.51 (5) p-Br -8675968.28 -8675968.95 +0.67 -172.20 -170.73 (6) p-CN -2161998.43 -2162001.02 +2.59 -158.10 -153.80 (7) p-NO2 -2456733.13 -2456736.2 +3.07 -153.29 -149.20 (8) o-OMe -2220490.2 -2220487.11 -3.09 -192.50 -201.55 (9) o-Me -2023045.48 -2023043.92 -1.56 -182.52 -186.92 (10) di o-Me -2126272.45 -2126269.49 -2.96 -177.02 -192.33 (11) o-NO2 -2456702.73 -2456709.03 +6.30 -173.13 -186.34


S15

Table S6: Camide-Namide-Cipso-Cortho dihedral angle measured from the DFT/B3LYP/6-31G* minimised

conformers for balances 1 to 11. All values are reported in degrees. O-Conformer H-Conformer

Compound F Ring X Ring F Ring X Ring

(1) p-NEt2 49 44 36 59

(2) p-OMe 50 45 38 56

(3) H 53 40 42 50

(4) p-Ph 53 38 42 49

(5) p-Br 54 38 49 49

(6) p-CN 59 31 47 45

(7) p-NO2 61 29 48 42

(8) o-OMe 47 115 36 62

(9) o-Me 43 119 33 63

(10) di o-Me 41 70 9 85

(11) o-NO2 57 124 52 124


S16

Crystallographic data

Figure S12: Crystal structures with EDG and EWG at the para positions of the aromatic rings from

the CCDB (CCDB codes: LUVREZ, UHOPIQ, LUVRID, UHOPOW)


S17

NMR Chemical Shift Data

Table S7: 1H-NMR Chemical shifts () obtained in CDCl3 for balances 1 to 11 for the O- and H-

conformers

Table S8: Difference in 1H- NMR chemical shifts () in CDCl3 for balances 1 to 11

F ring X ring

Ha/ ppm Hb/ ppm Hc/ ppm Hd/ ppm He/ ppm Hf/ ppm

Compound O H O H O H O H O H O H

(1) p-NEt2 7.07 7.03 7.14 7.31 7.05 7.01 6.64 6.66 - - - -

(2) p-OMe 7.12 7.05 7.14 7.28 7.19 7.11 6.91 6.94 - - - -

(3) H 7.12 7.09 7.18 7.27 7.29 7.16 7.4 7.42 - - - -

(4) p-Ph 7.14 7.11 7.21 7.32 7.35 7.23 7.6 7.63 - - - -

(5) p-Br 7.12 7.1 7.16 7.25 7.18 7.03 7.51 7.54 - - - -

(6) p-CN 7.19 7.14 7.21 7.21 7.44 7.2 7.63 7.68 - - - -

(7) p-NO2 7.25 7.21 7.26 7.26 7.54 7.29 8.25 8.29 - - - -

(8) o-OMe 7.07 7.03 7.16 7.32 3.78 3.78 7.06 7.06 7.22 7.22 7.06 7.06

(9) o-Me 7.08 7.03 7.08 7.33 7.16 7.32 7.3 7.35 7.27 7.37 7.35 7.35

(10) di o-Me 7.03 7.03 7.03 7.36 - - 7.23 7.23 7.26 7.26 - -

(11) o-NO2 7.16 7.07 7.28 7.28 7.25 7.48 7.52 7.61 7.66 7.77 8.05 8.03

Chemical shifts have error of ±0.05 ppm

F ring X ring

Compound Ha /ppm Hb /ppm Hc /ppm Hd /ppm He /ppm Hf/ppm

(1) p-NEt2 -0.04 0.17 -0.04 0.02 - -

(2) p-OMe -0.07 0.14 -0.08 0.03 - -

(3) H -0.03 0.09 -0.13 0.02 - -

(4) p-Ph -0.03 0.11 -0.12 0.03 - -

(5) p-Br -0.02 0.09 -0.15 0.03 - -

(6) p-CN -0.05 0.00 -0.24 0.05 - -

(7) p-NO2 -0.04 0.00 -0.25 0.04 - -

(8) o-OMe -0.04 0.16 0.00 0.00 0.00 0.00

(9) o-Me -0.05 0.25 0.16 0.05 0.10 0.00

(10) di o-Me 0.00 0.33 - 0.00 0.00 -

(11) o-NO2 -0.09 0.00 0.23 0.09 0.11 -0.02

Chemical shifts have error of ±0.05 ppm


S18

Conformer assignment by NMR

All molecular balances were initially characterised by NMR in CDCl3, to assign conformer

peaks of all the balances. The following figures present the NMR spectra (1H,

13C, HSQC,

COSY, NOESY and HMBC) of N-(4-fluorophenyl)-N-(2-nitrophenyl)formamide (compound

11, o-NO2) in deuterated acetonitrile, showing the full spectral assignment for both

conformers. In this example proton resonances have been labelled numerically and carbon

resonances alphabetically. Green peaks with prime notation (’) denotes a minor conformer,

while red indicates the major conformer.

Figure S13: Equilibrium of balance 11 in MeCN-d3

After the initial assignment of major/minor conformers for each compound, 19

F-NMR spectra

were obtained in a range of deuterated and non-deuterated solvents. The fluorine chemical

shift difference of the two conformers was plotted across the different solvents for all the

balances. This method was used to identify outliers that might arise due to changes in the

preferred conformer as the solvent was varied. A full NMR analysis was performed on any

outliers identified. For the few cases where a deuterated solvent was not available, it was

assumed that the dominant conformer matched the assignment in CDCl3 in the case of DCM

outliers, and MeOH in the case of EtOH outliers. The majority of the balances did not appear

to be outliers in the 19

F-ppm analysis and in these cases it was assumed that the

conformational assignment matched that determined in CDCl3.


S19

Figure: S14 1H NMR of 11 in MeCN-d3. The green trace is the minor conformer and the red trace is

the major conformer.

Figure S15: 13

C NMR of 11 in MeCN-d3. Carbon signals on the fluorinated ring are split as

doublets due to 13

C-19

F coupling.


S20

Figure S16: Proton coupled 19

F NMR of 11 in MeCN-d3


S21

Figure S17: HSQC of 11 in MeCN-d3

Figure S18: HMBC spectra of 11 in MeCN-d3


S22

The formyl proton has a cross peak with only the trans-quaternary aromatic carbon of

each aromatic ring in the HMBC spectrum (Figure S18); H-C correlation through multiple

bonds). This feature allowed us to unambiguously distinguish between major and minor

conformers in deuterated solvents. In the ring example depicted in Figure S18 the major

formyl proton 1 couples to carbon F, and the minor formyl proton 1’ couples with D’, as.

represented schematically in Figure S19.

Figure S19: Coupling of the formyl protons 1 and 1’ to quaternery carbons F and D’ respectively

Figure S20: NOESY of 11 in MeCN-d3

This assignment is supported by the NOESY spectrum of 11 (Figure S20) in which there is a

through-space coupling of the major formyl proton peak, 1, and the major aromatic proton 5.


S23

There is not a cross peak for the minor conformer, one explanation for this is the relatively

low concentration of the minor conformer. NOESY was not used to assign the major

conformer for all the balances as there are often cross peaks for the major and minor

conformers in the spectra since they are partial exchange on the NOESY timescale.

Conversely there is never a cross peak between major and minor conformers in the HMBC

spectrum.

Measurement of the barrier to rotation by EXSY NMR

EXSY experiments provide a method of determining the barrier to rotation, which basically

consists of a series of 1D NOESY experiments where the mixing time is varied. 2, 3

This

method was used to calculate the activation energy barrier for the rotation of the formyl

group in N-(4-fluorophenyl)-N-phenylformamide (3). 1D NOESY NMRs were taken of this

compound in CDCl3 with mixing times ranging from 0.01 s to 0.7 s. The formyl proton of the

major conformer was specifically irradiated and the exchange of the formyl proton with the

minor conformer was measured at each mixing time. The integral ratio for the response signal

compared to the irradiated peak was plotted against the mixing times as shown in Figure S21.

The slope of the line corresponds to the rate constant of conformational exchange, k (s-1

).


S24

Figure S21. Graph of the integral ratio between the response signal compared to the

irradiated peak versus mixing time for N-(4-fluorophenyl)-N-phenylformamide (3) at 298 K.

The rate constant in this experiment was found to be k = 0.4193 s-1

.

where R = 8.314 J·K-1

·mol-1

, kB = 1.38 x 10-23

J·K-1

and h = 6.63 x 10-34

J·s

Thus, the barrier to rotation for the formyl group was determined to be 75.1 kJ mol–1

, which

is similar to that of the acetyl group in N,N-dimethylacetamide (~71.1 kJ mol–1

).4

Synthetic Methods and Compound Characterisation

General procedures

All chemicals were obtained from commercial sources and used as received. All reactions

were carried out under a nitrogen atmosphere. Analytical TLC was carried out on Merck

aluminium sheets coated with silica gel 60F and visualised using UV light (254 nm).

Preparative TLC was carried out on Analtech 20 x 20 cm glass mounted plates on 2000

micron silica and flash chromatography was carried out on silica gel 60. Solvent ratios have

been indicated in brackets. Mass spectrometry was performed by the University of Edinburgh

technician-supported mass spectrometry service, using a ThermoElectron MAT XP

y = 0.4193x + 0.0167 R² = 0.9982

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0 0.2 0.4 0.6 0.8Inte

gra

tion r

atio b

etw

een r

esponse t

o

irra

dia

ted p

eak

mixing time tm (s)


S25

spectrometer for EI-HRMS. IR spectra were obtained on neat samples using a Shimadzu

IRAffinity-1 machine. Absorptions are reported in frequency of absorption (cm-1

).

Absorptions in the fingerprint region are not reported. Melting points were measured in a

Gallenkamp melting point apparatus and are uncorrected. 1H and

13C NMR spectra were

recorded on either 400 or 500 MHz Bruker Avance III spectrometer. 19

F NMR spectra were

recorded on a 400 MHz Bruker Avance III spectrometer. NMR chemical shifts are reported

in parts per million (δ) relative to trimethylsilane ( = 0) or CDCl3 (1H δ = 7.26 and

13C δ =

77.16) as an internal reference. Where non-deuterated solvents being used, 19

F chemical

shifts have been recorded against TFA in D2O ( = –75.6) inside a sealed capillary tube as a

reference. 13

C and 19

F spectra have been 1H decoupled. Both major and minor conformer

chemical shifts were recorded for all balances where unambiguous assignment was possible.

Minor conformers are denoted by prime notations (‘). Coupling constants, J, are reported in

Hertz. Signal splitting patterns in 1H NMR spectra could not be determined in cases where

conformer signals resulted in overlapping peaks. The chemical shifts of aromatic protons

were often identified using HSQC/HMBC spectra and the signals are recorded as multiplets

(m).

Figure S22: General procedure for the copper-mediated coupling of halo-aromatics to aryl-amides


S26

All the balances described in this paper (except balance 4) were cross-coupled with copper (I)

iodide catalyst under the same general conditions: The amide, aryl-halide, catalyst and base

(CsF/ K3PO4) were added to an oven-dried flask which was sealed before evacuating and

back filling with nitrogen three times. Dry solvent (THF/ toluene) and ligand

(N,N’-dimethylethylenediamine (DMEDA)/ ethylenediamine) were added via syringe and the

system was evacuated and back filled with nitrogen twice more. The suspension was heated

at reflux overnight then cooled to ambient temperature, diluted with EtOAc or DCM and

quenched with sat. ammonium chloride. The aqueous phase was extracted with organic

solvent and the combined phases were washed with brine, dried over MgSO4 and

concentrated in vacuo. The resulting products were further purified by chromatography.

Formamides 12, 13 and 14 were prepared according to the procedure outlined in Figure S45.


S27

N-(4-(Diethylamino)phenyl)-N-(4-fluorophenyl)formamide (1)

Prepared using the general procedure:

THF (1 mL), N-(4-(diethylamino)phenyl)formamide (104 mg,

0.54 mmol), 4-fluoroiodobenzene (0.05 mL, 0.45 mmol), Cu(I)I

(43 mg, 0.22 mmol), CsF (171 mg, 1.13 mmol) and DMEDA (4.8 μL, 0.04 mmol).

Purification with prep-TLC (DCM) yielded 1 as a yellow oil (82 mg, 0.29 mmol, 64%).

υmax (neat) /cm-1

2966.52, 2926.01, 2893.22, 2870.08, 1681.93 (C=O), 1610.56, 1516.05,

1504.48; 1H NMR (CDCl3) δ 8.60 (1’, s, 1H), 8.52 (1, s, 1H), 7.31 (2, dd, J = 9.0, 4.9 Hz,

2H), 7.14 (2’, dd, J = 8.9, 4.7 Hz, 2H), 7.07 (3’, m, 2H), 7.05 (4’, m, 2H), 7.03 (3, m, 2H),

7.01 (4, m, 2H), 6.66 (5, m, 2H), 6.64 (5’, m, 2H), 3.37 (6, m, 2H), 3.35 (6’, m, 2H), 1.18 (7,

m, 2H), 1.16 (7’, m, 2H); 13

C NMR (CDCl3) δ 162.24 (A), 161.87 (A’), 161.16 (B’, d, J =

246.8 Hz), 160.56 (B, d, J = 245.5 Hz), 147.29 (C), 146.94 (C’), 138.74 (D’), 136.70 (D),

129.19 (E), 127.60 (F), 127.46 (F’), 127.24 (E’), 126.82 (G, d, J = 8.1 Hz), 126.12 (G’, d, J =

8.4 Hz), 116.44 (H’, d, J = 22.9 Hz), 115.79 (H, d, J = 22.6 Hz), 112.08 (I), 111.91 (I’), 44.59

(J), 44.55 (J’), 12.66 (K’), 12.60 (K); 19

F NMR (CDCl3) δ -115.66, -116.05 (major);

EI-HRMS: obtained m/z 286.147467 M +

(expected m/z 286.14814).


S28

Figure S23: 1H NMR of 1 in CDCl3 at 25 ºC

Figure S24: 13

C NMR of 1 in CDCl3 at 25 ºC


S29

N-(4-Methoxyphenyl)-N-(4-fluorophenyl)formamide (2)


THF (2 mL), N-(4-methoxyphenyl)formamide (112.4 mg, 0.74

mmol), 4-fluoroiodobenzene (74 μL), Cu(I)I (58 mg, 0.30 mmol),

CsF (238 mg, 1.57 mmol) and DMEDA (7 μL, 0.06 mmol). Purification with prep-TLC (1:1

EtOAc: n-Hex) yielded 2 as a pale yellow oil (73 mg, 0.30 mmol, 49%). υmax (neat) /cm-1

1681.93 (C=O), 1505; 1H NMR (400 MHz, CDCl3) δ 8.60 (1’, s, 1H), 8.55 (1, s, 1H), 7.28 (2,

m, 2H), 7.19 (3’, m, 2H), 7.14 (2’, m, 2H), 7.12 (4’, m, 2H), 7.11 (3, m, 2H), 7.05 (4, m, 2H),

6.94 (5, m, 2H), 6.91 (5’, m, 2H), 3.83 (6, s, 3H), 3.81 (6’, s, 3H); 13

C NMR (101 MHz,

CDCl3) δ 161.37 (A’, d, J = 247.3 Hz), 161.89 (B), 161.72 (B’), 160.81 (A) (d, J = 246.5 Hz),

158.96 (C), 158.45 (C’), 138.21 (D’, d, J = 3.1 Hz), 136.15 (D, d, J = 3.1 Hz), 134.43 (E),

132.42(E’), 127.45 (F’), 127.27(F), 127.17 (G, d, J = 2.3 Hz), 126.56 (G’, d, J = 8.5

Hz), 116.66 (H’, d, J = 22.9 Hz), 116.01 (H, d, J = 22.7 Hz), 115.09 (I), 114.68 (I’), 55.67 (J),

55.59 (J’); 19

F NMR (376 MHz, CDCl3) δ -114.83, -115.24 (major); EI-HRMS: obtained m/z

245.08491 M+ (expected m/z 245.08466 M

+).


S30


Figure S26: 13



S31

N-(4-Fluorophenyl)-N-phenylformamide (3)


Toluene (1 mL), formanilide (65 mg, 0.54 mmol),

1-fluoro-4-iodobenzene (0.05 mL, 0.45 mmol), Cu(I)I (17 mg, 0.08

mmol), K3PO4 (191 mg, 0.9 mmol) and ethylenediamine (12 μL, 0.17 mmol). The crude was

filtered through Celite before purification with prep-TLC (DCM) to yield 3 as a brown solid

(52 mg, 0.24 mmol, 54%). MP: 69-71 °C; υmax (neat) /cm-1

2924.09, 2852.72, 1676.14 (C=O),

1591.27, 1504.48, 1492.9, 1462.04; 1

H NMR (CDCl3) δ 8.66 (1, s, 1H), 8.61 (1’, s, 1H), 7.42

(2, m, 2H), 7.4 (2’, m, 2H), 7.33 (3, t, J = 7.4 Hz, 1H), 7.29 (4’, m, 2H), 7.26 – 7.28 (5 and

3’, m, 3H), 7.18 (5’, m, 2H), 7.16 (4, m, 2H), 7.12 (6’, m, 2H), 7.09 (6, m, 2H); 13

C NMR

(CDCl3) δ 161.62 (A’, d, J = 247.7 Hz), 161.17 (A, d, J = 246.9 Hz), 161.88 (B), 161.65 (B’),

141.76 (C), 139.76 (C’), 137.91 (D’, d, J = 3.1 Hz), 135.67 (D, d, J = 3.1 Hz), 129.94 (E),

129.37 (E’), 128.04 (F, d, J = 8.4 Hz), 127.33 (F’, d, J = 8.8 Hz), 127.3 (G), 127.02 (G’),

125.88 (H’), 124.99 (H), 116.80 (I’, d, J = 22.9 Hz), 116.25 (I, d, J = 22.7 Hz); 19

F NMR

(CDCl3) δ -114.27, -114.61 (major); ESI-HRMS: obtained m/z 216.081301 (M + H)

+

(expected m/z 216.08347 ).


S32


Figure S28:

13C NMR of 3 in CDCl3 at 25 ºC


S33

N-([1,1’-Biphenyl]-4-yl)-N-(4-fluorophenyl)formamide (4)

A suspension of N-(4-bromophenyl)-N-(4-fluorophenyl)

formamide (200 mg, 0.68 mmol) and Pd(Ph3P)4 (24 mg, 0.02

mmol) were stirred in DME (8 mL) for 10 min at 50 oC. To this

was added phenylboronic acid (115 mg, 0.94 mmol) dissolved in a minimum amount of

EtOH: DME (1:2) followed by aq. Na2CO3 (2 M, 9.26 mmol). The mixture was refluxed

overnight then cooled to ambient temperature. The suspension was treated with saturated aq.

NH4Cl solution then extracted with CHCl3. The organic layer was washed with brine, dried

over MgSO4, and concentrated in vacuo to yield the crude product. Further purification; first

with column chromatography (DCM) and then with prep-TLC (DCM), yielded 4 as a yellow

solid (155 mg, 0.53 mmol, 78%). MP: 111-114 °C; υmax (neat) /cm-1

2920.23, 1685.79 (C=O),

1606.7, 1504.48, 1485.19; 1

H NMR (CDCl3) δ 8.72 (1, s, 1H), 8.63 (1’, s, 1H), 7.63 (2, m,

2H), 7.60 (2’, m, 2H), 7.59 (3’, m, 2H), 7.57 (3, m, 2H), 7.46 (4, m, 2H), 7.44 (4’, m, 2H),

7.40 (5’, m, 1H), 7.37 (5, m, 1H), 7.35 (6’, m, 2H), 7.32 (7, m, 2H), 7.23 (6, m, 2H), 7.21 (7’,

m, 2H), 7.14 (8’, m, 2H), 7.11 (8, m, 2H); 13

C NMR (CDCl3) δ 161.78 (A), 161.72 (A’),

161.70 (B’, d, J = 247.8 Hz), 161.24 (B, d, J = 247.1 Hz), 140.88 (C), 140.34 - 140.31 (D, E’),

139.92 - 139.89 (D’, E), 138.93 (C’), 137.79 (F’), 135.59 (F), 129.09 (G), 128.98 (G’),

128.56 (H), 128.12 (I, d, J = 8.6 Hz), 128.04 (H’), 127.90 (J), 127.66 (J’), 127.47 (I’, d, J =

8.5 Hz), 127.21 (K’), 127.15 (K), 126.01 (L’), 125.15 (L), 116.88 (M’, d, J = 22.9 Hz),

116.32 (M, d, J = 22.8 Hz); 19

F NMR (CDCl3) δ -114.03, -114.42 (major); EI-HRMS:

obtained m/z 291.105367 M +



S34


Figure S30: 13



S35

N-(4-Bromophenyl)-N-(4-fluorophenyl)formamide (5)


THF (2 ml), N-(4-bromophenyl)formamide (108 mg, 0.54 mmol),

1-fluoro-4-iodobenzene (0.05 mL, 0.45 mmol), Cu(I)I (43 mg, 0.23

mmol), CsF (171 mg, 1.13 mmol) and DMEDA (4.8 μl, 0.45 mmol). Purification with flash

chromatography (1:1 n-hex: DCM to 100% DCM) yielded 5 as a white solid (113 mg, 0.38

mmol, 85%). MP: 84-87 °C; υmax (neat) /cm-1

1668.43 (C=O), 1639.49, 1602.85, 1583.56,

1504.48, 1485.19; 1

H NMR (CDCl3) δ 8.63 (1’, s, 1H), 8.57 (1, s, 1H), 7.54 (2’, m, 2H), 7.51

(2, m, 2H), 7.25 (3’, m, 2H), 7.18 (4, m, 2H), 7.16 (3, m, 2H), 7.12 (5, m, 2H), 7.10 (5’, m,

2H), 7.03 (4’, m, 2H); 13

C NMR (CDCl3) δ 161.82 (A, d, J = 248.4 Hz), 161.34 (A’, d, J =

247.7 Hz), 161.52 (B’), 161.40 (B), 140.85 (C’), 138.86 (C), 137.33 (D, d, J = 3.1 Hz),

135.20 (D’, d, J = 3.2 Hz), 133.10 (E’), 132.44 (E), 128.11 (F’, d, J = 8.5 Hz), 127.62 (F, d, J

= 8.6 Hz), 127.14 (G), 126.30 (G’), 120.86 (H’), 120.27 (H), 117.03 (I, d, J = 22.9 Hz),

116.44 (I’, d, J = 22.8 Hz); 19

F NMR (CDCl3) δ -113.50 (major), -113.99; EI-HRMS:

obtained m/z 292.984671 M +



S36


Figure S32: 13



S37

N-(4-Cyanophenyl)-N-(4-fluorophenyl)formamide (6)


THF (2 mL), N-(4-fluorophenyl)formamide (105 mg, 0.75 mmol),

4-bromobenzonitrile (157 mg, 0.86 mmol), Cu(I)I (72 mg, 0.38 mmol),

CsF (233 mg, 1.53 mmol) and DMEDA (14 μL, 0.15 mmol). Purification with flash

chromatography (2:1 n-Hex: EtOAc) yielded 6 as a yellow solid (63 mg, 0.26 mmol, 35%).

MP; 71-73 ºC; υmax (neat) /cm-1

2240, 1683.86 (C=O), 1600.92, 1604.48; 1H NMR (400 MHz,

CDCl3) δ 8.79 (1’, s, 1H), 8.55 (1, s, 2H), 7.68 (2’, d, J = 8.3 Hz, 2H), 7.63 (2, d, J = 8.5 Hz,

3H), 7.44 (3, d, J = 8.5 Hz, 3H), 7.21 (4, m, 2H), 7.21 (4’, m, 2H), 7.20 (3’, m, 2H), 7.19 (5,

m, 2H), 7.14 (5’, m, 2H); 13

C NMR (101 MHz, CDCl3) δ 162.26 (A, d, J = 249.6 Hz), 161.84

(A’ d, J = 248.9 Hz), 161.60 (B), 161.10 (B’), 145.67 (C’), 143.86 (C), 136.28 (D, d, J = 3.4

Hz), 134.14 (D’, d, J = 1.8 Hz), 133.88 (E’), 133.11 (E), 129.01 (F’, d, J = 8.8 Hz), 128.78 (F,

d, J = 8.7 Hz), 124.79 (G), 123.45 (G’), 118.40 (H), 118.06 (H’), 117.37 (I, d, J = 23.0 Hz),

116.85 (I’, d, J = 22.9 Hz), 110.20 (J’), 109.58 (J); 19

F NMR (376 MHz, CDCl3) δ -112.03

(major), -112.65; EI-HRMS: obtained m/z 260.05960 M+

(expected m/z 260.05917 M+).


S38


Figure S34: 13



S39

N-(4-Nitrophenyl)-N-(4-fluorophenyl)formamide (7)



4-nitroiodobenzene (862 mg, 3.46 mmol), Cu(I)I (280 mg, 1.47 mmol),

CsF (883 mg, 5.81 mmol) and DMEDA (35 μL, 0.33 mmol). Purification with flash

chromatography (3:1 n-Hex: EtOAc) yielded 7 as a pale orange solid (449 mg, 1.73 mmol,

58%). MP: 91-94 ºC; υmax (neat) /cm-1

1683.68 (C=O), 1591.27, 1504.48, 1492.90; 1H NMR

(400 MHz, CDCl3) δ 8.89 (1’, s, 1H), 8.62 (1, s, 1H), 8.29 (2’, d, J = 8.2 Hz, 2H), 8.25 (2, d,

J = 8.7 Hz, 2H), 7.54 (3, d, J = 8.6 Hz, 2H), 7.29 (3’, d, J = 2.4 Hz, 2H), 7.26 (4, m, 2H), 7.26

(4’, m, 2H), 7.25 (5, m, 2H), 7.21 (5’, m, 2H); 13

C NMR (101 MHz, CDCl3) δ 162.55 (A, d, J

= 204.1 Hz), 162.10 (A’, d, J = 208.2 Hz), 161.60 (B), 160.99 (B’), 147.24 (C), 145.48 (D),

144.94 (D’), 136.15 (E, J = 1.6 Hz), 129.04 (F’, d, J = 7.5 Hz), 128.90 (F, d, J = 8.5 Hz),

125.44 (G’), 124.61 (G), 124.31 (H), 122.85 (H’), δ 117.42 (d, J = 23.1 Hz), 116.90 (d, J =

21.9 Hz) N.b. C’ and E’ too small to see; 19

F NMR (376 MHz, CDCl3) δ -111.67

(major), -112.35; EI-HRMS: obtained m/z 240.06946 M+ (expected m/z 240.06934 M+).


S40


Figure S36: 13



S41

N-(4-Fluorophenyl)-N-(2-methoxyphenyl)formamide (8)


THF (3 mL), N-(4-methoxyphenyl)formamide (498 mg, 3.29 mmol),

4-fluoroiodobenzene (460 μL, 3.98 mmol), Cu(I)I (49 mg, 0.32 mmol),

CsF (1.20 g, 6.30 mmol) and DMEDA (71 μL, 0.65 mmol). Purification

with flash chromatography (2:1 n-Hex: EtOAc) yielded 8 as an oil (526 mg, 2.14 mmol,

65%). υmax (neat) /cm-1

1681.93 (C=O),1595.13, 1498.69; 1H NMR (400 MHz, CDCl3) δ 8.65

(1’,s, 1H), 8.39 (1, s, 1H), 7.38 (2/2’, m, 2H), 7.32 (3, m, 2H), 7.22 (4/4’, m, 2H), 7.16 (3’, m,

2H), 7.09-7.01 (m, 5/5’/6/6’/7/7’, 8H), 3.81 (8/8’, s, 6H); 13

C NMR (101 MHz, CDCl3) δ

162.84 (A), 161.81 (A’), 160.96 (B’, d, J = 246.0 Hz), 160.46 (B, d, J = 245.5 Hz), 155.59

(C), 155.06 (C), 138.01 (D, d, J = 2.9 Hz), 136.22 (D,’ d, J = 3.1 Hz), 129.81 (E/E’), 129.71

(F), 129.62 (G), 129.56 (G’,s), 127.77 (F’), 126.47 (H, d, J = 8.3 Hz), 125.20 (H’,d, J = 8.4

Hz), 121.21 (I/I’), 116.19 (J’, d, J = 22.8 Hz), 115.55 (J, d, J = 22.6 Hz), 112.56 (K’), 112.42

(K), 55.80 (L’), 55.77 (L); 19

F NMR (376 MHz, CDCl3) δ -115.86, -116.05 (major);

EI-HRMS: obtained m/z 245.08470M+

(expected m/z 245.0846 M+).


S42


Figure S38: 13



S43

N-(4-Fluorophenyl)-N-(2-methylphenyl)formamide (9)


THF (4 mL), N-(4-methylphenyl)formamide (515 mg, 3.81 mmol),

4-fluoroiodobenzene (320 μL, 616 mg, 2.77 mmol), Cu(I)I (108 mg,

0.71 mmol), CsF (1.30 g, 6.83 mmol) and DMEDA (120 μL, 98 mg,

1.11 mmol). Purification with flash chromatography (1:4 EtOAc: n-Hex) yielded 9 as an oil

(560 mg, 2.44 mmol, 88%). υmax (neat) /cm-1

1681.93 (C=O), 1505.48, 1492.90; 1H NMR

(400 MHz, CDCl3) δ 8.75 (1’, s, 1H), 8.46 (1, s, 1H), 7.37 (2/3, m, 2H), 7.35 (4, m, 1H), 7.34

(4’, m, 1H), 7.33 (5, m, 2H), 7.32 (2’, m, 1H), 7.30 (3’, m, 1H), 7.27 (6, m, 1H), 7.17 (6’, m,

1H), 7.08 (5’/7’, m, 4H), 7.03 (7, m, 2H), 2.20 (8’, s, 3H), 2.15 (8, s, 3H); 13

C NMR (101

MHz, CDCl3) δ 162.01 (A, s), 161.29 (A’, s), 160.81 (B’, d, J = 246.3 Hz), 160.07 (B, d, J =

245.0 Hz), 139.27 (C, s), 137.76 (C’, s), 137.71 (D’, d, J = 2.9 Hz), 136.29 (E, s), 135.82 (E’,

s), 135.76 (D, d, J = 3.0 Hz), 131.98 (F, s), 131.59 (F’, s), 129.27 (G, s), 128.99 (H, s),

128.61 (H’, s), 128.50 (G’, s), 127.49 (I, s), 127.26 (I’, s), 125.27 (J, d, J = 8.2 Hz), 124.24

(J’, d, J = 8.3 Hz), 116.51 (K, d, J = 22.9 Hz), 115.68 (K’, d, J = 22.6 Hz), 18.21 (L’, s),

18.03 (L, s); 19

F NMR (376 MHz, CDCl3) δ -115.83, -116.12 (major); EI-HRMS: obtained

m/z 229.08951M+ (expected m/z 229.08974 M+).


S44


Figure S40: 13



S45

N-(2,6-Dimethylphenyl)-N-(4-fluorophenyl)formamide (10)


Toluene (15 mL), N-(2,6-dimethylphenyl)formamide (505 mg, 3.38

mmol), 4-fluoroiodobenzene (770 mg, 3.46 mmol), Cu(I)I (411 mg, 2.15

mmol), K3PO4 (149 mg, 7.01 mmol) and DMEDA (100 μL, 0.93 mmol). Before

chromatography, excess N-(2,6-dimethylphenyl)formamide was triturated from solution with

ca 1:1 EtOAc: n-Hex (40 mL). The remaining crude was further purified by flash

chromatography (3:1 n-Hex: EtOAc) to yield 10 as a brown solid (323 mg, 1.32 mmol, 39%).

MP: 66-69 ºC υmax (neat) /cm-1

1684 (C=O). 1H NMR (400 MHz, CDCl3) δ 8.83 (1, s, 1H),

8.29 (1’, s, 1H), 7.36 (5’, m, 2H), 7.26 (2/2’, m, 2H), 7.23 (3/3’, m, 4H), 7.03 (4/4’/5, m, 6H),

2.18 (6’, s, 3H), 2.13 (6, s, 3H); 13

C NMR (101 MHz, CDCl3) δ 162.33 (A’, s), 160.94 (A, s),

160.46 (B, d, J = 245.8 Hz), 159.68 (B’, d, J = 245.2 Hz), 137.97 (D’, s), 137.56 (E’, s),

136.89 (C, d, J = 2.8 Hz), 136.41 (D, s), 136.20 (E, s), 135.40 (C’, d, J = 2.9 Hz), 129.36 (F’,

s), 129.28 (G’, s), 129.13 (F, s), 128.90 (G, s), 123.53 (H’, d, J = 8.0 Hz), 122.35 (H, d, J =

8.2 Hz), 116.65 (I, d, J = 22.9 Hz), 115.75 (I’, d, J = 22.5 Hz), 18.40 (J, s), 18.22 (J’, s); 19

F

NMR (376 MHz, CDCl3) δ -116.62 (major), -116.80; EI-HRMS: obtained m/z 243.105309

M+

(expected m/z 243.10539 M+).


S46


Figure S42: 13


4/4’/5


S47

N-(4-Fluorophenyl)-N-(2-nitrophenyl)formamide (11)



1-iodo-2-nitrobenzene (882 mg, 3.54 mmol), Cu(I)I (280 mg, 1.47

mmol), CsF (905 mg, 5.96 mmol) and DMEDA (25 μL, 0.23 mmol). Purification with flash

chromatography (3:2 n-Hex: EtOAc) yielded 11 as a yellow solid (181 mg, 0.70 mmol, 24%).

MP: 108-110 ºC; 1H NMR (400 MHz, CDCl3) δ 8.54 (1, s, 1H), 8.49 (1’, s, 1H), 8.05 (2, dd,

J = 8.2, 1.5 Hz, 1H), 8.03 (2’, dd, J = 6.6, 1.5 Hz, 1H), 7.77 (3’, ddd, J = 7.8, 1.6, 7.7 Hz, 1H),

7.66 (3, ddd, J = 7.8, 7.8, 1.6 Hz, 1H), 7.61 (4’, ddd, J = 1.2, 7.8, 7.9 Hz, 1H), 7.52 (4, ddd, J

= 8.1, 7.7, 1.4 Hz, 1H), 7.48 (6’, dd, J = 8.0, 1.3 Hz, 1H), 7.28 (5/5’ m, 4H), 7.25 (6, dd, J =

6.6, 1.4 Hz, 1H), 7.16 (7, m, 2H), 7.07 (7’, m, 2H); 13

C NMR (101 MHz, CDCl3) δ 161.87 (A,

d, J = 216.7 Hz), 161.38 (B), 160.48 (B’), 146.36 (C), 136.42 (D, d, J = 3.1 Hz), 134.40 (‘F),

134.24(E’), 133.97 (E), 132.51 (F), 130.91 (G’), 129.69 (G), 129.37 (H’), 128.56 (H), 127.07

(I’, d, J = 8.5 Hz), 126.66 (I, d, J = 8.6 Hz), 126.09 (J’), 125.42 (J), 116.89 (K, d, J = 23.0

Hz), 116.06 (K’, d, J = 22.9 Hz) N.b. A’, C’ and D’ lost to noise; 19

F NMR (376 MHz, CDCl3)

δ -113.48 (major), -114.01; EI-HRMS: obtained m/z 260.05946 M+ (expected m/z 260.05917

M+).


S48


Figure S44: 13



S49

General Procedure for the Formylation of Anilines (12-14)

Figure S45: General Procedure for the Formylation of Anilines (12-14)

Anilines were heated at reflux in neat formic acid. The reactions were cooled to ambient then

quenched with sat. bicarbonate solution to neutral pH and the aqueous phase extracted with

organic solvent. The formamides were used without further purification unless otherwise

stated. Existing characterisations within the literature were used to confirm the identity of

each compound.

N-(4-Fluorophenyl)-formamide (12)

4-Fluoroaniline (256 μL, 2.7 mmol) was refluxed for 2.5 hours in formic acid

(15.25 mL). After quenching, the aqueous phase was extracted with EtOAc (3 x 15

mL) and concentrated in vacuo to yield N-(4-fluorophenyl)-formamide as a brown

solid (342 mg, 2.46 mmol, 91 %). MP = 63-65 ºC; 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J =

11.4 Hz, 1H, trans), 8.37 (d, J = 1.6 Hz, 1H, cis), 7.90 (s, NH), 7.51 (m, 2H), 7.28 (s, NH),

7.03 (m, 2H); 13

C NMR (101 MHz, CDCl3) δ 163.35’, 160.47’ (d, J = 244.8 Hz), 159.64 (d, J

= 244.1 Hz), 159.62, 133.06 (d, J = 2.9 Hz), 132.89’ (d, J = 2.9 Hz), 122.03 (d, J = 7.9 Hz),

121.14’ (d, J = 8.2 Hz), 116.57’ (d, J = 22.9 Hz), 115.77 (d, J = 22.5 Hz); 19

F NMR (376

MHz, CDCl3) δ -116.96, -117.09 (major); EI-HRMS: obtained m/z 139.042796 M+ (expected

m/z 139.04279 M+).

5


S50

N-(2-Methoxyphenyl)formamide (13)

o-Anisidine (2 mL, 15.9 mmol) was refluxed for two hours in formic acid (4

mL, 162 mmol) then cooled to ambient temperature. After quenching, the

aqueous phase was extracted with DCM (3 × 30 mL) before concentrating in

vacuo to yield a pink solid (2.38 g, 15.8 mmol, 99%). MP: 81-83 ºC; 1H NMR (400 MHz,

CDCl3) δ 8.67’ (d, J = 11.6 Hz, 1H, trans), 8.39 (d, J = 1.6 Hz, 1H, cis), 8.31 (dd, J = 8.0, 1.4

Hz, 1H), 8.03 (s, NH), 7.83’ (s, NH), 7.14’ (d, J = 7.8 Hz, 1H), 7.08’ (td, J = 7.9, 1.3 Hz, 1H),

7.02 (td, J = 7.9, 1.6 Hz, 1H), 6.90 (m, 1H), 6.85 (m 1H), 6.73’ (m, 1H), 6.67’ (m, 1H), 3.82

(s, 3H), 3.80 (s, 3H); 13

C NMR (101 MHz, CDCl3) δ 161.70’, 159.04, 148.83’, 147.89,

126.73, 126.11’, 125.26’, 124.24, 120.99’, 120.93, 120.42, 118.36’, 116.88’, 114.98’, 110.39’

110.09, 55.65, 55.34’; EI-HRMS: obtained 151.062607 m/z M+ (expected m/z 151.06278

M+).

6

N-(2,6-Dimethylphenyl)formamide (14)

2,6-Dimethylaniline (3.00 g, 24.7 mmol) was dissolved in formic acid (20 mL,

530 mmol) and heated at 83 ºC for five hours. The solution was cooled to

ambient temperature before the addition of sat. sodium hydrogen carbonate (to

neutral pH). The aqueous suspension was extracted in to DCM (3 × 40 mL). The organic

solution was dried over MgSO4 and concentrated in vaccuo to yield

N-(2,6-dimethylphenyl)formamide as a white solid (2.92 g, 19.6 mmol, 79%) which was used

directly without further purification. MP: 167-172 ºC;; 1H NMR (500 MHz, CDCl3) δ 8.42 (d,

J = 1.4 Hz, 1H, cis), 8.10 (d, J = 11.9 Hz, 1H, trans), 7.13 (m, 3H), 6.84 (NH, s, 1H), 6.75

(NH, s, 1H), 2.31 (s, 3H), 2.27 (s, 3H); 13

C NMR (126 MHz, CDCl3) δ 164.81, 159.36,


S51

135.43, 133.14, 132.46, 128.89, 128.46, 127.93, 127.91, 18.89, 18.74. N.b.conformers in

equal ratio; EI-HRMS: obtained m/z 149.083294 M+ (expected m/z 149.08352 M+).

7

Additional references

1. F. R. Fischer, P. A. Wood, F. H. Allen and F. Diederich, Proc. Nat. Acad. Sci. USA,

2008, 105, 17290-17294.

2. S. M. Goldup, D. A. Leigh, P. J. Lusby, R. T. McBurney and A. M. Z. Slawin, Angew.

Chem., Int. Ed., 2008, 47, 3381-3384.

3. C. Naumann, B. O. Patrick and J. C. Sherman, Tetrahedron, 2002, 58, 787-798.

4. F. P. Gasparro and N. H. Kolodny, J. Chem. Educ., 1977, 54, 258-261.

5. M. Hosseini-Sarvari and H. Sharghi, J. Org. Chem., 2006, 71, 6652-6654.

6. A. S. K. Hashmi, Y. Yu and F. Rominger, Organomet., 2012, 31, 895-904.

7. M. J. Deetz, J. E. Fahey and B. D. Smith, J. Phys. Org. Chem., 2001, 14, 463-467.


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