CC BY-NC-ND 4.0 · Synlett 2023; 34(20): 2455-2460
DOI: 10.1055/a-2118-6813
cluster
Special Issue Dedicated to Prof. Hisashi Yamamoto

Synthesis of Halogen-Bond-Donor-Site-Introduced Functional Monomers through Wittig Reaction of Perfluorohalogenated Benzaldehydes: Toward Digitalization as Reliable Strategy in Small-Molecule Synthesis

Tatsuaki Hori
a   Institute for Molecular Science, Okazaki, Aichi 444-8787, Japan
b   SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan
,
Shuya Kakinuma
a   Institute for Molecular Science, Okazaki, Aichi 444-8787, Japan
,
Naoya Ohtsuka
a   Institute for Molecular Science, Okazaki, Aichi 444-8787, Japan
b   SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan
,
Takeshi Fujinami
a   Institute for Molecular Science, Okazaki, Aichi 444-8787, Japan
,
Toshiyasu Suzuki
a   Institute for Molecular Science, Okazaki, Aichi 444-8787, Japan
,
a   Institute for Molecular Science, Okazaki, Aichi 444-8787, Japan
b   SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Aichi 444-8787, Japan
› Institutsangaben
This work was partially supported by the ASAHI GLASS Foundation, the NAGAI Foundation for Science and Technology, a Grant-in-Aid for Precise Formation of a Catalyst Having a Specified Field for Use in Extremely Difficult Substrate Conversion Reactions (KAKENHI Grant No. 18H04275), and the Grant-in-Aid for Transformative Organic Synthesis (Digi-TOS) (KAKENHI Grant No. 21H05218) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. N.M. and T.F. gratefully acknowledge JST-ACCEL for their financial support.
 


This paper is dedicated to Professor Hisashi Yamamoto in celebration of his 80th birthday.

Abstract

The Wittig reaction of perfluoromonohalobenzaldehydes was systematically studied to synthesize 2,3,5,6-tetrafluoro-4-halostyrene (TFXSs) as functional monomers bearing halogen-bond donor sites. The reaction proceeded efficiently in tetrahydrofuran using 1,1,3,3-tetramethylguanidine as an organic base. Correlation analysis quantitatively identified three key factors required to obtain TFXSs in reasonable yields. The present approach not only contributes to the study of halogen-bond-based functional molecules, but also presents digitalization as a potential strategy in small-molecule synthesis.


#
Zoom Image
Figure 1 Wittig reaction of perfluoromonohalobenzenes. (a) Pioneering work by Takeuchi, et al. and (b) this work

Table 1 Initial Study for the Wittig Reaction of 1a a

Entry

Ph3PMeBr
(equiv)

DBU
(equiv)

Solvent

Tempb (°C)

Yieldc (%)

2a

Ph3P=O

 1

1.2

1.2

CH2Cl2

 55

 7

10

 2

1.2

1.5

CH2Cl2

 55

 8

12

 3

2.4

3.0

CH2Cl2

 55

12

17

 4

3.6

4.5

CH2Cl2

 55

11

24

 5

3.6

4.5

THF

 80

35

71

 6

3.6

4.5

MeCN

 95

<1

17

 7

3.6

4.5

toluene

125

9

23

 8

3.6

4.5

Et2O

 45

29

37

 9

3.6

4.5

t-BuOMe

 65

25

31

10

3.6

4.5

glyme

 95

21

59

11

3.6

4.5

1,4-dioxane

115

11

76

12d

3.6

4.5

THF

 60

37

61

13d

3.6

4.5

THF

 40

27

44

a Reactions conditions: 1a (0.50 mmol), Ph3PMeBr, DBU, solvent (6.5 mL), 2 h.

b Set by the hotplate stirrer temperature controller under reflux conditions.

c Yields were determined by 19F and 31P NMR with (trifluoromethyl)benzene and Ph3P, respectively, as internal standards.

d Reactions were performed at the indicated temperature.

Halogen bonding (XB) is a unique noncovalent interaction between the Lewis acidic site of a halogen atom and the Lewis basic site of a molecule.[1] XB-driven smart polymer materials have recently attracted significant attention in polymer science.[2] In particular, iodoperfluorohydrocarbons[3] are frequently used as XB donors. Among these, perfluorohalogenated styrenes are potential functional monomers, owing to their synthetic accessibility, donor tunability, and hydrophobicity. Takeuchi et al. reported molecularly imprinted polymers with XB-based molecular recognition sites, in which 2,3,5,6-tetrafluoro-4-iodostyrene (TFIS) was used as the functional monomer (Figure [1a]).[4] Despite their potential utility, applications of 2,3,5,6-tetrafluoro-4-halostyrene (TFXS)-derived synthetic polymers, including those of TFIS, have not been reported, except for the work of Takeuchi et al. This limitation is hypothesized to be due to the inherent volatility and instability of TFXSs, originating from their fluorine and halogen atoms. Furthermore, detailed synthesis of TFXS functional monomers by the Wittig reaction of perfluorohalogenated benzaldehydes has not been reported. This study reports the Wittig reaction of perfluorohalogenated benzaldehydes, and provides insights into the key factors for obtaining TFXSs based on a correlation analysis, thereby permitting a quantitative understanding of the reaction and facilitating future research endeavors (Figure [1b]).

Table 2 Study of Organic Bases for the Wittig Reaction of 1a a

Entry

1

Base

pK BH b

Tempc (°C)

Time (h)

Yieldd (%)

2

Ph3P=O

 1

1a

TBD

20.1

60

 2

 8

33

 2

1a

MTBD

18.0

60

 2

36

56

 3

1a

DBN

17.2

60

 2

15

16

 4

1a

DBU

16.9

60

 2

37

61

 5

1a

TMG

15.5

60

 2

43

52

 6

1a

piperidine

14.3

60

 2

<1

<1

 7

1a

quinuclidine

13.1

60

 2

 3

<1

 8

1a

i-Pr2EtN

12.7

60

 2

<1

<1

 9

1a

Et3N

12.5

60

 2

 1

<1

10

1a

DABCO

11.7

60

 2

<1

<1

11

1a

TMG

15.5

80

 2

46

64

12

1a

TMG

15.5

80

 4

51

69

13

1a

TMG

15.5

80

 6

53

82

14

1a

TMG

15.5

80

24

54

80

15

1b

TMG

15.5

80

 6

39

70

16

1b

TMG

15.5

80

 6

29

73

a Reaction conditions: 1 (0.50 mmol), Ph3PMeBr (1.80 mmol), organic base (2.25 mmol), solvent (6.5 mL).[10]

b Leito and co-workers.[7]

c Set by the hotplate stirrer temperature controller.

d Determined by 19F and 31P NMR with (trifluoromethyl)benzene and Ph3P, respectively, as internal standards.

Table 3 Molecular Electrostatic Potential Maps, V s,min, and NBO chargesa

MEPs

Organic base

TBD

MTBD

DBN

DBU

TMG

piperidine

quinuclidine

i-Pr2EtN

Et3N

DABCO

Vs,min (kJ/mol)

–187

–176

–200

–197

–187

–132

–140

–112

–118

–127

NBO (a.u.)b

–0.68

–0.67

–0.64

–0.64

–0.84

–0.73

–0.58

–0.62

–0.60

–0.57

a DFT calculations were performed at the SMD(THF)/M06-2X-D3/6-311+G(d,p) level at 333 K.

b a.u. = atomic unit.

Table 4 Classifications of the Descriptors Used in the Correlation Analysis of the Organic-Base-Mediated Wittig Reaction of 1a

Category

Descriptor

Physical meaning

reaction

yield (%) of Ph3P=O

yield of triphenylphosphine oxide

UDR-Pro

undesired reaction producta

temp (°C)

reaction temperature

time (h)

reaction time

SVI-PC5[13] [14]

reaction solvent index

basicity center

pKBH

basicity of organic base

Vs min (kJ/mol)

electrostatic potential energyb

NBO (a.u.)

NBO chargeb

delta G (kcal/mol)

ΔG: Gibbs free energy c

Mayr-N

Mayr’s nucleophilicity parameter

structure

NXBA

number of halogen bond acceptors

cyclic/acyclic

structure of the organic based

NRing

number of rings in the organic base

ring size of N

size of the ring with the basicity centere

ring size of S

size of the ring without the basicity centerf

a Calculated according to the following equation: UDR-Pro (%) = 100 – [recovery yield of 1a (%) + yield of 2a (%)].

b For the nitrogen atom as the active center.

c For the protonation of an organic base.

d Equal to 1 if the structure is cyclic; equal to 0 if the structure is acyclic.

e Value = 0 if the active center is not in a ring.

f Value = 0 if the organic base lacks a ring structure or a ring structure.

Initially, the Wittig reaction of 2,3,5,6-tetrafluoro-4-iodobenzaldehyde (1a) was investigated at room temperature in tetrahydrofuran (THF) using conventional bases such as n-BuLi, t-BuOK, NaH, or K2CO3 (see Supporting Information). Although n-BuLi and t-BuOK produced triphenylphosphine oxide (Ph3P=O) as an indicator of reaction progress (64% in the case of n-BuLi and 71% in the case of t-BuOK), the yields of TFIS (2a) were 31 and 34%, respectively, and multiple unidentified products were observed. In contrast, NaH and K2CO3 were unable to initiate the Wittig reaction to afford 2a (<1%), and less than 10% Ph3P=O was formed. In these cases, multiple unidentified products were detected, and 1a was not fully recovered. Next, several organic bases were examined, and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) was selected as the organic base because had been reported to be useful for the Wittig reaction of electron-deficient aldehydes[5] (Table [1]). Careful examination under reflux conditions revealed that the choice of the solvent was more significant than the amount of the reagent (Ph3PMeBr) or base (DBU) (Table [1], entries 1–11). In particular, the ether-type solvents afforded better yields of 2a compared with CH2Cl2, toluene, or MeCN. THF was the best in suppressing unidentified products (entry 5), although the yield of 2a was not sufficient. Moreover, when the reaction was conducted in THF, reflux was unnecessary (entries 12 and 13), and a temperature of 60 °C was sufficient to produce 2a in a yield similar to that obtained under reflux conditions.

To improve the yield of 2a, several organic bases were investigated, based on their pK BH values (Table [2]).[6] [7] [8] 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) were found to be stronger bicyclic bases than DBU (entries 1–3). Importantly, MTBD afforded 2a in a yield similar to that obtained in the presence of DBU, whereas TBD and DBN afforded 2a in less than half the yield obtained in the presence of DBU. When bases weaker than DBU, such as 1,1,3,3-tetramethylguanidine (TMG), piperidine, quinuclidine, N,N-diisopropylethylamine (i-Pr2EtN), triethylamine (Et3N), and 1,4-diazabicyclo [2.2.2]octane (DABCO), were used (entries 5–10), 2a was obtained only with TMG (entry 5). Consequently, TMG was determined to be the best organic base among those tested in this study. After optimizing the reaction temperature and reaction time (entries 11–14), the best yield was achieved in the presence of TMG at 80 °C for six hours, where the yield Ph3P=O, an important indicator of the reaction progress, attained 82% (entry 13). This reaction also enabled the production of 4-bromo-2,3,5,6-tetrafluorostyrene (TFBrS) (2b) and 4-chloro-2,3,5,6-tetrafluorostyrene (TFClS) (2c) in yields of 39% (entry 15) and 29%, respectively (entry 16). Overall, the yields of TFXS were approximately 30–55%; however, considering the properties and inherent side reactions of the bases,[9] the Wittig reaction of 1 mediated by TMG is an important finding that enables the production of TFXSs as functional monomers.

To identify the important factors for the production of TFXSs, density functional theory (DFT) calculations were performed. The molecular electrostatic potentials (MEPs) of organic bases in THF were mapped on the isodensity surface using the solvation model based on density (SMD), where the minimum negative electrostatic potential energies (V s,min) and natural bond orbital (NBO) charges on the active nitrogen were quantitatively evaluated with regard to the activity of the organic bases (Table [3]). The DFT calculations suggested that the production of TFXSs requires V s,min and NBO values of less than –175 kJ/mol and –0.60 a.u., respectively. Although basicity-related physicochemical indices, such as pK BH, V s,min, and NBO values, are useful in understanding the ylide formation in the Wittig reaction, they are insufficient to explain the superior utility of TMG compared with TBD, MTBD, DBN, or DBU.

To further elucidate the key factors that facilitate the organic-base-mediated Wittig reaction of 1, correlation analyses were performed and heatmaps were created for visualization.[11] The descriptors were classified into three categories (Table [4]; see Supporting Information): (i) reaction parameters, (ii) basicity center parameters, and (iii) structure parameters. These feature parameters were used as the explanatory variables for the yields of TFIS 2a as the objective variable in the correlation analyses. The variational Bayesian Gaussian mixture regression (VBGMR) machine-learning model was used to fill in the previously unreported pK BH, the nucleophilicity parameter N,[12] and the unavailable V s,min (kJ/mol), NBO (a.u.), and ΔG (kcal/mol) values (see Supporting Information). The key factors in the organic-base-mediated Wittig reaction are quantitatively discussed based on the absolute values of the correlation coefficients (|r|). The strength of correlations is determined according to the following magnitudes: very high, 0.9 < |r| < 1.0; high, 0.7 < |r| < 0.9; moderate, 0.5 < |r| < 0.7; low, 0.3 < |r| < 0.5; weak, |r| < 0.3.

Zoom Image
Figure 2 Correlation analysis. (a) Heatmap with r values for the yield (%) of TFIS and (b) feature ranking based on the |r| values.

The correlation analysis revealed that the yields of 2a are highly correlated to the yield of triphenylphosphine oxide (|r|: 0.88) (Figure [2a], left). This clearly indicates that the ylide formation is of primary importance for the product formation of 2a. The |r| of the five reaction parameters to the yield of 2a followed the order: yield (%) of Ph3P=O (|r|: 0.88) > time (h) (|r|: 0.44) > SVI-PC5 (|r|: 0.23) > UDR-Pro (|r|: 0.12) > temp (°C) (|r|: 0.06) (Figure [2b], left). These results suggest that prolonging the reaction time and increasing the reaction temperature do not necessarily guarantee favorable outcomes. Among the descriptors of the basicity center, the nucleophilicity parameter (Mayr-N) exhibited a highly negative relationship with the yield of 2a (|r|: 0.75). This indicates that nucleophilic organic bases might initiate the decomposition of 1a and/or 2a through nucleophilic attack, thereby leading to low yields of 2a. This can explain why the low nucleophilicity of organic bases is of secondary importance in achieving better yields of 2a (for example, 11.4 for TMG and 16.6 for DBN). V s,min and NBO exhibited moderate correlations with yields of 2a (|r|: 0.64 for NBO, |r|: 0.41 for V s,min) (Figure [2a], center), thereby indicating the importance of an appropriate basicity for initiating ylide formation. The third key factor is the number of halogen-bond acceptors (NXBA), which exhibited a strong positive relationship with 2a yields (|r|: 0.73, Figure [2b], right). This provides a rational explanation for the assistance of XB between 2a and organic bases in suppressing the decomposition of 2a through complexation. In fact, NBO and V s,max, the representative indicators for XB donor abilities of TFXSs, were markedly correlated to the yields (coefficients of determination R2: 0.99 for NBO and 0.96 for V s,max) (see Supporting Information).

In summary, we have developed an organic-base-mediated Wittig reaction for the synthesis of TFXSs (2) from 2,3,5,6-tetrafluoro-4-halobenzaldehydes (1). Among the organic bases examined, TMG was found to be the most suitable. Correlation analysis quantitatively suggested the following are key factors: (i) a highly negative charge on the organic base for ylide formation, (ii) a low nucleophilicity of the organic base to suppress the decomposition of 1 and 2, and (iii) and XB acceptor ability of the organic base for complexation with 2. We believe that this study has the potential to become a practical example of digitalization in small-molecule synthesis.[15] The ongoing application of TFXSs to XB-driven smart polymer materials in our laboratory will be presented in due course.


#

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We would like to express sincere gratitude to Professor Nobuyuki Mase (Shizuoka University) for his fruitful advice on the solvent index in data analysis. Part of this study was conducted at the Institute for Molecular Science and supported by the Advanced Research Infrastructure for Materials and Nanotechnology in Japan (Organic Synthesis DX No. JPMXP1223MS5005) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

Supporting Information

  • References and Notes

    • 1a Halogen Bonding: Impact on Materials Chemistry and Life Sciences, Vols. I and II. Metrangolo P, Resnati G. Springer; Cham: 2015
    • 1b Gilday LC, Robinson SW, Barendt TA, Langton MJ, Mullaney BR, Beer PD. Chem. Rev. 2015; 115: 7118
    • 1c Cavallo G, Metrangolo P, Milani R, Pilati T, Priimagi A, Resnati G, Terraneo G. Chem. Rev. 2016; 116: 2478
    • 1d Costa PJ. Phys. Sci. Rev. 2017; 2: 20170136
    • 2a Biswas S, Das A. ChemNanoMat 2021; 7: 748
    • 2b Kampes R, Zechel S, Hager MD, Schubert US. Chem. Sci. 2021; 12: 9275
    • 3a Bertani R, Metrangolo P, Moiana A, Perez E, Pilati T, Resnati G, Rico-Lattes I, Sassi A. Adv. Mater. (Weinheim, Ger.) 2002; 14: 1197
    • 3b Houbenov N, Milani R, Poutanen M, Haataja J, Dichiarante V, Sainio J, Ruokolainen J, Resnati G, Metrangolo P, Ikkala O. Nat. Commun. 2014; 5: 4043
    • 3c Vanderkooy A, Taylor MS. J. Am. Chem. Soc. 2015; 137: 5080
    • 3d Kumar V, Pilati T, Terraneo G, Meyer F, Metrangolo P, Resnati G. Chem. Sci. 2017; 8: 1801
  • 4 Takeuchi T, Minato Y, Takase M, Shinmori H. Tetrahedron Lett. 2005; 46: 9025
  • 5 Okuma K, Sakai O, Shioji K. Bull. Chem. Soc. Jpn. 2003; 76: 1675
  • 6 Tshepelevitsh S, Kütt A, Lõkov M, Kaljurand I, Saame J, Heering A, Plieger PG, Vianello R, Leito I. Eur. J. Org. Chem. 2019; 6735
  • 7 Rodima T, Kaljurand I, Pihl A, Mäemets V, Leito I, Koppel IA. J. Org. Chem. 2002; 67: 1873
  • 8 Vazdar K, Margetić D, Kovačević B, Sundermeyer J, Leito I, Jahn U. Acc. Chem. Res. 2021; 54: 3108
    • 9a Präsang C, Whitwood AC. Bruce D. W. Cryst. Growth. Des. 2009; 9: 5319
    • 9b Lu W, Gao J, Yang J.-K, Liu L, Zhao Y, Wu H.-C. Chem. Sci. 2014; 5: 1934
  • 10 2,3,5,6-Tetrafluoro-4-iodostyrene (2a); Typical Procedure 1,1,3,3-Tetramethylguanidine (282 μL, 2.25 mmol, 4.5 equiv) was added to a solution of methyl(triphenyl)phosphonium bromide (0.643 g, 1.80 mmol, 3.6 equiv) in THF (5 mL) was added, and the resulting mixture was stirred at 80 °C for 30 min. A solution of 2,3,5,6-tetrafluoro-4-iodobenzaldehyde 1a (0.152 g, 0.50 mmol, 1.0 equiv) in THF (1.5 mL) was added, and the resulting mixture was stirred for 6 h. Subsequently, H2O (10 mL) was added to the mixture and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL), and the combined organic layers were washed with brine (10 mL) and dried (MgSO4). Small aliquots from the organic layers were analyzed by 19F NMR with PhCF3 as a standard (NMR yield: 53%). The organic layers were concentrated under a reduced pressure to afford a colorless oil. Due to its instability, the product was characterized as a mixture, and full data could not be collected. Rf = 0.53 (hexane). IR (ATR): 1471, 1416, 1259, 1101, 983, 953, 794 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.69 (dd, J = 11.9, 6.2 Hz, 1 H), 6.15 (d, J = 18.1 Hz, 1 H), 5.76 (d, J = 11.9 Hz, 1 H). 19F NMR (376 MHz, CDCl3): δ = –121.65 to –121.74 (m, 2 F), –141.56 to –141.66 (m, 2 F). 13C NMR{19F} (100 MHz, CDCl3): δ = 147.2, 144.0 (d, J = 4.9 Hz), 124.3 (t, J = 160 Hz), 122.3 (dd, J = 163, 2.9 Hz), 117.6–117.3 (m), 70.3.
  • 11 Datachemical LAB (accessed July 31, 2023): https://www.datachemicallab.com
  • 12 May’s Database of Reactivity Parameters (accessed July 31, 2023): https://www.cup.lmu.de/oc/mayr/reaktionsdatenbank2/
  • 13 Solvent Selection Tool, Version 1.0.0, 2018 (accessed July 31, 2023): https://www.acs.org/greenchemistry/research-innovation/tools-for-green-chemistry/solvent-selection-tool.html
  • 14 Diorazio LJ, Hose DR. J, Adlington NK. Org. Process Res. Dev. 2016; 20: 760
  • 15 Saito N, Nawachi A, Kondo Y, Choi J, Morimoto H, Ohshima T. Bull. Chem. Soc. Jpn. 2023; 96: 465

Corresponding Author

Norie Momiyama
Institute for Molecular Science
Okazaki, Aichi 444-8787
Japan   

Publikationsverlauf

Eingereicht: 17. Mai 2023

Angenommen nach Revision: 26. Juni 2023

Accepted Manuscript online:
27. Juni 2023

Artikel online veröffentlicht:
17. August 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References and Notes

    • 1a Halogen Bonding: Impact on Materials Chemistry and Life Sciences, Vols. I and II. Metrangolo P, Resnati G. Springer; Cham: 2015
    • 1b Gilday LC, Robinson SW, Barendt TA, Langton MJ, Mullaney BR, Beer PD. Chem. Rev. 2015; 115: 7118
    • 1c Cavallo G, Metrangolo P, Milani R, Pilati T, Priimagi A, Resnati G, Terraneo G. Chem. Rev. 2016; 116: 2478
    • 1d Costa PJ. Phys. Sci. Rev. 2017; 2: 20170136
    • 2a Biswas S, Das A. ChemNanoMat 2021; 7: 748
    • 2b Kampes R, Zechel S, Hager MD, Schubert US. Chem. Sci. 2021; 12: 9275
    • 3a Bertani R, Metrangolo P, Moiana A, Perez E, Pilati T, Resnati G, Rico-Lattes I, Sassi A. Adv. Mater. (Weinheim, Ger.) 2002; 14: 1197
    • 3b Houbenov N, Milani R, Poutanen M, Haataja J, Dichiarante V, Sainio J, Ruokolainen J, Resnati G, Metrangolo P, Ikkala O. Nat. Commun. 2014; 5: 4043
    • 3c Vanderkooy A, Taylor MS. J. Am. Chem. Soc. 2015; 137: 5080
    • 3d Kumar V, Pilati T, Terraneo G, Meyer F, Metrangolo P, Resnati G. Chem. Sci. 2017; 8: 1801
  • 4 Takeuchi T, Minato Y, Takase M, Shinmori H. Tetrahedron Lett. 2005; 46: 9025
  • 5 Okuma K, Sakai O, Shioji K. Bull. Chem. Soc. Jpn. 2003; 76: 1675
  • 6 Tshepelevitsh S, Kütt A, Lõkov M, Kaljurand I, Saame J, Heering A, Plieger PG, Vianello R, Leito I. Eur. J. Org. Chem. 2019; 6735
  • 7 Rodima T, Kaljurand I, Pihl A, Mäemets V, Leito I, Koppel IA. J. Org. Chem. 2002; 67: 1873
  • 8 Vazdar K, Margetić D, Kovačević B, Sundermeyer J, Leito I, Jahn U. Acc. Chem. Res. 2021; 54: 3108
    • 9a Präsang C, Whitwood AC. Bruce D. W. Cryst. Growth. Des. 2009; 9: 5319
    • 9b Lu W, Gao J, Yang J.-K, Liu L, Zhao Y, Wu H.-C. Chem. Sci. 2014; 5: 1934
  • 10 2,3,5,6-Tetrafluoro-4-iodostyrene (2a); Typical Procedure 1,1,3,3-Tetramethylguanidine (282 μL, 2.25 mmol, 4.5 equiv) was added to a solution of methyl(triphenyl)phosphonium bromide (0.643 g, 1.80 mmol, 3.6 equiv) in THF (5 mL) was added, and the resulting mixture was stirred at 80 °C for 30 min. A solution of 2,3,5,6-tetrafluoro-4-iodobenzaldehyde 1a (0.152 g, 0.50 mmol, 1.0 equiv) in THF (1.5 mL) was added, and the resulting mixture was stirred for 6 h. Subsequently, H2O (10 mL) was added to the mixture and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL), and the combined organic layers were washed with brine (10 mL) and dried (MgSO4). Small aliquots from the organic layers were analyzed by 19F NMR with PhCF3 as a standard (NMR yield: 53%). The organic layers were concentrated under a reduced pressure to afford a colorless oil. Due to its instability, the product was characterized as a mixture, and full data could not be collected. Rf = 0.53 (hexane). IR (ATR): 1471, 1416, 1259, 1101, 983, 953, 794 cm–1. 1H NMR (400 MHz, CDCl3): δ = 6.69 (dd, J = 11.9, 6.2 Hz, 1 H), 6.15 (d, J = 18.1 Hz, 1 H), 5.76 (d, J = 11.9 Hz, 1 H). 19F NMR (376 MHz, CDCl3): δ = –121.65 to –121.74 (m, 2 F), –141.56 to –141.66 (m, 2 F). 13C NMR{19F} (100 MHz, CDCl3): δ = 147.2, 144.0 (d, J = 4.9 Hz), 124.3 (t, J = 160 Hz), 122.3 (dd, J = 163, 2.9 Hz), 117.6–117.3 (m), 70.3.
  • 11 Datachemical LAB (accessed July 31, 2023): https://www.datachemicallab.com
  • 12 May’s Database of Reactivity Parameters (accessed July 31, 2023): https://www.cup.lmu.de/oc/mayr/reaktionsdatenbank2/
  • 13 Solvent Selection Tool, Version 1.0.0, 2018 (accessed July 31, 2023): https://www.acs.org/greenchemistry/research-innovation/tools-for-green-chemistry/solvent-selection-tool.html
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Figure 1 Wittig reaction of perfluoromonohalobenzenes. (a) Pioneering work by Takeuchi, et al. and (b) this work
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Figure 2 Correlation analysis. (a) Heatmap with r values for the yield (%) of TFIS and (b) feature ranking based on the |r| values.