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
Ph3 PMeBr
DBU
Solvent
Tempb (°C)
Yieldc (%)
2a
Ph3 P=O
1
1.2
1.2
CH2 Cl2
55
7
10
2
1.2
1.5
CH2 Cl2
55
8
12
3
2.4
3.0
CH2 Cl2
55
12
17
4
3.6
4.5
CH2 Cl2
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
Et2 O
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), Ph3 PMeBr, DBU, solvent (6.5 mL), 2 h.
b Set by the hotplate stirrer temperature controller under reflux conditions.
c Yields were determined by 19 F and 31 P NMR with (trifluoromethyl)benzene and Ph3 P, 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
Ph3 P=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 -Pr2 EtN
12.7
60
2
<1
<1
9
1a
Et3 N
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), Ph3 PMeBr (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 19 F and 31 P NMR with (trifluoromethyl)benzene and Ph3 P, 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 -Pr2 EtN
Et3 N
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 Ph3 P=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 K2 CO3 (see Supporting Information). Although n -BuLi and t -BuOK produced triphenylphosphine oxide (Ph3 P=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 K2 CO3 were unable to initiate the Wittig reaction to afford 2a (<1%), and less than 10% Ph3 P=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 (Ph3 PMeBr) or base (DBU) (Table [1 ], entries 1–11). In particular, the ether-type solvents afforded better yields of
2a compared with CH2 Cl2 , 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 -Pr2 EtN), triethylamine (Et3 N), 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 Ph3 P=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.
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 Ph3 P=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.
