CHAPTER 4
97
THE CF 2 GROUP
4.1. INTRODUCTION
The difl uoromethylene (CF 2 ) group is encountered in a large variety of environments within molecules of pharmaceutical and agrochemical interest. It imparts signifi cant effects upon the acidity and basicity of proximate OH and NH functions, and it has signifi cant effects upon the reactivity of most organic functional groups because of fl uorine ’ s potent inductive, electron - withdrawing power. Thus, the CF 2 group can func-tion as an important structural component within a molecule, having a signifi cant impact upon that molecule ’ s chemical and biological activ-ity. 1 A few illustrative examples of bioactive compounds that contain a difl uoromethylene group are (a) the difl uoro analogue of thromboxane A 2 ( 4 - 1 ), which enhances the bioactivity of the powerful vasoconstrictor and platelet - aggregating nonfl uorinated compound while greatly enhancing its hydrolytic stability; (b) the fl uorinated prostaglandin anti-fertility drug 16,16 - difl uoro PGE 1 ( 4 - 2 ), in which the CF 2 group enhances the acidity and inhibits the metabolic oxidation of its neighboring OH group while enhancing the activity of the compound; (c) the fungicide fl udioxonil ( 4 - 3 ); (d) the herbicide primisulfuron - methyl ( 4 - 4 ), the CF 2 groups of which impart multiple benefi cial effects upon their effi cacy as agrochemicals, and (e) the anticancer drug gemcitabine ( 4 - 5 ) (Fig. 4.1 ).
Guide to Fluorine NMR for Organic Chemists, by William R. Dolbier, Jr.Copyright © 2009 by John Wiley & Sons, Inc.
98 THE CF2 GROUP
Therefore, it is quite common for organic chemists with an interest in designing and synthesizing novel bioactive compounds to consider how a well - placed CF 2 group may help them attain their goals. This will require that they be able (a) to synthesize and (b) to characterize the structures of new compounds that they prepare, which contain CF 2 groups in specifi c structural environments. Explicit interpretation of the 19 F NMR spectra of such compounds usually will provide defi nitive structural characterization, especially when combined with 1 H and 13 C NMR spectra. The chemical shift and coupling constant data contained in this chapter should be all that one needs to derive the most informa-tion possible from fl uorine, proton, and carbon NMR spectra of com-pounds containing a CF 2 group.
4.1.1. Chemical Shifts — General Considerations
The CF 2 group exhibits a wide range of chemical shift possibilities, with, for example, difl uoromethane compounds appearing at both
FIGURE 4.1. Examples of bioactive compounds containing a CF 2 group
O
O
FF
OH
HO2C
Difluoro-thromboxane A2
CO2H
OH
O
HO
FF
16,16-Difluoro PGE1
OO
FF NH
CN
Fludioxonil
Fungicide
ON
N
HO
O
NH2
F F
OH
Gemcitabine (Lilly)Anticancer
O2S
NH
NH
N
N
OCHF2
OCHF2
CO2Me
O
Primisulfuron-methyl
Herbicide
4-1
4-2
4-3
4-4
4-5
SATURATED HYDROCARBONS CONTAINING A CF2 GROUP 99
extremes, upfi eld at − 143.6 ppm for CF 2 H 2 and downfi eld at +18.6 ppm for CF 2 I 2 .
However, realistically, most CF 2 groups that one would encounter in molecules of synthetic interest to organic chemists have 19 F chemical shifts that lie within the much narrower range of − 80 to − 120 ppm. In fact the lack of sensitivity to structural environment of a CF 2 group can sometimes be quite surprising, a good example being the similarity of chemical shifts for the vinylic and alkyl CF 2 groups in CF 2 = CH 2 ( δ − 81.8) and CH 3 CF 2 CH 3 ( δ − 84.5), respectively.
When looking at the different classes of CF 2 compounds, those bound to saturated and unsaturated carbon, those bound to hydrogen, and those bound to heteroatoms and proximate to functional groups, it will be seen that there are predictable trends in chemical shifts.
4.1.2. Spin – Spin Coupling Constants — General Considerations
With respect to spin – spin coupling constants , although not as large as those to a single fl uorine substituent, the normal three - bond H – F spin – spin coupling constants between a CF 2 group and vicinal hydrogens remain quite large and consistent in magnitude (generally between 15 and 22 Hz).
Geminal, two - bond H – F coupling constants for CF 2 H groups are larger than those seen for CH 2 F groups and are usually in the range of 57 Hz.
One - bond F – C coupling constants for – CF 2 – or – CF 2 H groups are in the 234 - to 250 - Hz range, which is characteristically larger than the 160 – 170 Hz observed for – CHF – or – CH 2 F groups, but is much smaller than the 275 – 285 Hz observed for CF 3 groups.
Two - bond F – F coupling constants between diastereotopic fl uorines in a CF 2 group can be quite variable. They can be as small as 14 Hz for some vinylic C = CF 2 groups (see Section 4.7.1 ), of moderate magnitude ( ∼ 50 Hz) for cyclopropyl CF 2 groups, or as large as 240 – 285 Hz for dia-stereotopic, acyclic CF 2 groups.
4.2. SATURATED HYDROCARBONS CONTAINING A CF 2 GROUP 2
The rules governing trends in chemical shift for hydrocarbon CF 2 groups are virtually the same as those that govern monofl uoroalkanes. Thus, the fl uorine nuclei within primary CF 2 groups (that is, CF 2 H groups ) are the most shielded, with secondary CF 2 groups (i.e., those
100 THE CF2 GROUP
bound to two alkyl groups) being substantially deshielded (20 – 30 ppm). Again, branching of the chain near the CF 2 group increases the shield-ing of both 1 ° and 2 ° CF 2 groups (that is more negative chemical shifts).
4.2.1. Alkanes Bearing a Primary CF 2 H Group
Typical 19 F chemical shifts for n - C n H 2n+1 CF 2 H compounds are between − 116 and − 117 ppm, with the usual branching effects being observed. Thus, a CF 2 H group attached to a secondary carbon is more shielded (7 – 10 ppm), and one attached to a tertiary carbon is still farther upfi eld.
The coupling constants given in Scheme 4.1 are typical two - and three - bond F – H values for such systems.
When a 19 F NMR spectrum is obtained for typical compounds con-taining a CF 2 H group, scanning the usual huge range for fl uorine NMR, from about 0 to − 220 ppm, the signals will generally look like singlets (in spite of the typical F – H coupling constant of 58 Hz), as can be seen in Fig. 4.2 , for the spectrum of 1,1 - difl uorobutane. However, when one expands the region of the signal, one can clearly see both the larger, two - bond H – F coupling and the smaller three - bond H – F coupling , as depicted in the expanded inset in the fi gure. The chemical shift and coupling constant data for this fl uorine spectrum of 1,1 - difl uorobutane are as follows: δ − 116.4 (d of t, 2 J FH = 58 Hz, 3 J FH = 16.6 Hz).
When the CF 2 H is attached to a carbocyclic ring, its chemical shift is not signifi cantly affected (Scheme 4.2 ) as compared to the analogous acyclic systems above.
Scheme 4.1
Primary CF2H groups
CH3CF2H –110 CH3CH2CF2H –120, 2JHF = 57, 3JHF = 17.5
n-C7H15CF2H –116, 2JHF = 57, 3JHF = 18
CF2H CF2H
–127 –123
CF2H –129
SATURATED HYDROCARBONS CONTAINING A CF2 GROUP 101
4.2.2. Secondary CF 2 Groups
Alkanes that contain an internal CF 2 group exhibit a signifi cant down-fi eld shift (15 – 20 ppm) in their 19 F NMR spectra compared to those compounds bearing a CF 2 H group, typically absorbing at about − 102 ppm. Again, there is a signifi cant shielding impact due to branch-ing as can be seen in Scheme 4.3 .
A typical 19 F NMR spectrum of a compound with a secondary CF 2 group, that of 2,2 - difl uoropentane, is given in Fig. 4.3 . Its single signal appears as a sextet at − 90.8 ppm with identical three - bond coupling of 18.6 Hz to both its vicinal CH 2 and its CH 3 protons.
CF 2 groups within a carbocyclic ring system are unremarkable, gener-ally absorbing slightly downfi eld from those contained in a straight - chain acyclic system, with the remarkable exception of cyclopropane
FIGURE 4.2. 19 F NMR spectrum of 1,1 - difl uorobutane
CH3CH2CH2CHF2
0 –50 –100 –150 –200 ppm
–115.0 –115.5 –116.0 –116.5 –117.0
Scheme 4.2
CF2H
–1242JFH = 573JFH = 14
H
CF2H
–1192JFH = 57
102 THE CF2 GROUP
systems, the fl uorines of which exhibit a characteristic ( ∼ 40 ppm) upfi eld shift to absorb at about − 139 ppm (Scheme 4.4 ).
Note the very large difference in chemical shift between axial and equatorial fl uorines in the rigid 4 - t - butyl - 1,1 - difl uorocyclohexane system (11.6 ppm), with axial fl uorines being more shielded. Of course, because of the presence of the t - butyl group, the axial and equatorial fl uorines cannot interchange via a ring - fl ipping process. However, in 1,1 - difl uorocyclohexane itself, the interchange of axial and equatorial fl uorines can be readily examined via dynamic NMR . In spite of the fact that the energy required for ring fl ip in fl uorinated cyclohexanes is not much different from that of cyclohexane itself ( Δ G ‡ = approx. 10 kcal mol − 1 ), the relatively huge difference in axial – equatorial fl uorine chemical shifts causes the CF 2 group of 1,1 - difl uorocyclohexane to exhibit broadening, even at room temperature, with coalescence occur-ring at a much higher temperature than for non - fl uorine - containing systems. Equation 4.1 defi nes the relationship between Δ G ‡ , coales-cence temperature, and chemical shift difference of the equilibrating nuclei.
Scheme 4.3
Secondary CF2 groups
CH3CF2CH3 –84.5, 3JHF = 18CH3CH2CF2CH3 –93.3CH3CH2CF2CH2CH3 –102.4(CH3)3CCF2CH3 –102.2
FIGURE 4.3. 19 F NMR spectrum of 2,2 - difl uoropentane
CH3CF2CH2CH2CH3
0 –20 –40 –60 –80 –100 –120 –140 ppm
–89.0 –89.5 –90.0 –90.5 –91.0 –91.5 –92.0
SATURATED HYDROCARBONS CONTAINING A CF2 GROUP 103
ΔG TT‡ in kcal mol c c A B− −( ) = × + − −( )⋅1 34 57 10 9 97. . log log ν ν (4.1)
The temperature dependence of the 19 F NMR spectrum of 1,1 - difl uorocyclohexane is shown in Fig. 4.4 . With an observed Δ ν of 15.3 ppm (4315 Hz) and a coalescence temperature ( T c ) of 249 K, the Δ G ‡ for ring fl ipping of 1,1 - difl uorocyclohexane is calculated to be 9.9 kcal mol − 1 . One can see the axial – equatorial AB system emerging in the − 50 ° C spectrum.
4.2.3. Comments on Coupling Constants
Two - bond F – H coupling constants within CF 2 H groups are almost invariably around 57 Hz regardless of the environment. Three - bond F – H coupling constants between CF 2 H or CF 2 groups and vicinal hydrogens are usually in the 18 to 20 Hz range (Scheme 4.5 ).
Scheme 4.4
F F–102.4
F
F
FFFF
–97.0 –93.3
HO2C
–84.0 and –98.02JFF = 190
F
F
F
F
–91.5 –91.5
Fa
Fe
δ Fe = –92 (s), 2JFF = 234
δ Fa = –103.6 (dtt)
2JFF = 2343JHF = 40JHF = 11
F
F
–139
F
F
H3C
H3C
–157.1
–127.7
2JFF = 157
Scheme 4.5
CH3CF2H (2JHF = 57 Hz 3JHF = 21 Hz) CH3CF2CH3 (3JHF = 17.8 Hz)
104 THE CF2 GROUP
4.2.3.1. Coupling between Diastereotopic CF 2 Atoms. The three examples below provide insight into trends observed for the geminal coupling constants between diastereotopic fl uorine atoms. Diastereo-topic fl uorines in an acyclic CF 2 group appear to have generally the largest observed geminal coupling constants, ranging from about 250 to 290 Hz. Those in six - and fi ve - membered rings are slightly smaller, but the geminal coupling constants for CF 2 groups within a cyclobutane or cyclopropane ring are characteristically much smaller, in the 190 - and 150 - Hz range, respectively (Scheme 4.6 ).
Although Fig. 4.4 showed the AB system of 1,1 - difl uorocyclohexane emerging, Fig. 4.5 provides a classic example a CF 2 AB system, that which derives from the two diastereotopic fl uorines in n - butyl 2,2 - difl uorocyclopropanecarboxylate. In this case, 2 J AB = 164 Hz .
FIGURE 4.4. Temperature dependence of 19 F NMR spectrum of 1,1 - difl uorocyclohexane
–75 –80 –85 –90 –95 –100 –105 –110 –115
–20°C
–24°C
–30°C
–40°C
–50°C
–10°C
20°C
10°C
0°C
ppm
Scheme 4.6
F
F
n-BuF
FPh O
OH
F F
O
Et
–41.0 and – 48.82JFF = 261, 3JHF = 15
–100.2 and –107.62JFF = 225
–128.2 and –145.02JFF = 153
SATURATED HYDROCARBONS CONTAINING A CF2 GROUP 105
4.2.4. Pertinent 1 H Chemical Shift Data
Proton chemical shifts for CF 2 H groups at the terminus of a straight - chained saturated hydrocarbon appear almost invariably at about 5.79 ppm, When the CF 2 H group is attached to secondary carbon, it appears at a slightly higher fi eld. 2 J FH coupling constants for such systems are always about 56 – 58 Hz (Scheme 4.7 ).
A typical proton NMR spectrum for a primary CF 2 H system, that of 1,1 - difl uorobutane, is given in Fig. 4.6 . Note the characteristically large two - bond F – H coupling constant of 57 Hz, along with the small
FIGURE 4.5. 19 F NMR spectrum of n - butyl 2,2 - difl uorocyclopropanecarboxylate
CO2-n-Bu
H
FF
–110 –120 –130 –140 –150 –160 ppm
–125.5 –126.0 –126.5 –127.0 –127.5 –140.5 –141.0 –141.5
FIGURE 4.6. 1 H NMR spectrum of 1,1 - difl uorobutane
CH3CH2CH2CHF2
6.2 6.0 5.8 5.6
7 6 5 4 3 2 1 ppm
106 THE CF2 GROUP
three - bond H – H coupling constant of 4.5 Hz depicted in the inserted expansion. Complete details as to chemical shift and coupling constant data for this proton spectrum of 1,1 - difl uorobutane are as follows: δ 0.98 (t, 3 J HH = 7.2 Hz, 3H), 1.49 (sextet, 3 J HH = 7.5 Hz, 2H), 1.80 (m, 2H), 5.80 (t of t, 2 J FH = 57 Hz, 3 J HH = 4.5 Hz, 1H).
Typical chemical shifts for CH 3 and CH 2 groups contiguous to a CF 2 group are given in Scheme 4.8 .
Vicinal coupling constants between fl uorine and hydrogen are gener-ally between 18 – 20 Hz for both primary and secondary CF 2 groups. On the other hand, H – H coupling constants between vicinal hydrogens are much smaller in these compounds, between 4 and 8 Hz.
Figure 4.7 provides a typical 1 H NMR spectrum of a hydrocarbon containing a secondary CF 2 group. In this spectrum, one can distinguish the triplet at 1.58 ppm deriving from the C - 1 methyl group, which is coupled to the two adjacent fl uorines of the CF 2 group with a char-acteristically large 18.6 Hz three - bond F – H coupling constant. Note the triplet at δ 0.96 deriving from the C - 5 methyl group, which has the characteristically much smaller characteristic three - bond H – H coupling constant of 7.5 Hz. Complete details as to chemical shift and coupling constant data for this proton spectrum of 2,2 - difl uoropentane are as follows: δ 0.96 (t, 3 J HH = 7.5 Hz, 3H), 1.51 (sextet, 3 J HH = 7.8 Hz, 2H), and 1.58 (t, 3 J FH = 18.6 Hz, 3H), 1.81 (m, 2H).
Scheme 4.7
1H chemical shifts for hydrocarbon CF2H protons
n-R-CF2H
n-C5H11CF2H, 5.79n-C8H17CF2H, 5.78n-C9H19CF2H, 5.79All with 2JFH = 57
CF2H CF2H
5.52 5.66
CF2 H 5.712JFH = 58 Hz
Scheme 4.8
CH3-CF2-CH2-CH3
1.57 1.84
SATURATED HYDROCARBONS CONTAINING A CF2 GROUP 107
4.2.5. Pertinent 13 C NMR Data
Both the 13 C chemical shifts and the F – C coupling constants for CF 2 carbons are quite characteristic in value, as can be seen from the exam-ples in Scheme 4.9 . A review article on 13 C NMR spectra of fl uorinated cyclopropanes has recently appeared. 3
Typical examples of such spectra, those of 1,1 - difl uorobutane and 2,2 - difl uoropentane, are given in Figs. 4.8 and 4.9 , respectively. The chemical shift and F – C coupling constant data for each are given below the respective spectra.
FIGURE 4.7. 1 H NMR spectrum of 2,2 - difl uoropentane
CH3CH2CH2CF2CH3
7 6 5 4 3 2 1 ppm
Scheme 4.9
CF2H
CF2H
1JFC = 2452JFC = 21
1JFC = 2382JFC = 20
FFFF
F F124.5
1JFC = 245
126.11JFC = 250
123.61JFC = 245
CH3CF2H 1JFC = 2342JFC = 23
Primarysystems
Secondarysystems
116.920.8
117.534.1
117.534.2
108 THE CF2 GROUP
FIGURE 4.8. 13 C NMR spectrum of 1,1 - difl uorobutane. δ 117.59 (t, 1 J FC = 239 Hz), 36.23 (t, 2 J FC = 20 Hz), 15.84 (t, 3 J FC = 6.0 Hz), 13.79 (s)
CH3CH2CH2CHF2
120 100 80 60 40 20 ppm
36.8
36.6
36.4
36.2
36.0
35.8
35.6
16.4 16.2 16.0 15.8 15.6 15.4
14.2 14.0 13.8 13.6
FIGURE 4.9. 13 C NMR spectrum of 2,2 - difl uoropentane. δ 124.57 (t, 1 J FC = 238 Hz), 40.25 (t, 2 J FC = 25 Hz), 23.39 (t, 2 J FC = 28 Hz), 16.46 (t, 3 J FC = 4.8 Hz), 14.11 (s)
CH3CH2CH2CF2CH3
120 100 80 60 40 20 ppm
24.5 24.0 23.5 23.0 22.5 22.0
41.041.5 40.5 40.0 39.5 39.0
17.4
17.2
17.0
16.8
16.6
16.4
16.2
16.0
4.3. INFLUENCE OF SUBSTITUENTS/FUNCTIONAL GROUPS
Electronegative substituents, such as halogens, alcohol, and ether func-tions, deshield the fl uorine nuclei of CF 2 groups when they are attached directly to the carbon bearing the two fl uorine substituents, whereas electronegative substituents at the β - position always have a shielding infl uence.
INFLUENCE OF SUBSTITUENTS/FUNCTIONAL GROUPS 109
4.3.1. Halogen Substitution
As was the case for the monofl uoro series, halogens attached directly to the CF 2 carbon deshield the fl uorine nuclei (Tables 4.1 and 4.2 ). Iodine has the greatest deshielding effect: I > Br > Cl > F.
The chemical shifts for CF 2 X groups attached to either aliphatic or aromatic systems are similar and are characteristic for X = Cl or Br, as seen in Scheme 4.10 .
Halogens at the β - position routinely give rise to shielding of the fl uorine nuclei of primary CF 2 H groups, with β - fl uorine imparting a greater shielding impact than chlorine (Table 4.3 ). 4
The data in Table 4.4 for halogenated 2,2 - difl uoropropanes indicate a similar shielding infl uence by β - halogens on secondary CF 2 groups. 5,6
TABLE 4.1. 19 F Chemical Shifts of X - CF 2 H Compounds, δ (ppm)
X - CF 2 H
X H CH 3 F Cl Br I δ – 143.6 – 110 – 78.3 – 73 – 70 – 68
TABLE 4.2. 19 F Chemical Shifts of X 2 CF 2 Compounds, δ (ppm)
X 2 CF 2
X H CH 3 F Cl Br I δ – 143.6 – 84.5 – 64.6 – 6.8 +6.3 +18.6
Scheme 4.10
CH3-CF2Cl n-C7H15CH2CF2Cl
–49–463JHF =15 3JHF =13
n-C4H9CH2CF2Br
–443JHF =15
n-C4H9CF2-CF2Br
–66 (s)
–1133JHF = 20
CF2 Br
–44
CF2X
CF2X
X= Cl –50
X = Br –46
i -Pr-O2CCH2CF2Cl
–58
I-CH2-CH2-CF2I
–39
110 THE CF2 GROUP
TABLE 4.5. 19 F Chemical Shifts of CF 2 C l Compounds — Effect of β - Halogen
CH 3 CF 2 Cl XCH 2 CF 2 Cl X 2 CHCF 2 Cl X 3 CCF 2 Cl
X = Cl – 47
– 59 – 62 – 65 X = F – 66 – 74 – 75
There is an old but good review dealing with chemical shift and coupling constant data for chlorodifl uorocyclopropanes. 7
β - Halogens also give rise to shielding of the fl uorines of CF 2 Cl groups (Table 4.5 ). 4
There are limited related data available dealing with the infl uence of β - Br or I substitution, but the few that are given in Scheme 4.11 indicate that fl uorines are also shielded by β - bromine or iodine.
Although there are no clearly illustrative examples available in the literature, one would expect (based upon the limited data for mono-fl uoro - and trifl uoromethyl systems) that electronegative substituents
TABLE 4.3. 19 F Chemical Shifts of Primary CF 2 H Compounds — Effect of β - Halogen
CH 3 CF 2 H XCH 2 CF 2 H X 2 CHCF 2 H X 3 CCF 2 H
X = Cl – 110
– 120 – 124 – 122 X = F – 130 – 138
Also: CHClFCF 2 H AB − 131, − 132
– 142
TABLE 4.4. 19 F Chemical Shifts of Secondary CF 2 Groups — Effect of β - Halogen
CH 3 CF 2 CH 3 XCH 2 CF 2 CH 3 X 2 CHCF 2 CH 3 X 3 CCF 2 CH 3
X = Cl – 85
– 95 – 98 – 100 X = F – 103 – 109 – 111
3 J H,F = 18.7 Hz CF 3 CF 2 CH 2 CH 3 – 121
Scheme 4.11
PhCF2CH3
–87.93JFH = 18
vs. PhCF2CH2Br
–98.23JFH = 14
BrCH2CF2C4H9
–99.2
ICH2CF2C4H9
–94.93JHF =14
CH3CF2CH2CH2CH3
–91
INFLUENCE OF SUBSTITUENTS/FUNCTIONAL GROUPS 111
at the γ - or δ - position relative to CF 2 will have little effect (or a slightly shielding) effect upon CF 2 chemical shifts.
4.3.1.1. 1 H and 13 C NMR Data. Proton and carbon data are presented in Scheme 4.12 for some compounds bearing the CF 2 Cl or CF 2 Br groups. Notable are the much larger one - bond F – C coupling constants for CF 2 X than CF 2 H, which can probably be attributed to the greater degree of s - character of the carbon orbitals bound to fl uorine in CF 2 Cl than to the CF 2 H fl uorines.
Data related to the effect of β - halogen on the proton and carbon chemical shifts of CF 2 H or CF 2 groups are scarce (Scheme 4.13 ), although there is a recent review of 13 C spectra of chlorofl uorocyclo-propanes. 3
4.3.2. Alcohol, Ether, Thioether, and Related Substituents
All Group 6 element substituents deshield the fl uorine nuclei of CF 2 groups when directly attached to the CF 2 group, oxygen substituents having the greatest infl uence (Table 4.6 ). Whereas the fl uorines of a CF 3 group became progressively more deshielded when bound to O, S, Se, and Te, one can see that this is not the case for the CF 2 H group
Scheme 4.12
CH3-CF2Cln-C4H9CH2CF2Br
2.10
123.344.3
2.33
2JFC = 21 1JFC = 304
CF2Cl
ClF2C
125.7
139.2
125.3
1JFC = 3082JFC = 273JFC = 5
CF2Br
BrF2C
117.3
140.7
124.9
1JFC = 3022JFC = 243JFC = 5
ClCH2-CF2Cl
47.3 126.5
1JFC = 2902JFC = 30
Scheme 4.13
Cl CF2H
H
Cl1JFC = 2472JFC = 29
CH3-CF2-CH2F3JFH = 19
5.78
112.6
68.4
4.401.56
3JFH = 12
2JFH = 56
112 THE CF2 GROUP
where, compared to O, S leads to shielding, with Se and Te then deshield-ing relative to S, but with all shielding more than O.
Compounds with the OCF 2 H and SCF 2 H groups attached to aro-matic ring systems are quite common in bioactive compounds. The examples in Scheme 4.14 are representative of the fl uorine chemical shifts and coupling constants that should be expected for such com-pounds. Note that the 2 J FH coupling constants for OCF 2 H compounds are not in the 56 - to 58 - Hz range that is characteristic of carbon - bound CF 2 H groups, but are signifi cantly larger.
Secondary CF 2 groups are affected similarly by O, S, and Se substitu-tion, as is exemplifi ed by the examples in Scheme 4.15 .
As was the case with β - halogens, β - hydroxy groups and ether func-tions shield both primary CF 2 H and secondary CF 2 groups (Schemes 4.16 – 4.18 ).
TABLE 4.6. 19 F Chemical Shifts of CH 3 XCF 2 H Compounds — Effect of α - Substitution
X CH 2 O S Se Te
δ – 120 – 86.9 – 96.4 – 94.4 – 91.8
Scheme 4.14
X OCF2H X = H –76.0, 2JFH = 78
X = OCH3 –75.8X = NO2 –79.3
X SCF2H X = H –90.0, 2JFH = 60
X = OCH3 –89.0X = NO2 –91.6
Scheme 4.15
PhOCF2Ph
PhSCF2Ph
PhSeCF2Ph
CH3OCF2Ph CH3OCF2C7H15
–66
–72
–71
–72 –79
INFLUENCE OF SUBSTITUENTS/FUNCTIONAL GROUPS 113
Scheme 4.16
n-C6H13 C CF2H
OH
H
Ph C CF2H
OH
H
Ph C CF2H
OH
CH3
δAB –130.0, –130.42JFF = 2852JFH = 563JFH = 10
δAB –130.0, –130.92JFF = 2782JFH = 56
δAB –127.2, –128.22JFF = 2842JFH = 563JFH = 9
CH3CH2CF2H vs.
–120
EtO
EtOCF2H –137
Scheme 4.17
OHFF
F F
OH
–96.1–111.8
2JFF = 248
FF
–84.5
vs.
F F
–102.4
vs. OF F
–107.53JFH = 17 and 13
PhCF2CH3
–87.93JFH = 18
vs. PhCF2CH2OH
–107.93JFH = 13.4
PhCF2CH2OAc
–105.03JFH = 13.4
Scheme 4.18
Other related compounds:
PhCF2CH(OH)CO2H PhCF2C(OH)2CO2H
–1042JFF = 2533JFH = 7.6
–110
Again, one would not expect hydroxy or ether substituents more distant (i.e., γ or δ ) to the CF 2 group to have signifi cant effect upon fl uorine chemical shifts.
4.3.2.1. 1 H and 13 C NMR Data. The 1 H chemical shifts of CF 2 H protons of difl uoromethyl ethers lie between 6.00 and 6.3 ppm, with a signifi cantly enhanced F – H two - bond coupling constant of around
114 THE CF2 GROUP
76 Hz (Scheme 4.19 ). The protons of difl uoromethyl sulfi des appear still farther downfi eld at about 6.8 ppm with a more “ normal ” F – H coupling constant of 57 Hz.
Surprisingly, the 13 C chemical shifts of CF 2 H carbons of difl uoro-methyl ethers and of CF 2 carbons of 1,1 - difl uoroalkyl ethers are almost unchanged compared to those of the analogous non - ethers. Compare this to the ∼ 40 - ppm downfi eld incremental shift that is generally observed for a hydrocarbon carbon bearing an ether substituent (Scheme 4.20 ). However, one can distinguish the ether - bound CF 2 groups from the non - ether - bound CF 2 groups on the basis of the
Scheme 4.19
CH3CH2-O-CF2 H CH3CH2-S-CF2H
6.152JFH = 76
6.842JFH = 57
OCF2H6.30
2JFH = 786.80
2JFH = 60
SCF2H
H-O-CH2-CF2 H4.78 5.87
JFH = 15 57
HO-CH2-CF2 -CH3
3.58 1.503JFH = 12 19
Scheme 4.20
116.41JFC = 264
115.81JFC = 260
CH3CH2-O-CF2H CF3CH2-O-CF2H
n-C7H15CF2-O-CH3
125.91JFC = 263
CF2OCH3
126.51JFC = 264
n-C7H15CF2H
n-C3H7CF2CH3
Compare the hydrocarbon analogs:
CH3CH2CH2CH3 CH3CH2-O-CH2CH3
24.8 65.2
115.81JFC = 238
124.61JFC = 238
INFLUENCE OF SUBSTITUENTS/FUNCTIONAL GROUPS 115
signifi cantly (20 – 25 Hz) larger one - bond F – C coupling constants of the difl uoromethyl ethers.
4.3.3. Compounds with Two Different Heteroatom Groups Attached to CF 2 Including Chlorodifl uoromethyl Ethers
There are an increasing number of compounds being prepared that contain two heteroatoms attached to a CF 2 group, in particular halodi-fl uoromethyl ethers and thioethers, but also – OCF 2 O - and – OCF 2 S - compounds. Some representative examples are given in Schemes 4.21 and 4.22 .
4.3.3.1. 13 C NMR Data. Some carbon NMR data for OCF 2 Cl groups and others bearing two heteroatoms are provided in Scheme 4.23 .
Scheme 4.21
O-CF2-Br
–13
S-CF2-Br
–22
O-CF2-Cl
–26
Cl n-C7H15-CH2-O-CF2Cl
–27
Scheme 4.22
O-CF2-O
–56
S-CF2-S
–49
O-CF2-S
–43
OO
FF
PPh2
2
–50
116 THE CF2 GROUP
4.3.4. Amines, Phosphines, and Phosphonates
Unlike monofl uorosystems, which could not tolerate an amino nitrogen bound directly to the carbon bearing fl uorine, the CF 2 group has greater thermodynamic (and kinetic) stability, and although uncommon and generally quite reactive, spectra of R 2 NCF 2 H compounds are known. An amino nitrogen gives rise to less deshielding when α - substituted than any of the group 6 atoms, with a phosphine group providing still less deshielding. A phosponate CF 2 is somewhat more deshielded (Scheme 4.24 ).
There is also an interesting example of an N - CF 2 H amide (Scheme 4.25 ).
Scheme 4.23
O-CF2-ClCl n-C7H15-CH2-O-CF2Cl
120.9 128.51JFC = 254
O-CF2-O O-CF2-S
1JFC = 295
3.99
3JHH = 7
125.769.11JFC = 286
124.91JFC = 289
Scheme 4.24
Me2NCF2H –100.0, 2JFH = 65
Ph2PCF2H –117, 2JFP = 120
CH3CH2CF2H –120.0,
P CF2-CH2-C4H9
O
EtOEtO
–112 2JPF = 1103JHF = 20
Scheme 4.25
N CH3
CF2H
O
–982JFH = 61
INFLUENCE OF SUBSTITUENTS/FUNCTIONAL GROUPS 117
Undoubtedly because of its chemical instability, examples of a sec-ondary CF 2 group bound to amino nitrogen are rare, with a chemical shift being reported only for PhCF 2 N(CH 3 ) 2 ( − 72 ppm).
Examples of azide bound to a CF 2 group also are unusual, but two examples are given in Scheme 4.26 .
When a CF 2 H group is attached to an ammonium nitrogen, its fl uo-rines are considerably shielded relative to the respective amine. Thus, the fl uorine chemical shifts of difl uoromethyl trialkyl ammonium salts are in the − 113 - to − 115 - ppm range, as exemplifi ed by difl uoromethyl triethyl ammonium chloride (Scheme 4.27 ).
β - Amino groups have a shielding effect on chemical shift similar to that of an OH group (Scheme 4.28 ).
It should also be noted that although the phenyl substituent gives rise to approximately 5 - ppm shielding when it is the only affecting substituent on a CF 2 group, it appears to have little effect when a more strongly infl uencing Group like OH, NH 2 , or carbonyl is also proximate.
Scheme 4.26
Ph
O
O
N3N3
F F F F–78 –70
Scheme 4.27
C4H9N
C4H9
C4H9
CF2H
–114.3
2JHF = 58
Scheme 4.28
PhCF2CH3
–87.9
PhCF2CH2OH
–107.9
PhCF2CH2NH2
–106.5
CH3CH2CF2CH3
–93.3
n-C8H17CF2CH2NH2
–107.8
C2H5CF2CHC2H5
δAB = –110.3, –110.52JFF = 243
OH
n-C3H7CF2CHC3H7
NH2
–111.8
118 THE CF2 GROUP
4.3.4.1. 1 H and 13 C NMR Data. The protons of CF 2 H groups bound to nitrogen are only slightly deshielded as compared to those at the end of an alkyl chain (Scheme 4.29 ). Again, note the somewhat large 2 J FH coupling constants for such compounds. The proton, carbon, and phosphorous NMR data are provided for a representative difl uorophosphonate.
4.3.5. Silanes
As was the case with silanes bearing a CH 2 F group, the fl uorines of those bearing a CF 2 H group are also considerably shielded by the attached Si substituent (Scheme 4.30 ).
Fluorine chemical shift data are also given in Scheme 4.31 for silanes bearing a CF 2 - halogen group.
4.3.6. Organometallics
Organometallics with either the CHF 2 group or the RCF 2 group directly attached to a metal are not as stable as those of CF 3 . Nevertheless,
Scheme 4.29
P CF2-CH2-C4H9
O
EtOEtO
C4H9N
C4H9
C4H9
CF2H
8.51 2JHF = 58
N CH3
CF2H
O
2JFH = 61
CF2H N CF2HH3C
H3C
2JFH = 572JFH = 65
n-C8H17CF2CH2NH2 CF2CH2NH2
3JFH = 15 3JFH = 15
5.79 5.98
7.55
107.9
2.93 3.17
1JFC = 241
115.21JFC = 276
121.1 34.22JFC = 212JPC = 14
1JFC = 2601JPC = 215
31P, δ 7.59
2.03JFH = 20
Scheme 4.30
CF2H Si CF2H
–1292JFH = 57
–1402JFH = 47
CARBONYL FUNCTIONAL GROUPS 119
organocadmium, zinc, and copper derivatives have now been reported (Scheme 4.32 ). 8
There do not appear to be proton or carbon spectra available for these compounds, but note the relatively small 2 J FH coupling constants of these compounds.
4.4. CARBONYL FUNCTIONAL GROUPS
Carbonyl functional groups bound directly to primary CF 2 H or second-ary CF 2 groups give rise to shielding of the respective fl uorine nuclei by about 10 ppm.
4.4.1. Aldehydes and Ketones
Typical chemical shift data for primary (CF 2 H) and secondary (CF 2 ) groups proximate to aldehyde or ketone carbonyls are provided in Scheme 4.33 . Unfortunately, there does not appear to be any available NMR data for difl uoroacetaldehyde.
4.4.1.1. 1 H and 13 C NMR Data. A ketone or aldehyde carbonyl group bound to a CF 2 H group shields its proton slightly (0.1 ppm), and even more surprisingly, it also has a shielding effect upon its carbon chemical
Scheme 4.31
Si CF2Cl
–63
Si CF2Br
–58
Scheme 4.32
HCF2CdI –118 ppm2JFH = 432J113CdF = 3422J111CdF = 327
(HCF2)2Cd –119
2JFH = 432J113CdF = 2922J111CdF = 278
HCF2ZnI –1262JFH = 44
(HCF2)2Zn –1262JFH = 44
CHF2Cu –1152JFH = 44
(all in DMF)
120 THE CF2 GROUP
shift of about 8 ppm (Scheme 4.34 ). By comparison, a hydrocarbon ketone, as in 2 - butanone, has the effect of deshielding the C - 3 CH 2 carbon by about 12 ppm. A CF 2 H group when bound to a ketone car-bonyl also has the effect of shielding the carbonyl carbon relative to that in acetone.
4.4.2. Carboxylic Acids and Derivatives
The impact of a carboxylic acid function upon the chemical shift of a CF 2 H group is almost indistinguishable from the impact of a ketone, whereas secondary CF 2 groups next to an acid or ester function are slightly deshielded relative to those next to a ketone or aldehyde (Scheme 4.35 ).
Attaching a double bond to the α , α - difl uoroester leads to signifi cant deshielding of the CF 2 group (Scheme 4.36 ).
An ester function one carbon removed from a CF 2 group , if anything, deshields the fl uorines: PhCF 2 CH 2 CO 2 Et ( δ F = − 96) vs. PhCF 2 CH 2 CH 3 ( δ F = − 98).
Scheme 4.33
Primary CF2H
H3C CF2H
O
–1272JFH = 54
Ph CF2H
O
–1242JFH = 54
CH3CH2CF2H
–120.0
vs.
OF
F
–111
Ph CF2CH3
O
–943JFH = 20
Ph CF2Ph
O
–99
CH3CF2Ph
–882JFH = 54
F
F
–97
vs.
vs.
Secondary CF2
PhCF2CHO–112
3JFH = 3.1
n-C8H17CF2CHO
–1113JFH = 12.3
O
FF
OCl
–102
CARBONYL FUNCTIONAL GROUPS 121
Scheme 4.34
O
H3C CF2H2JFH = 54
O
CF2HO
H3C CF2-CH31JFC = 2492JFC = 332JFC = 25
5.67
109.8197.4
1JFC = 2522JFC = 27
1JFC = 254
2JFH = 54 3JFH = 191.68
117.7 19.0198.8
6.30
111.0
O
H3C CH3206
O
H3C CH2-CH3
CH3-CH2-CH2-CF2-CH3
CH3-CH2-CH2-CH3
124.6
36.9
24.8
compare:
O
F F
OCl
115.6
177.1
1JFC = 2552JFC = 33
Primary CF2H
CF2HCO2H CF2HCO2CH3 CF2HCONMe2
–127.0 –127.3 –122.7
Secondary CF2
CH3CF2CO2Et CH3CH2CF2CO2CH3
–1003JFH = 19
–1083JFH = 17
CH3CH2CF2CH3
–93
PhCF2CO2CH3
–104.3
n-C7H15 CF2CO2Et
–105
Scheme 4.35
Scheme 4.36
Ph
HH
CO2Et
F F–95
3JFH = 11
CO2Et
F F
C4H9
–98
CO2Et
F F
Ph
–88 3JFH = 14
122 THE CF2 GROUP
4.4.2.1. 1 H and 13 C NMR Data. The ester function of ethyl difl uoroac-etate deshields the CF 2 H proton slightly (about 0.1 ppm), whereas as was the case for ketones and aldehydes, it shields the carbon of either a CF 2 H or a CF 2 - alkyl group signifi cantly (by about 10 ppm) (Scheme 4.37 ).
4.5. NITRILES
Unlike carbonyl functions, a nitrile function bound to a secondary CF 2 does not generally lead to shielding of the CF 2 group (Scheme 4.38 ), the exception being the unique HCF 2 CN.
4.5.1. 1 H and 13 C NMR Spectra of Nitriles
The few data that are available of such compounds are provided in Scheme 4.39 .
Scheme 4.37
2JFH = 54O
EtO CF2H
O
EtO CF2CH3
O
EtO CF2CH2CH3
2JFC = 2472JFC = 250
5.90
106.9162.7 116.7
1.81
115.1
2JFH = 19
Scheme 4.38
CH3CF2CH3
–84.5
–83.5
CH3CF2CN
–853JFH = 18.1
PhCF2CN PhCF2CH3
–87.9
vs.
vs.
HCF2CN vs. HCF2CH3
–110–1202JHF = 52
Scheme 4.39
CF2-CN
H3C
109.1 112.7
1JFC = 2422JFC = 48
CH3-CF2-CN H-CF2 -CN5.92
2JFH = 52
1.973JFH = 18.1
BIFUNCTIONAL CF2 COMPOUNDS 123
4.6. BIFUNCTIONAL CF 2 COMPOUNDS
The impact of combinations of functional groups on CF 2 chemical shifts depends on how they are arranged. If they are consecutive, then the closest one largely determines the chemical shift (Scheme 4.40 ).
Note that the last compound in Scheme 4.40 , the 3,3 - difl uoro - α - keto ester, exists in aqueous solution at 98% in the hydrate form , with the CF 2 of the hydrate being more shielded than that of the keto form, with a chemical shift of − 110 ppm.
On the other hand, when the two functionalities are each directly bound to the CF 2 group, as in the examples in Scheme 4.41 , the effect of each is felt.
A couple of examples of β - dicarbonyl systems are also given in Scheme 4.42 . In each case, the second carbonyl gives rise to additional shielding.
Scheme 4.40
PhCF2CHCO2CH3
NH2
PhCF2CHCO2CH3
OH
δAB = –105.46, –105.53 –104.0
CH3CF2CCO2Et
O
CH3CF2CHCN
OHδAB = –101.3 and –102.5
H2O H3CF2C CO2Et
OHHO
–100 –1102% 98%
Scheme 4.41
PhCHCF2CO2H
OHδF = –113.4, 2JFF = 261 Hz, 3JFH = 8 HzδF = –121.2, 2JFF = 261 Hz, 3JFH = 15 Hz
PhCHCF2CO2H
NH2
δF = –106.0, 2JFF = 262 Hz, 3JFH = 8.4 HzδF = –110.9, 2JFF = 262 Hz, 3JFH = 15 Hz
AB systems
Scheme 4.42
EtO OC6H13
O O
F FPh OC6H13
O O
F F
–108.1 –112.6
124 THE CF2 GROUP
4.7. ALKENES AND ALKYNES
4.7.1. Simple Alkenes with Terminal Vinylic CF 2 Groups
Vinylidine fl uoride (CF 2 = CH 2 ) exhibits a 19 F chemical shift of − 82 ppm. As seen in Scheme 4.43 , one alkyl substitution at the 2 - position leads to about 10 ppm of shielding, with two alkyl groups providing 6 – 7 ppm more. The two - bond F – F coupling constant in such AB systems is typically around 50 Hz. Modest shielding of the Z - fl uorine is generally observed relative to the E - fl uorine of 1,1 - difl uoroalkenes.
Figure 4.10 provides the 19 F NMR spectrum of 1,1 - difl uorobutene. The chemical shifts for its Z - and E - fl uorines are − 92.8 and − 90.8 ppm, respectively, with the geminal 2 J FF coupling constant being 50 Hz, and the trans 3 J HF coupling constant being 25.5 Hz. The cis coupling was too small to be seen in the fl uorine spectrum, but was determined to be 2.7 Hz from the proton spectrum shown in Fig. 4.11 . The magnitudes of these vicinal F – H coupling constants are considerably diminished as compared to those of monofl uoroalkenes.
The proton spectrum (Fig. 4.11 ) exhibited three signals, a triplet at δ 1.00 due to the methyl group ( 3 J HH = 7.5 Hz), a quintet of triplets at δ 1.99 due to the CH 2 group ( 3 J HH(CH3) = 3 J HH(CH) = 7.5 – 8.0 Hz), and a doublet of triplets of doublets due to the vinylic H ( 3 J FH( trans ) = 25.7, 3 J HH = 8.0 & 3 J FH( cis ) = 2.7 Hz).
The 13 C spectrum of 1,1 - difl uorobutene (Fig. 4.12 ) exhibited four signals, a doublet of doublets at 156.2 ppm for the CF 2 group bearing diastereotopic fl uorines, with almost identical one - bond F – C coupling
Scheme 4.43
Fa
Fb Hc
CH2CH2CH2CH3
δF(a) = –92.8, 2JFF = 49.6, 3JFH(trans) = 25.5δF(b) = –90.4, 2JFF = 49.4, 3JFH(cis) = 3
F
F CH3
CH3
–984JFH = 3.1
4.13
F
F CH2-CH3
CH2-CH380.7152.5
14.0
1.56
152.7 91.8
19.0 12.4
2.00 1.00
1JFC = 2802JFC = 20.63JFC = 1.5
–984JFH = 2.2
1JFC = 2832JFC = 16.4
Fa
Fb Hc
CH3
δF(a) = –92.6 2JFF = 47.8δF(b) = –88.9,
,2JFF = 47.8
3.99
1.49
ALKENES AND ALKYNES 125
FIGURE 4.10. 19 F NMR spectrum of 1,1 - difl uorobutene
F
F
H
CH2-CH3
–88 –90 –92 –94 –96 ppm
FIGURE 4.11. Proton NMR spectrum of 1,1 - difl uorobutene
F
4.4 4.3 4.2 4.1 4.0 3.9
F
H
CH2-CH3
5 4 3 2 1 ppm
2.10 2.05 2.00 1.95 1.90
1.15 1.
101.
15 1.00
0.95 0.
900.
85
constants of 282 – 285 Hz, a triplet for the CH vinyl carbon at δ 79.8, with two - bond F – C coupling of 21.8 Hz, a doublet for the CH 2 group at δ 15.9 (coupling with only one of the vinylic fl uorines), with three - bond coupling of 4.2 Hz, and a broad singlet at δ 14.3 due to the methyl group.
126 THE CF2 GROUP
4.7.2. Conjugated Alkenes with Terminal Vinylic CF 2 Group
Conjugation, in the form of a phenyl substituent at the 2 - position, leads to 8 - to 10 - ppm shielding of the fl uorines of a terminal vinylic CF 2 group, whereas for a conjugating vinyl group at the 2 - position (as in 1,1 - difl uoro - 1,3 - butadiene), such shielding is somewhat less (Scheme 4.44 ). The two - bond, F – F coupling constant observed in such conju-gated systems is much smaller than those of the nonconjugated alkene systems.
Pertinent 1 H and 13 C NMR data are included, where available, in Schemes 4.43 and 4.44 . As expected, trans F – H coupling is character-
FIGURE 4.12. 13 C NMR spectrum of 1,1 - difl uorobutene
CF2=CHCH2CH3
160 140 120
81.5 81.0 80.5 80.0 79.5 79.0
16.4
14.8 14.6 14.4 14.2 14.0
16.2 16.0 15.8 15.6 15.4
100 80 60 40 20 ppm
Scheme 4.44
Fa
Fb Hc
Ph
δF(a) = –82.9, 2JFF = 31, 3JFH(trans) = 26δF(b) = –84.8, 2JFF = 34, 3JFH(cis) = <5
3JHF 26 and 4
δF(a) = –86.1, 2JFF = 28, 3JFH(trans) = 24δF(b) = –88.6, 2JFF = 28, 3JFH(cis) = <5
Fa
Fb Hc
F
F
H2JFH = 26.4 and 4
1JFC = 288 and 298
–852JFF = 34 Hz
–832JFF = 31
F
F Ph
Ph F
F CH3
Ph
–88.3 –91.0 and –91.42JFF = 44
5.306.25
5.30
156.6
ALKENES AND ALKYNES 127
istically much larger than the analogous cis coupling. Conjugation does not noticeably affect the carbon chemical shift of the CF 2 carbon.
1,1 - Difl uoro allenes have characteristically higher fi eld fl uorine chemical shifts than typical 1,1 - difl uoroalkene, as can be seen from the data in Scheme 4.45 , which includes 1 H NMR data as well.
4.7.3. Effect of Vicinal Halogen or Ether Function
A chlorine substituent at the 2 - position of a 1,1 - difl uoroalkene will deshield the fl uorines modestly, but as seen in Scheme 4.46 , a vicinal alkoxy group shields both fl uorines, the trans fl uorine more greatly. With the additional electronegative substituent, three - bond F – H cou-pling constants for such compounds become even smaller.
4.7.4. Polyfl uoroethylenes
Fluorine chemical shift and coupling constant data are provided in Scheme 4.47 for all of the hydrofl uoroethylenes.
4.7.5. The Trifl uorovinyl Group
Although the presence of a chlorine at the 2 - position of a 1,1 - difl uoro-alkene has almost no infl uence upon the chemical shifts of the fl uorine
Scheme 4.45
CH
HF
FC
CH3
CH3F
F–102–107 6.04 1.97
4JFH = 3.5 5JFH = 5.1
Scheme 4.46
F
F Cl
H
–87
–925.18
2JFF = 413JHF(trans) = 16.63JHF(cis) = 1.1
F
F O
H
CF3–95
–114
2JFF = 583JHF(trans) = 133JHF(cis) = 3.6
6.86
–65
F
F O
H
CH2-Ph
5.66
–101
–122
2JFF = 783JHF(trans) = 163JHF(cis) = 2.9
128 THE CF2 GROUP
nuclei, a fl uorine substituent at the 2 - position gives rise to very signifi -cant shielding, and it causes a much greater “ split ” of the diastereotopic fl uorines at the 1 - position and much greater coupling constants, both geminal and vicinal (Scheme 4.48 ). Further data for trifl uorovinyl com-pounds can be found in Chapter 6 .
4.7.6. α , β - Unsaturated Carbonyl Systems with a Terminal Vinylic CF 2 Group
The fl uorines of a CF 2 = group of an α , β - unsaturated carbonyl system are considerably deshielded, and the geminal and vicinal coupling con-
Scheme 4.47
H
F H
H F
F H
H F
F F
H F
F F
F
H
F H
F H
F F
H
–1132JFH = 853JFH = 523JFH = 20
–813JFH = 343JFH = 1
–205
–126
–100
2JFH = 713JFF= 1193JFF = 33
2JFF = 873JFH = 133JFF = 33
–1342JFF = 873JFF = 1193JFH = 4
–186 –1652JFH = 743JFF = 1253JFH = 4
2JFH = 733JFF = 193JFH = 20
Scheme 4.48
Fa
Fb Fc
CH2CH2CH2CH3Fa
Fb Fc
δF(a) = –125.8, 2JFF = 90, 3JFF(trans) = 114δF(b) = –106.7, 3JFF(cis) = 32δF(c) = – 174.8
δF(a) = –115.2, 2JFF = 71, 3JFF(trans) = 109δF(b) = –100.4, 3JFF(cis) = 32δF(c) = –177
ALKENES AND ALKYNES 129
stants dramatically diminished, as seen from the examples given in Scheme 4.49 .
4.7.6.1. 1 H and 13 C NMR Data . Typical proton and carbon NMR data for α , β - unsaturated carbonyl compounds with a terminal vinylic CF 2 group are given in Scheme 4.50 . The pertinent F – H coupling constants have been given in the previous Scheme 4.49 . Conjugation with a car-bonyl group deshields the β - CF 2 carbon by 4 – 5 ppm.
4.7.7. Allylic and Propargylic CF 2 Groups
A vinyl substituent deshields both primary (CF 2 H) and secondary (CF 2 ) groups by between 6 and 10 ppm. There are little available data on the impact of an acetylenic group, but it seems to have slightly
Scheme 4.49
δF(a) = –64.2, 2JFF = 14, 3JFH(cis) = 3δF(b) = –59.0, 2JFF = 14, 3JFH(trans) = 22
Hc
OFb
Fa
H
O
O
Fb
Fa
δF(a) = –63.5, 2JFF = 14, 3JFH(cis) = 3δF(b) = –58.0, 2JFF = 14, 3JFH(trans) = 22
Hc
O
OC8H17
Fb
Fa
C6H13
OFb
Fa OCH3
δF(a) = –70.7, 2JFF = 16, 3JFH(cis) = 2δF(b) = –64.7, 2JFF = 16, 3JFH(trans) = 22
δF(a) = –75.0 (s)δF(b) = –70.2 (s)
Scheme 4.50
4.98
H
OF
F
H
O
O
F
F
5.24.8
H
O
OC8H17
F
FC6H13
OF
F OCH3161.9
77.1
163.0 159.8
88.7
165.5
130 THE CF2 GROUP
greater deshielding infl uence than either a vinyl or a phenyl substituent on a CF 2 H group (Scheme 4.51 ).
Notice that the CF 2 fl uorines of the Z isomer of 4,4 - difl uoro - 2 - butene are signifi cantly deshielded relative to those of the E isomer. This is another probable example of “ steric deshielding ” by a proximate, in this case cis - alkyl group (see Chapter 2 , Section 2.2.1 ).
Placing a carbonyl function next to an allylic CF 2 group leads to the usual shielding, but its impact appears to be dampened by the infl uence of the double bond (Scheme 4.52 ).
4.7.7.1. 1 H and 13 C NMR Data. The protons of allylic CF 2 H groups are deshielded by the vinylic group to the extent of ∼ 0.2 ppm, and its carbon is shielded by about 2 ppm. The carbons of allylic secondary CF 2 groups are shielded to the extent of about 4 ppm (Scheme 4.53 ).
4.8. BENZENOID AROMATICS BEARING A CF 2 GROUP
The 10 ppm deshielding caused by direct phenyl substitution on a CF 2 H group is cut in half when the phenyl is moved one carbon farther away.
Scheme 4.51
CH3CH2CF2H –120
CH2=CHCF2H –113
CH3CH=CHCF2CH3 –83.8 (Z isomer)
–87.3 (E isomer)
Ph CF2H
CH3CH2CF2CH3 –93.3PhCH=CHCF2H –108, 2JFH = 56
n-C3H7CH=CHCF2H –110, 2JFH = 56
CF2H
–116, 2JFH = 56–106, 2JFH = 55
Scheme 4.52
Ph
HH
CO2Et
F F–95
3JFH = 11
CO2Et
F F
C4H9
–98
CO2Et
F F
Ph
–88 3JFH = 14
BENZENOID AROMATICS BEARING A CF2 GROUP 131
Donating or electron - withdrawing para substituents on ArCF 2 H give rise to characteristic, modest deshielding or shielding, respectively. Direct phenyl substitution on a secondary CF 2 group only has a 5 ppm deshielding infl uence. Examples of each of these types of compounds are given in Scheme 4.54 .
4.8.1. 1 H and 13 C NMR Data
The characteristic 1 H chemical shifts for ArCF 2 H protons lie between 6.6 and 7.0 ppm, and the characteristic 13 C chemical shift for the CF 2 H carbon of such compounds is ∼ 115 ppm (Table 4.7 ).
Scheme 4.53
Ph
HH
CO2Et
F F
n-C6H13CH=CHCF2CH3
n-C3H7CH=CHCF2HCF2H
1JFC = 233 Hz
1JFC = 234 Hz
1JFC = 234
n-C4H9CH=CHCF2C4H9
1JFC = 238 Hz
5.97
115.6
5.84
117.4
121.7120.7
6.35
112.6
3JFH = 12
1JFC = 246
Scheme 4.54
CF2H
X
X = NO2 H OCH3
δF = –113 –111 –109
2JFH = 56
–115–88
PhCF2CH3 PhCH2CF2H
132 THE CF2 GROUP
4.9. HETEROAROMATIC CF 2 GROUPS
There can be more variation in the 19 F chemical shifts of CF 2 H groups on heteroaromatic than on benzenoid systems, depending on the posi-tion of substitution.
4.9.1. Pyridines
The fl uorines of CF 2 H groups, attached at the 2 - or 3 - position of a pyridine ring, appear at approximately − 116 ppm, whereas a CF 2 H substituent at the 4 - position appears at − 113 ppm. A secondary CF 2 substituent exhibits a similar trend in chemical shift (Scheme 4.55 ).
TABLE 4.7. Proton and Carbon Data for Aryl CF 2 H Groups
δ H δ C
X
CF2H
X = OCH 3 6.65 114.9 X = H 6.55 114.8 X = NO 2 6.80 113.2
Scheme 4.55
N
CF2H2– –1163– –1134– –116
2JFH = 56
N
CF2CH32– – 913– – 894– – 92
3JFH = 18
4.9.2. Furans, Thiophenes, and Pyrroles
On the basis of the few data available, thiophene CF 2 H groups appear at a lower fi eld than furan CF 2 H groups Scheme 4.56 ). This is consistent with the trend for CF 3 groups. On the basis of trends observed for CF 3 chemical shifts, one would also expect that CF 2 groups in the 2 - position should appear at lower fi elds (less negative) than CF 2 H groups at the 3 - position of furans, thiophenes, and pyrroles. However, there are no
HETEROAROMATIC CF2 GROUPS 133
data to confi rm this prediction. Indeed, there does not appear to be any NMR data related to pyrrole CF 2 H groups in the literature.
4.9.3. Imidazoles and Other Heterocyclic CF 2 H Compounds
The CF 2 H group on an imidazole is more highly shielded than those on furan or thiophene (Scheme 4.57 ).
Scheme 4.56
–99 (2JFH = 56)
–106
S
O
CF2H
CF2H
OCF2H
–140 (2JFH = 54)
Scheme 4.57
–115–114
2JFH = 54
N
HN
N
HN
CF2H
HF2C
HCl
hydrochloride salt
–1122JFH = 53
Chemical shifts for examples of a number of other heterocyclic - bound CF 2 H compounds are given in Scheme 4.58 , including some with the CF 2 H bound to a nitrogen.
4.9.4. 1 H and 13 C NMR Data for Heterocyclic - Bound CF 2 Groups
Typical proton and carbon chemical shift data for heterocycles bearing a CF 2 H group and, in the case of pyridine, a CF 2 R group are provided in Scheme 4.59 .
134 THE CF2 GROUP
Scheme 4.58
N
N
O
HS
CF2H
N
N
O
S
N
N
OH
SHF2CH3C
CF2H–98
2JFH = 55 –1072JFH = 58
–1022JFH = 61
N
HN
SCF2H
–922JFH = 55
N
NS
CF2H
CH3
N
NS
CF2H
CH3
–1002JFH = 60
–1032JFH = 59
Scheme 4.59
OCF2H
N
CF2H2– 113.83– 113.04– 113.0
2JFH = 240
N
CF2CH3 2– 121.03– 121.84– 121.4
3JFH = 240
SCF2H
δC
1JFC = 235
2JFH = 54
N
HN
N
HN
CF2H HF2C
HCl
hydrochloride salt
2JFH = 53
7.38
6.52
108.5
7.236.75δC
6.62
108.51JFC = 233
2JFH = 60
N
N
O
HS
CF2H
N
N
O
S
N
N
OH
SHF2CH3C
CF2H
2JFH = 56
2JFH = 58
N
NS
CF2H
CH3
N
NS
CF2H
CH3
2JFH = 602JFH = 59
N
HN
SCF2H
2JFH = 55
7.57
109.31JFC = 248 7.88
117.6
7.89
119.5
7.72
109.4
8.02
111.27.36
1JFC = 249
1JFC = 337
1JFC = 161
1JFC = 250
REFERENCES 135
REFERENCES
1. Percy , J. M. Chim. Oggi 2004 , June , 18 – 22 . 2. Wiberg , K. B. ; Zilm , K. W. J. Org. Chem. 2001 , 66 , 2809 – 2817 . 3. Brey , W. S. Magn. Res. Chem. 2008 , 46 , 480 – 492 . 4. Weigert , F. J. J. Fluorine Chem. 1990 , 46 , 375 – 384 . 5. Tanuma , T. ; Irisawa , J. J. Fluorine Chem. 1999 , 99 , 157 – 160 . 6. Weigert , F. J. J. Fluorine Chem. 1993 , 60 , 103 – 108 . 7. Cavalli , L. Org. Magn. Reson. 1970 , 2 , 233 – 244 . 8. Burton , D. J. ; Hartgraves , G. A. J. Fluorine Chem. 2007 , 128 , 1198 – 1215 .