Level 3 – Case 37
244
Table 37.1
pK a
K K
base
primary k
H
k k /k
D
k k
secondary k
H
k k /k
D
k k
a leaving group k
18 /k
19
3.7
formate
3.2 ± 0.1
1.038 ± 0.013
1.0037 ± 0.0020
4.7
acetate
3.7 ± 0.1
1.050 ± 0.014
1.0047 ± 0.0012
6.95 imidazol 7.45 ± 0.1
1.014 ± 0.017
1.0013 ± 0.0012
a These values correspond to 5-15% of the es
a
timated maximum F KIE of 1.03 (this value
is the one expected for a complete C-F bond breakage).
2. Computational studies have indicated that secondary F KIEs as large as 1.0058
may appear for the deprotonation step in an E1cB elimination reaction.
3. No H/D exchange with the solvent was observed during the reaction.
4. The reaction rate increases with the strength of the base: formate < acetate <
imidazol.
5. The double-isotopic fractionation method was employed in this study. This
d
procedure consists of the use of deuterium substitution to selectively slow down
the rate of one step in a reaction and observing the changes in a second kinetic
isotope effect. In this study the aim is to obtain information from the secondary
D KIE at C4 and the fluorine isotope effects, respectively. For that reason, subf f
strates on which the deuterium has been placed at C3 to slow down the step in
which the C3-H bond is being broken, have been employed. Then, the extra labels were deuterium at C4 (compound 4) and labeled fluorine (compound 6)
(atoms colored red in Fig. 37.1). Compounds 3 and 4 were used to determine
the effect of the deuterium at C3 on the secondary D KIE values at C4 (
n
k 3
k k
H /k 4
k k
D )
(Fig. 37.1). Similarly, compounds 5 and 6 were used to study the influence of
the deuterium label at C3 on the leaving group F KIEs (k 6
k k
18F
/k 5
k k
19F
).
1
14 CD 3
O
O 2 N
D D
F
CD 3
O
O 2 N
D D
F
CD 3
O
O 2 N
D D
F F F D
CD 3
O
O 2 N
D D
18 F
5
6
3
4
3
4
4
3
4
3
3
4
Figure 37.1
1 The F KIEs are calculated from the
18 F/
19 F isotopic ratios. As
18 F is radioactive while
naturally abundant
19 F is not, a remote radioactive
14 C label was introduced in substrate 5
to enable radioactivity measurements.
244
Table 37.1
pK a
K K
base
primary k
H
k k /k
D
k k
secondary k
H
k k /k
D
k k
a leaving group k
18 /k
19
3.7
formate
3.2 ± 0.1
1.038 ± 0.013
1.0037 ± 0.0020
4.7
acetate
3.7 ± 0.1
1.050 ± 0.014
1.0047 ± 0.0012
6.95 imidazol 7.45 ± 0.1
1.014 ± 0.017
1.0013 ± 0.0012
a These values correspond to 5-15% of the es
a
timated maximum F KIE of 1.03 (this value
is the one expected for a complete C-F bond breakage).
2. Computational studies have indicated that secondary F KIEs as large as 1.0058
may appear for the deprotonation step in an E1cB elimination reaction.
3. No H/D exchange with the solvent was observed during the reaction.
4. The reaction rate increases with the strength of the base: formate < acetate <
imidazol.
5. The double-isotopic fractionation method was employed in this study. This
d
procedure consists of the use of deuterium substitution to selectively slow down
the rate of one step in a reaction and observing the changes in a second kinetic
isotope effect. In this study the aim is to obtain information from the secondary
D KIE at C4 and the fluorine isotope effects, respectively. For that reason, subf f
strates on which the deuterium has been placed at C3 to slow down the step in
which the C3-H bond is being broken, have been employed. Then, the extra labels were deuterium at C4 (compound 4) and labeled fluorine (compound 6)
(atoms colored red in Fig. 37.1). Compounds 3 and 4 were used to determine
the effect of the deuterium at C3 on the secondary D KIE values at C4 (
n
k 3
k k
H /k 4
k k
D )
(Fig. 37.1). Similarly, compounds 5 and 6 were used to study the influence of
the deuterium label at C3 on the leaving group F KIEs (k 6
k k
18F
/k 5
k k
19F
).
1
14 CD 3
O
O 2 N
D D
F
CD 3
O
O 2 N
D D
F
CD 3
O
O 2 N
D D
F F F D
CD 3
O
O 2 N
D D
18 F
5
6
3
4
3
4
4
3
4
3
3
4
Figure 37.1
1 The F KIEs are calculated from the
18 F/
19 F isotopic ratios. As
18 F is radioactive while
naturally abundant
19 F is not, a remote radioactive
14 C label was introduced in substrate 5
to enable radioactivity measurements.