1
042
L. DiMichele et al.
for ortho, meta and para were approximately 20–25, 6–10 and
1 3
tabulated (Table 2) for C through C . There are three general
2
–4 Hz, respectively. The substituted and protic carbons
trends from the literature for mono substituted aromatic
1
13
3
were readily distinguished in the H coupled C spectrum,
although the reduced signal intensity of the C –C carbons
in the decoupled spectrum presented a reliable indicator
for substitution as well. Using this combined information,
the assignments for the carbons in compound 2a were
made, which appear in Table 3. A significant observation
systems: (i) J
CH
couplings are larger (6–12 Hz) than the
2
1
3
JCH couplings (0–4 Hz) and easier to discern; (ii) The
magnitude of the J
3
CH
couplings are directly proportional
to the increased electronegativity of the substituent. Thus,
3
6
for halogen substitution the J couplings are quite large,
CH
¾10–13 Hz; (iii) If a substituent is on the coupling pathway,
1
13
3
in the H coupled C data revealed that the acid carbonyl
showed no long-range carbon–hydrogen couplings (JCH),
the J values decrease with increased electronegativity.
3
6,7
For halogenated substituents, the JCH values decrease
which strongly suggested its substitution at C
2
. This applied
to ¾4–6 Hz. Although our system is tri-substituted, these
to all the major regioisomers (2a–2f) with the exception of
trends were still applicable and were key to making the
3
3
the methyl analog (3g) where a JCH coupling of 4.5 Hz to the
regioisomer assignments. For the compound 2a, the JCH
acid carbonyl was observed. The more commonly used 2-D
HMBC (heteromultiple bond correlation) experiment would
easily have shown this three-bond correlation; however, the
absence of these correlations in 2a–2f would not conclusively
3
3
coupling for C
indicative of halogen substitution, in this case, F and
Br, respectively. Subsequently, the C carbon bearing the
carboxylic acid group showed the expected smaller couplings
3 1
( J35) and C ( J15) were both 12.5 Hz
2
prove carboxyl substitution at C
on the substituted carbons in the coupled C spectrum. The
positional assignment of the C carbon (triplet) was readily
, the former having two similar
carbons were assigned on the basis of
2
. It was necessary to focus
3
3
(
t, J24 D J26 D 4.5) associated with halogen substitution
1
3
along the coupling pathway. Consequently C
2
was assigned
3
2
to the quench site. Similar
obtained for 2b and are illustrated in Fig. 1 (Although the
literature indicates that the relative proximity of proton
J
CH coupling constants were
distinguished from C
1
and C
3
8
3
J
CH couplings. The C
3
8
one of several strategies: chemical shifts (2b, 2e, 2f), the JCF
couplings (2c), the symmetry of the compound (2d) and the
chemical shifts can produce second-order effects in the
coupled carbon-13 depending on the field strength used,
these only apply to the protic carbons, whereas, the coupled
patterns for the quaternary carbons are first order). The
2
J
CH couplings from the C
With these assignments in place, the focus returned
to the regiochemistry of C and C . From the coupled
3
-methyl for (3g).
1
2
3
3
C
2
carbon appears as a triplet where
J
24
D
J
26 D 4.5.
1
3
3
C data, the three-bond J couplings were measured and
This trend was observed for compounds 2d–2f. Owing
to overlap, the values for compound 2c could not be
Table 1. Regioisomer ratio and yields
measured. All (2c–2f) had bromine substitution on the
3
C
1
carbon and yielded the large diagnostic
J
15 values
R
2 : 3
Yield %
3
(
11.4–13.1). There was some expected variation in the J35
2
2
2
2
2
2
3
a
b
c
d
e
f
F
Cl
CF3
99 : 1
95 : 5
94 : 6
90 : 10
90 : 10
92 : 8
1 : 99
84
62
89
73
75
54
85
3
couplings (9.0–12.5) at C related to the electronegativity
of the R group; the least electronegative groups, CH
3
and
3
CF
3
, showed the smallest J35 coupling of 7.6 and 8.3 Hz,
Br
respectively. For the methyl analog, compound 3g, the C
carbon revealed a small J15 coupling of 7.6 Hz relative to the
1
3
OMe
CO2Me
CH3
large values observed for the other isomers. This indicated
g
that the carboxylic acid group was now on the C
Additionally, as noted previously, the J to the carbonyl was
1
carbon.
3
observed.
Table 2. Three-bond (3JCH) coupling constants for the major
regioisomer
C1
C2
C3
R
3J15
3J24
3J26
3J35
2
2
2
2
2
2
3
a
b
c
d
e
f
F
Cl
CF3
12.5
13.1
11.8
12.5
13.1
11.4
7.6
4.5
5.5
a
6.2
5.2
4.5
5.5
a
6.2
5.2
12.5
12.5
8.3
12.5
9.3
Br
OMe
CO2Me
CH3
b
b
6.9
9.8
5.5
9.8
9.0
7.6
c
c
g
a
Owing to overlap, the couplings could not be measured.
Using coupled 13C with selective irradiation of the C4 –H,
b
unequivocal assignments of the couplings were made.
Figure 1. (a) Aromatic region of 13C spectrum of 2b with
labeled quaternary carbons; (b) Corresponding coupled 13C
spectrum with 3JCH coupling constants and multiplicities.
c
A coupled 13C with selective irradiation of the C3 –Me was
used to obtain these measurements.
Copyright 2006 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2006; 44: 1041–1043
DOI: 10.1002/mrc