Strongly Directing Substituents in the Radical Arylation of Substituted Benzenes

Article abstract of DOI:10.1021/acs.joc.6b01840

Although general interest in radical arylation reactions has grown rapidly in recent years, poor regioselectivities and the need to use a large excess of the radical-accepting arene have hindered their application to substituted benzenes. We now describe experimental and computational investigations into the substituent effects that lead to regioselective addition based on the recent discovery of anilines as outstanding substrates for radical arylations.

Full text of DOI:10.1021/acs.joc.6b01840

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Article
Strongly directing substituents in the radical arylation of substituted benzenes
Josefa Hofmann, Timothy Clark, and Markus Rolf Heinrich
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01840 • Publication Date (Web): 19 Sep 2016
Downloaded from http://pubs.acs.org on September 23, 2016
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Strongly directing substituents in the radical arylation of
substituted benzenes
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Josefa Hofmann,a Timothy Clark,b Markus R. Heinricha,*
aDepartment of Chemistry and Pharmacy, Pharmaceutical Chemistry, FriedrichꢀAlexanderꢀ
Universität ErlangenꢀNürnberg, Schuhstraße 19, 91052 Erlangen, Germany
bComputerꢀChemieꢀCentrum and Interdisciplinary Center for Molecular Materials, Friedrichꢀ
AlexanderꢀUniversität ErlangenꢀNürnberg, Nägelsbachstraße 25, 91052 Erlangen, Germany.
markus.heinrich@fau.de
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
ABSTRACT:
Although the general interest in radical arylation reactions has grown rapidly in recent years,
poor regioselectivities and the need to use a large excess of the radicalꢀaccepting arene have
hindered their application to substituted benzenes. We now describe experimental and
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computational investigations into the substituent effects that lead to regioselective addition
based on the recent discovery of anilines as outstanding substrates for radical arylations.
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Introduction
The GombergꢀBachmann reaction, which dates back to 1924,1 represents one of the
fundamental transformations in aryl radical chemistry.2,3 Starting from aryl diazonium salts as
classical radical sources,4 and arenes or heteroarenes acting as radical acceptors, a broad range
of biaryls can be obtained in a reaction5 whose result is comparable to an arylꢀCꢀH
activation.6 Recent versions of the GombergꢀBachmann reaction rely on a photocatalytic
conversion of diazonium salts,7 on aryl radical generation from chloroꢀ, bromoꢀ or
iodobenzenes in the presence of strong bases,8 on arylhydrazines,9 or on the in situ
diazotization of anilines.10
Although GombergꢀBachmann reactions could, on this basis, be very attractive due to the
cheap and readily available starting materials, their application, also in the newly developed
versions, has remained mostly limited to unsubstituted benzene and selected heteroarenes.7ꢀ10
Explanations for this are both the relatively slow addition of aryl radicals to benzene and its
derivatives,11 which requires the use of the radical acceptor in large excess, and the low
regioselectivities observed for most substituted benzenes.5,12 Heteroarenes, on the other hand,
and hereby especially electronꢀrich furans and pyrroles, show increased reactivity towards
aryl radicals and far higher regioselectivities.3e,7,8,13
The recent extension of the GombergꢀBachmann reaction to anilines provided motivation to
investigate the suitability of substituted benzenes as aryl radical acceptors in more detail.14
Both in these reactions, and in consecutively developed arylations with arylhydrazines,15
anilines showed outstanding properties as aryl radical acceptors in two ways: Firstly, the aryl
radical addition to anilines was found to proceed about one order of magnitude faster than to
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classically favored substrates such as nitrobenzenes or anisoles,15a and secondly, comparably
high regioselectivites were obtained.14,15
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Little attention has been paid in the literature over the last decades to how substituents affect
the regioselectivity in radical arylations of benzene derivatives with the last comprehensive
review dating back to 1973.12 Early studies had shown that a variation of substituents on the
attacking phenyl radical does influence the substrate selectivity in competition experiments
with nitrobenzene and benzene, but not the regioselectivity of the substitution at
nitrobenzene.12,16 Such observations led to a discussion of “polarity of free radicals”.17 All
substituents on the radical acceptor were considered to be weakly activating,12 and
comparably high regioselectivities were only obtained for particular combinations of donorꢀ
substituted phenyl radicals with acceptorꢀsubstituted benzenes, or vice versa.18 As these
studies have shown that it is particularly difficult to achieve regioselectivity with aryl radicals
such as the 4ꢀchlorophenyl radical,19 this radical was chosen for the experiments reported in
this communication. Based on experimental results, we will give insight into the fundamental
question as to whether kinetic or thermodynamic factors play a decisive role in the addition
step. So far, the low selectivity of phenyl radicals in arylations of substituted benzenes has
been attributed to a “little development of the new bond at the transition state”,12 so that “the
stability of the product radicals is also of importance”.20
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Results and Discussion
Three recently developed protocols, starting either from 4ꢀchlorophenyldiazonium chloride
(1) or 4ꢀchlorophenylhydrazine (2), were chosen to collect the required experimental data, as
these procedures allow in particular the radical arylation of anilines (Scheme 1).14a,15a,15b All
reactions were carried out under air atmosphere to ensure that rearomatization does not
become an influential factor.21 Moreover, the aromatic substrates 3ꢀ7 were not used as
solvents, but in a lower excess of 10ꢀ20 equivalents. In this way, the results also give an
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impression on the synthetic applicability and the relative reactivity of the arenes can be
evaluated, as the aryl radicals are not trapped quantitatively.
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Scheme 1. Reaction conditions A, B and C used for radical arylations.
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Tables 1ꢀ3 summarize the yields and product ratios obtained with anilines 3 (Table 1), phenols
4 and phenylethers 5 (Table 2), and with benzonitriles 6 and nitrobenzene (7a) (Table 3). The
conditions A, B and C refer to the reactions shown in Scheme 1. If available, further data from
literature (conditions DꢀI) have been added for comparison of regioselectivities.
Table 1. Arylation of aniline (3a) and 4ꢀfluoroaniline (3b)
conditions
biphenyl
isomers
A
80%
76
ꢀꢀ
26
B
54%
76
ꢀꢀ
24
C
60%
85
Da
62%
75
2 (8a)
3 (8a´)
4 (8a´´)
ꢀꢀ
ꢀꢀ
15
25
68%
100
ꢀꢀ
53%
100
ꢀꢀ
55%
100
ꢀꢀ
61%
100
--
2 (8b)
3 (8b´)
aConditions D: See ref. 15c.
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Table 2. Arylation of phenol (4a), 4ꢀfluorophenol (4b), anisole (5a) and 4ꢀfluoroanisole (5b).
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5
6
7
isomers
conditions
Ea
57% 58% 62%
biphenyl
A
B
C
Fb
Gc
¤
2 (9a)
3 (9a´)
4 (9a´´)
70
ꢀꢀ
76 68
ꢀꢀ ꢀꢀ
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30
24 32
9
49% 40% 56%
100 100 100
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2 (9b)
3 (9b´)
ꢀꢀ
ꢀꢀ ꢀꢀ
31% 34% 35%
59% 48%
68 75
2 (10a)
3 (10a´)
4 (10a´´)
64
17
19
73 73
12 12
15 15
17
15
12
13
36% 31% 36%
2 (10b)
3 (10b´)
72
28
88 89
12 11
aConditions E: Reaction of 4ꢀcyanophenyl radical with phenolate or 4ꢀbromophenolate, see ref. 22. bConditions F: Reaction of 4ꢀ
methylphenyl radical with anisole, see ref. 8e. cConditions G: Reaction of 3ꢀchlorophenyl radical with anisole, see ref. 5.
Table 3. Arylation of benzonitrile (6a), 4ꢀfluorobenzonitrile (6b) and nitrobenzene (7a).
conditions
biphenyl
isomers
A
49%
48
16
36
B
29%
62
C
62%
52
Ha
58%
51
Ib
2 (11a)
3 (11a´)
4 (11a´´)
11
15
14
35
27
33
20%
61
39
13%
67
49%
77
2 (11b)
3 (11b´)
33
23
36%
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14
52%
42
38%
41
30%
55
4
2 (12a)
3 (12a´)
4 (12a´´)
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aConditions H: See ref. 5; bConditions I: Reaction of phenyl radical with nitrobenzene, see refs. 23,24.
A comparison of the average yields obtained with the monoꢀsubstituted radical acceptors 3a,
4a, 5a, 6a and 7a under all available conditions gave the following trend in overall reactivity:
PhꢀNH2 > PhꢀOꢀ > PhCN > PhNO2 ≈ PhOMe, which is is in agreement with earlier
experimental studies.15a Note that, under the reaction conditions B, C and E, phenol (4a) and
4ꢀfluorophenol (4b) are present as phenolates.
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In terms of regioselectivity, only the anilines 3a-c (Table 1) and phenolates of 4a,b (Table 2,
entries 1 and 2) were able to suppress the formation of metaꢀisomers (3ꢀisomers), independent
of the presence of a substituent in paraꢀposition. Arylation of the anisoles 5a,b (Table 2,
entries 3 and 4), benzonitriles 6a,b and nitrobenzene (7a), in contrast, led to all basically
possible regioisomers. Remarkably, the effect of the electronꢀdonating methoxy group differs
from those of the electronꢀwithdrawing cyano and nitro groups, as anisole (5a) showed a
preference for the 2ꢀisomer (2/3/4 = 71:14:15), whereas benzonitrile (6a) and nitrobenzene
(7a) were attacked more frequently in 4ꢀposition via average selectivities of 2/3/4 = 53:14:33
and 2/3/4 = 45:13:42, respectively.25 This effect may be related to a threeꢀelectron interaction
between the radical and the oxygen atom of the methoxy group in the transition state. The
importance of the 4ꢀposition in arylations of electronꢀdeficient arenes also became obvious
from the significant decrease in yield caused by blocking this position by a fluorine
substituent (Table 3, entries 1 and 2). Arylation experiments with 4ꢀfluoronitrobenzene are not
included since they are complicated by competing nucleophilic substitution.
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In the next step, densityꢀfunctional theory (DFT) calculations were carried out to determine
whether the experimentally observed substituent effects in radical arylations could be
predicted computationally. It was of particular interest in this respect to evaluate the influence
of the transition state, TS compared to the stabilization of the cyclohexadienyl radical adduct
CA (Scheme 2).
All calculations were performed with Gaussian09, revision C.01.26 Geometries were
optimized using the B3LYP functional,27,28 and the augꢀccꢀpVDZ basis set.29,30 Structures
were shown to be minima or transition states by calculating the normal vibrations within the
harmonic approximation. Energies relative to the separated reactants are reported including
vibrational zeroꢀpoint energy taken from these calculations. B3LYP/augꢀccꢀpVDZ
calculations have been shown to underestimate radical activation energies by several kcal
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mol−1 in comparison to coupledꢀcluster reference calculations,31 although we expect the trends
to be correct for such closely related reactions.
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Scheme 2. Reaction course.
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Early calculations by James and Suart32 on the hydrogen atom addition to benzene gave an
activation energy of ca. 4 kcal mol−1 and suggested that the addition step is exothermic by ꢀ28
kcal mol−1. From these values, the activation energy for the attack of a phenyl radical onto
benzene was estimated to > 3 kcal mol−1 and the related reaction energy to ꢀ18 kcal mol−1.33
The results from our calculations are summarized in Figure 1 and Tables 4 and 5.
Figure 1. Schematic reaction profiles for the arylation of aniline and benzene with the 4ꢀ
chlorophenyl radical.
activation
barrier
complexation
energy
TS
heat of
reaction
CA
The data obtained for the arylation of aniline (3a) and benzene with the 4ꢀchlorophenyl
radical revealed that the radical attack on electronꢀrich aromatic systems proceeds via a preꢀ
reaction complex that has not been considered previously (Figure 2). One of the two more
polarized CꢀH bonds in ortho position to the radical center points to the πꢀsystem of the
radical accepting aniline. As shown by the activation energies summarized in Table 4, this
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complex plays an exceptional role in the arylation of phenolate ions. It is likely that both
specific solvation and counterionꢀeffects are important for these reactions, but considering
explicit solvent molecules and/or counterions would be outside the scope of this article.
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Figure 2. Preꢀreaction complex formed on attack of the 4ꢀchlorophenyl radical on aniline
(left) and on the orthoꢀposition of the phenolate anion (right). Distances are given in Å.
Table 4. Calculated activation barriers for the attack of a 4ꢀchlorophenyl radical.
directing
substituent
activation barriera for an attack in
R1 =
2ꢀposition
3ꢀposition
5.0
ꢀ2.3
5.4
4.8
5.6
4ꢀposition
3a: NH2
4a: O−
5a: OCH3
6a: CN
7a: NO2
benzene: H
3.3
ꢀ9.8b
3.7
4.5
3.8
4.1
ꢀ9.2
4.7
4.6
4.3
5.3
aRelative to the separated reactants (B3LYP/augꢀccꢀpVDZ + zeroꢀpoint energy). bA preꢀreaction complex with a binding energy of ꢀ9.8 kcal
mol−1 is formed (see Figure 2). The activation barrier from this complex to the 2ꢀisomer is essentially zero.
Table 5. Calculated heats of reaction for the attack of a 4ꢀchlorophenyl radical.
radical
acceptor
R1 = , R2 =
3a: NH2, H
3b: NH2, F
4a: O−, H
heats of the addition for an attack in
2ꢀposition
ꢀ22.8
3ꢀposition
ꢀ19.3
ꢀ20.6
ꢀ22.0
ꢀ22.3
ꢀ18.9
ꢀ19.6
ꢀ20.3
ꢀ19.9
ꢀ19.2
ꢀ19.7
4ꢀposition
ꢀ21.0
ꢀ24.0
ꢀ35.0b
ꢀ37.8b
ꢀ22.3
ꢀ23.1
ꢀ22.1
ꢀ27.7
ꢀ19.9
ꢀ20.6
ꢀ23.5
4b: O−, F
5a: OCH3, H
5b: OCH3, F
6a: CN, H
6b: CN, F
7a: NO2, H
benzene: H
ꢀ21.9
ꢀ22.6
aRelative (B3LYP/augꢀccꢀpVDZ + zeroꢀpoint energy) heats of addition and e to the separated reactants. A preꢀreaction complex with a
b
binding energy of ꢀ9.8 kcal mol−1 is formed. The activation barrier from this complex to the orthoꢀproduct is essentially zero.
The activation energies (relative to the separated reactants) for the neutral systems lie in range
from 3.3 to 5.6 kcal mol−1, consistent with the estimated value of > 3 kcal molꢀ1 (Table 4). The
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calculated heats of reaction lie in the range of −18.9 to −24.0 kcal mol−1, again consistent with
the experimental estimate of −18 kcal mol−1 for the addition of the phenyl radical to
benzene.33,34 The introduction of the fluorine atom in 4ꢀposition generally led to a weak
relative stabilization in the range of ꢀ0.3 to ꢀ1.3 kcal molꢀ1. A comparison of the heats of
reaction to those of benzene (ꢀ19.7 kcal molꢀ1) provided support for the longꢀstanding
assumption that all substitutents on the radical acceptor are weakly activating, independent of
their electronꢀdonating or withdrawing character. The activating effect is thereby much more
pronounced for 2ꢀ and 4ꢀpositions than for 3ꢀpositions.
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Figure 3 shows a plot of the calculated heats of reaction against the activation energies. The
correlation between the two quantities is good, so that we can conclude that the radical
addition is compatible with the BellꢀEvansꢀPolanyi principle.35 However, the 3- and 4-nitro
and 2-cyano cases deviate significantly and have been omitted from the correlation (indicated
in grey in Figure 3). Quite generally, the πꢀacceptor substituents lie above the correlation line
(i.e. the activation energies are higher than would be expected from the heat of reaction).
Nevertheless, we can conclude that the differences in calculated activation barriers for the
radical addition to substituted benzenes are largely controlled by the stabilization of the
product radical without significant specific kinetic effects. The slope of the calculated
regression line is approximately 0.5, suggesting that radical stabilization effects by the
substituents are approximately 50% developed in the transition states. The πꢀacceptors are
less well able to stabilize the transition states than the other substituents.
Figure 3. Calculated activation energies plotted vs. the calculated heats of reaction (all kcal
mol−1) for the addition of the 4ꢀchlorophenyl radical to neutral monosubstituted benzenes.a
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aThe regression line and the correlation equation do not include the two dataꢀpoints plotted in grey, which represent significant outliers, and
are both associated with strong πꢀacceptors, as discussed in the text.
Figure 4. Calculated and experimental yields of the individual neutral arylated products.a
aThe black filled circles and the regression line and equation are those obtained from the calculated gasꢀphase activation energies assuming
kinetic control with the addition as the rateꢀdetermining step. The red open circles indicate the predicted yields obtained by assuming
thermodynamic control of the product radicals. The line is that for perfect 1:1 agreement.
The question of whether the product distributions are best described by kinetic or
thermodynamic control of the addition reactions can be answered by comparing calculated
product distributions with those observed experimentally. Figure 4 shows a plot of the
calculated (from transitionꢀstate theory) % yield for each product of the addition of pꢀ
chlorophenyl radical to the monosubstituted benzenes vs. the experimental results expressed
as the mean of the product distributions for all reaction conditions with error bars that cover
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the range found experimentally. The agreement (RMSE = 15%) is good, so that we can
conclude that the product distributions are kinetically controlled. The corresponding
correlation obtained by assuming thermodynamic control gives a significantly worse RMSE
(21%). The product yields calculated assuming thermodynamic control are shown as red open
circles in Figure 4. Note that a statistical factor of 2:2:1 has been used for the 2ꢀ, 3ꢀ, and 4ꢀ
isomers, respectively, in order to take the fact that there is only one 4ꢀposition available for
each substituted benzene into account. The assumption of kinetic control for the arylation of
nitrobenzene leads to a predicted 2/4ꢀ ratio of 79:16, representing the strongest deviation in
this series, compared to 30:69 for thermodynamic control. As experiment (Table 3) gives
approximately equal yields of the two isomers with a slight preference for the 2ꢀisomer, the
arylation of nitrobenzene can be considered to proceed with a stronger thermodynamic
influence.
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The combination of our experimental and theoretical results therefore suggests that the
addition of aryl radicals to substituted benzenes largely takes place under kinetic control with
the radical addition as the rateꢀdetermining step and that substituent effects in the product
radicals are approximately 50% effective in the transition states. These conclusions are
consistent with those of an earlier theoretical study by Zhang34 on the arylation of aniline.
Zhang concluded that aryl radical addition to neutral anilines is the rateꢀdetermining step in a
kinetically controlled reaction, whereas arylation to protonated anilines may be
thermodynamically controlled.
Note that, even though the calculations can predict the product distributions well, the
calculated activation energies do not agree completely with the accepted reactivity series Phꢀ
NH2 > PhꢀOꢀ > PhCN > PhNO2 ≈ PhOMe;15a,26,36 in order of increasing calculated activation
energy for the most reactive isomer, the calculations predict Ph−NH2 > Ph−OCH3 ≈ Ph−NO2
> Ph−CN > benzene. PhꢀOꢀ cannot be treated on the same footing as the neutral systems
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because ionꢀpairing and solvation effects are likely to be dominant in determining reactions
rates for the phenolate anion.
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Conclusions
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In summary, it has been shown that DFT calculations can be used to predict experimental
product distributions in radical arylations of benzenes. Although not as regioselective as
arylations of alkenes, the aryl radical addition to substituted benzenes still proceeds with a
high degree of kinetically controlled selectivity. Substituent effects in the resulting
cyclohexadienyl radical adduct are reflected to about 50% in the transition state. All reactions
pass through a preꢀreaction complex, which was found to be particularly strongly stabilized in
the case of an aryl radical attack on phenolate ions. These results give more detailed insight
into the longꢀstanding question of how substituents affect the regioselectivity in radical
arylations of substituted benzenes.
Experimental section
1
General Experimental: Solvents and reagents were used as received. H NMR spectra
were recorded on 360 and 600 MHz spectrometers using CDCl3 and CD3OD as solvents
referenced to TMS (0 ppm), CHCl3 (7.26 ppm) and CHD2OD (3.31 ppm). Chemical shifts
are reported in parts per million (ppm). Coupling constants are in Hertz (J Hz). The
following abbreviations are used for the description of signals: s (singlet), d (doublet), dd
(double doublet), t (triplet), q (quadruplet), m (multiplet). 13C NMR spectra were recorded
at 90.6 and 150.9 MHz in CDCl3 and CD3OD using CDCl3 (77.0 ppm) and CD3OD (49.5
19
ppm) as standard. Chemical shifts are given in parts per million (ppm). F NMR spectra
were recorded at 338.8 MHz using CFCl3 (0 ppm) or C6F6 (ꢀ164.9 ppm) as standard. Mass
spectra were recorded using electron impact (EI). Analytical TLC was carried out on
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Merck silica gel plates using short wave (254 nm) UV light and Ninhydrin to visualise
components. Silica gel (Kieselgel 60, 40ꢀ63 ꢁm, Merck) was used for flash column
chromatography. Yields obtained after purification are summarized in Tables 1ꢀ3 in the
article.
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General procedure for the synthesis of biphenyls under Gomberg-Bachmann conditions
(conditions A): Preparation of the aryl diazotate by diazotization and addition of base: A
degassed solution of sodium nitrite (20.0 mmol, 1.38 g) in water (10 mL) was added dropwise
to an iceꢀcooled degassed solution of the aniline (20.0 mmol) in hydrochloric acid (3
20 mL) and water (20 mL) over a period of 15 min. The clear solution was stirred for 20 more
minutes at 0 °C. An aliquot of this 0.4 aryldiazonium chloride solution (2.00 mmol,
5.00 mL) was treated with a preꢀcooled aqueous solution of sodium hydroxide (4 , 3 mL).
N,
M
N
The resulting solution/suspension of the aryl diazotate was then used for the aryl–aryl
coupling. Radical arylation of substituted benzenes with a previously prepared aryl
diazotate: The previously prepared solution/suspension of the aryl diazotate (2.00 mmol,
5.00 mL) was added dropwise to the substituted benzene (20.0 mmol) at 75–95 °C under
vigorous stirring over a period of 10–15 min. After the addition was complete, the mixture
was left to stir for 10 more minutes. The resulting reaction mixture was then extracted with
organic solvents (e.g. diethyl ether or ethyl acetate, 3 × 75 mL). The combined organic phases
were washed with saturated aqueous sodium chloride and dried over sodium sulfate. The
solvent was removed under reduced pressure and the resulting product was dried in vacuo.
Depending on the product, further purification was carried out by distillation under reduced
pressure or column chromatography on silica gel.
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General procedure for the synthesis of biphenyls with MnO2 under single phase
conditions (conditions B): To a stirred suspension of the substituted benzene (20.0 mmol)
and MnO2 (435 mg, 5.00 mmol) in acetonitrile (5 mL) at r.t., a solution of the arylhydrazine
(1.00 mmol) in acetonitrile (2 mL) was added dropwise over a period of 1 h. After completion
of the reaction, as monitored by TLC, the reaction mixture was filtered over Celite. The filter
cake was further washed with ethyl acetate and the solvents were removed under reduced
pressure. The remaining benzene derivative was removed by Kugelrohr distillation, and the
products were purified by silica gel chromatography.
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General procedure for the synthesis of biphenyls from arylhydrazine hydrochlorides
under air (conditions C): A mixture of the substituted benzene (20.0 mmol) and aqueous
sodium hydroxide (1 N, 1.0 ml) was heated to 60–90 °C and the arylhydrazine hydrochloride
was added portion wise in ten batches over a period of 9 hours. The reaction was completed
after 24 hours at the given temperature, as monitored by TLC. After removal of water under
reduced pressure, the remaining aniline was recovered by Kugelrohr distillation, and the crude
biphenyls were purified by column chromatography on silica gel.
4'ꢀChlorobiphenylꢀ2ꢀamine (8a) and 4’ꢀchlorobiphenylꢀ4ꢀamine (8a´´) were prepared under
the conditions A, B and C. Separation and purification by column chromatography (hexane /
ethyl acetate 10:1) gave 8a and 8a´´ as dark solids. 4'-Chlorobiphenyl-2-amine (8a): Rf = 0.6
1
(hexane/EtOAc = 4:1) [UV]; mp = 65ꢀ67 °C; H NMR (600 MHz, CDCl3) δ 4.09 (bs, 2 H),
6.80 (dd, J = 1.1 Hz, J = 8.0 Hz, 1 H), 6.85 (dt, J = 1.1 Hz, J = 7.5 Hz, 1 H), 7.10 (dd,
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J = 1.6 Hz, J = 7.6 Hz, 1 H), 7.15ꢀ7.21 (m, 1 H), 7.40 (s, 4 H); C NMR (91 MHz, CDCl3) δ
115.7 (CH), 118.8 (CH), 126.3 (Cq), 128.8 (CH), 129.0 (2 × CH), 130.3 (CH), 130.4
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(2 × CH), 133.1 (Cq), 137.9 (Cq), 143.4 (Cq); MS (EI) m/z (%): 205 (35) [37ClꢀM+], 203 (100)
[35ClꢀM+], 168 (45), 167 (75); HRMS (ESI) calcd for C12H11ClN [M++H]: 204.0575, found:
204.0569. 4'-Chlorobiphenyl-4-amine (8a´´): Rf = 0.3 (hexane/EtOAc = 4:1) [UV]; mp = 118ꢀ
9
1
120 °C; H NMR (360 MHz, CDCl3) δ 4.09 (bs, 2 H), 6.81 (d, J = 8.6 Hz, 2 H), 7.35 (d,
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J = 8.5 Hz, 2 H), 7.39 (d, J = 8.6 Hz, 2 H), 7.45 (d, J = 8.7 Hz, 2 H); C NMR (151 MHz,
CDCl3) δ 115.4 (2 × CH), 127.5 (2 × CH), 127.8 (2 × CH), 128.7 (2 × CH), 130.2 (Cq), 132.1
(Cq), 139.6 (Cq), 146.1 (Cq); MS (EI) m/z (%): 205 (30) [37ClꢀM+], 203 (100) [35ClꢀM+], 167
(18); HRMS (ESI) calcd for C12H11ClN [M++H]: 204.0575, found: 204.0582. The spectral
data obtained are in agreement with those reported in literature.15b
4’ꢀChloroꢀ5ꢀfluorobiphenylꢀ2ꢀamine (8b) was prepared under the conditions A, B and C.
Purification by column chromatography (hexane / ethyl acetate 10:1) gave 8b as a dark brown
oil. 4’-Chloro-5-fluorobiphenyl-2-amine (8b): Rf = 0.6 (hexane/EtOAc = 4:1) [UV]; 1H NMR
(360 MHz, CDCl3) δ 3.54 (bs, 2 H), 6.69 (dd, JHF = 4.7 Hz, J = 8.5 Hz, 1 H), 6.83 (dd,
J = 2.8 Hz, JHF = 9.0 Hz, 1 H), 6.88 (ddd, J = 3.0 Hz, JHF = 8.1 Hz, J = 8.7 Hz, 1 H), 7.37 (d,
J = 8.7 Hz, 2 H), 7.42 (d, J = 8.7 Hz, 2 H); 13C NMR (151 MHz, CDCl3) δ 115.3 (d,
JCF = 22.2 Hz, CH), 116.5 (d, JCF = 22.6 Hz, CH), 116.7 (d, JCF = 7.7 Hz, CH), 127.4 (d,
JCF = 7.2 Hz, Cq), 129.1 (2 × CH), 130.3 (2 × CH), 133.6 (Cq), 136.9 (d, JCF = 1.7 Hz, Cq),
139.4 (d, JCF = 2.2 Hz, Cq), 156.4 (d, JCF = 236.9 Hz, Cq); MS(EI) m/z (%):224 (6), 223 (29)
[37ClꢀM+], 222 (18), 221 (100) [35ClꢀM+], 220 (10), 219 (20), 187 (8), 186 (45), 185 (60), 184
(13), 159 (5), 157 (7), 126 (6), 110 (10), 93 (37); HRMS (EI) calcd for C12H9ClFN [M+]:
221.0407, found: 221.0409. The spectral data obtained are in agreement with those reported in
literature.15b
4'ꢀChloroꢀ2ꢀhydroxybiphenyl (9a) and 4'ꢀchloroꢀ4ꢀhydroxybiphenyl (9a´´) were prepared
under the conditions B and C. Purification by column chromatography (hexane/EtOAc = 10:1
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→ 4:1) gave a mixture of 9a and 9a´´. 4'-Chloro-2-hydroxybiphenyl (9a): Rf = 0.5
1
(hexane/EtOAc = 4:1) [UV]; H NMR (600 MHz, CDCl3) δ 5.06 (bs, 1 H), 6.95 (dd,
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J = 0.9 Hz, J = 8.1 Hz, 1 H), 6.99 (dt, J = 1.2 Hz, J = 7.5 Hz, 1 H), 7.21 (dd, J = 1.7 Hz,
J = 7.6 Hz, 1 H), 7.23ꢀ7.29 (m, 1 H), 7.41 (d, J = 8.7 Hz, 2 H), 7.44 (d, J = 8.6 Hz, 2 H). 4'-
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Chloro-4-hydroxybiphenyl (9a´´): Rf = 0.5 (hexane/EtOAc = 4:1) [UV]; H NMR (600 MHz,
CDCl3) δ 4.82 (bs, 1 H), 6.90 (d, J = 8.7 Hz, 2 H), 7.37 (d, J = 8.7 Hz, 2 H), 7.43 (d,
J = 8.7 Hz, 2 H), 7.45 (d, J = 8.7 Hz, 2 H). The spectral data obtained are in agreement with
those reported in literature.37,38
4’ꢀChloroꢀ5ꢀfluorobiphenylꢀ2ꢀol (9b) was prepared under the conditions B and C. Purification
by column chromatography (dichloromethane 100%) gave 9b as a light yellow oil. 4’-Chloro-
1
5-fluorobiphenyl-2-ol (9b): Rf = 0.3 (DCM) [UV]; H NMR (360 MHz, CDCl3) δ 4.70 (bs,
1 H), 6.74ꢀ6.78 (m, 1 H), 6.85 (dd, J = 3.1 Hz, JHF =6.2 Hz, 1 H), 7.01 (dd, J = 8.8 Hz,
13
JHF = 10.0 Hz, 1 H), 7.40 (d, J = 8.7 Hz, 2 H), 7.46 (d, J = 8.6 Hz, 2 H); C NMR (91 MHz,
CDCl3) δ 115.5 (d, JCF = 8.2 Hz, CH), 116.5 (d, JCF = 3.1 Hz, CH), 116.9 (d, JCF = 25.0 Hz,
CH), 127.9 (d, JCF = 7.7 Hz, Cq), 129.3 (2 × CH), 130.3 (2 × CH), 134.3 (Cq), 134.6 (Cq),
148.3 (Cq), 156.0 (d, JCF = 239.2 Hz, Cq); HRMS (EI) calcd for C12H9ClFN [M+]: 221.01779,
found: 221.01749. The spectral data obtained are in agreement with those reported in
literature.39
4'ꢀChloroꢀ2ꢀmethoxybiphenyl (10a), 4'ꢀchloroꢀ3ꢀmethoxybiphenyl (10a´) and 4'ꢀchloroꢀ4ꢀ
methoxybiphenyl (10a´´) were prepared under the conditions A, B and C. Purification by
column chromatography (hexane/EtOAc = 12:1 → 4:1) gave a mixture of 10a, 10a´ and
1
10a´´. 4'-Chloro-2-methoxybiphenyl (10a): Rf = 0.2 (hexane) [UV]; H NMR (360 MHz,
CDCl3) δ 3.81 (s, 3 H), 6.98 (dd, J = 0.9 Hz, J = 8.3 Hz, 1 H), 7.02 (dt, J = 1.1 Hz,
J = 7.5 Hz, 1 H), 7.28 (dd, J = 1.8 Hz, J = 7.6 Hz, 1 H), 7.30ꢀ7.34 (m, 1 H), 7.36 (d, J = 8.8
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Hz, 2 H), 7.46 (d, J = 8.8 Hz, 2 H). 4'-Chloro-3-methoxybiphenyl (10a´): Rf = 0.2 (hexane)
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[UV]; H NMR (600 MHz, CDCl3) δ 3.86 (s, 3 H), 6.91 (ddd, J = 0.9 Hz, J = 2.4 Hz,
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J = 8.2 Hz, 1 H), 7.08 (dd, J = 1.9 Hz, J = 2.4 Hz, 1 H), 7.14 (ddd, J = 0.9 Hz, J = 1.9 Hz,
J = 7.6 Hz, 1 H), 7.35 (d, J = 7.9 Hz, 1 H), 7.40 (d, J = 8.7 Hz, 2 H), 7.51 (d, J = 8.7 Hz,
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2 H). 4'-Chloro-4-hydroxybiphenyl (10a´´): Rf = 0.2 (hexane) [UV]; H NMR (600 MHz,
CDCl3) δ 3.85 (s, 3 H), 6.97 (d, J = 8.9 Hz, 2 H), 7.37 (d, J = 8.7 Hz, 2 H), 7.45ꢀ7.50 (m,
4 H). The spectral data obtained are in agreement with those reported in literature.40ꢀ42
4'ꢀChloroꢀ5ꢀfluoroꢀ2ꢀmethoxybiphenyl (10b) and 4'ꢀchloroꢀ6ꢀfluoroꢀ3ꢀmethoxybiphenyl
(10b´) were prepared under the conditions A, B and C. Separation and purification by column
chromatography (hexane / ethyl acetate 10:1) gave 10b and 10b´ as a brown solids. 4'-Chloro-
1
5-fluoro-2-methoxybiphenyl (10b): Rf = 0.6 (hexane/EtOAc = 4:1) [KMnO4]; H NMR (360
MHz, CDCl3) δ 3.78 (s, 3 H), 6.88ꢀ6.94 (m, 1 H), 6.97ꢀ7.04 (m, 2 H), 7.38 (d, J = 8.9 Hz,
2 H), 7.46 (d, J = 8.8 Hz, 2 H);13C NMR (151 MHz, CDCl3) δ 56.2 (CH3), 112.4 (d,
JCF = 8.3 Hz, CH), 114.6 (d, JCF = 22.6 Hz, CH), 117.2 (d, JCF = 23.5 Hz, CH), 128.3
(2 × CH), 128.6 (Cq), 130.7 (2 × CH), 133.4 (Cq), 135.8 (d, JCF = 1.6 Hz, Cq), 152.5 (d,
JCF = 8.1 Hz, Cq), 157.3 (d, JCF = 240.4 Hz Cq); MS(EI) m/z (%): 237 (14), 236 (100), 221
(19), 186 (98), 157 (24); HRMS (EI) calcd for C13H10ClFO [M+]: 236.0404, found: 236.0404.
1
4'-Chloro-5-fluoro-2-methoxybiphenyl (10b´): Rf = 0.5 (hexane/EtOAc = 4:1) [KMnO4]; H
NMR (360 MHz, CDCl3) δ 3.83 (s, 3 H), 6.83ꢀ6.87 (m, 1 H), 6.88ꢀ6.94 (m, 1 H), 7.08 (dd,
J = 8.9 Hz, JHF = 10.0 Hz, 1 H), 7.42 (d, J = 8.9 Hz, 2 H), 7.47 (d, J = 8.8 Hz, 2 H); 13C
NMR (91 MHz, CDCl3) δ 55.8 (CH3), 114.8 (Cq), 115.3 (d, JCF = 8.0 Hz, CH), 116.8 (d,
JCF = 23.5 Hz, CH), 120.4 (d, JCF = 7.9 Hz, CH), 129.2 (2 × CH), 130.4 (2 × CH), 133.9 (Cq),
135.7 (d, JCF = 1.6 Hz, Cq), 146.3 (d, JCF = 20.2 Hz, Cq), 153.8 (d, JCF = 240.4 Hz, Cq);
MS(EI) m/z (%): 237 (8), 236 (14), 235 (4), 234 (9), 199 (5), 193 (7), 163 (9), 137 (6), 127
(5), 117 (5), 76 (6), 57 (4), 53 (6), 43 (4) 27 (6), 18 (100); HRMS (EI) calcd for C13H10ClFO
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[M+]: 236.0404, found: 236.0405. The spectral data obtained are in agreement with those
reported in literature.15b
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4'ꢀChlorobiphenylꢀ2ꢀcarbonitrile (11a), 4'ꢀchlorobiphenylꢀ3ꢀcarbonitrile (11a´) and 4’ꢀ
chlorobiphenylꢀ4ꢀcarbonitrile (11a´´) were prepared under the conditions A, B and C.
Purification by column chromatography (hexane/EtOAc = 10:1 → 4:1) gave a mixture of 11a,
11a´ and 11a´´. 4'-Chlorobiphenyl-2-carbonitrile (11a): Rf = 0.5 (hexane/EtOAc = 4:1) [UV];
1H NMR (600 MHz, CDCl3) δ 7.44–7.51 (m, 6 H), 7.65 (dt, J = 1.4 Hz, J = 8.5 Hz, 1 H),
7.77 (ddd, J = 0.5 Hz, J = 1.4 Hz, J = 7.8 Hz 1 H); 13C NMR (91 MHz, CDCl3) δ 111.2 (Cq),
118.4 (CH), 123.4 (CH), 127.9 (CH), 129.9 (CH), 130.1 (2 × CH), 132.9 (2 × CH), 133.9
(Cq), 135.0 (Cq), 136.5 (Cq), 144.2 (Cq). 4'-Chlorobiphenyl-3-carbonitrile (11a´): Rf = 0.5
(hexane/EtOAc = 4:1) [UV]; 1H NMR (600 MHz, CDCl3) δ 7.55 (t, J = 7.8 Hz, 1 H), 7.63ꢀ7ꢀ
67 (m, 3 H), 7.73 (d, J = 0.9 Hz, J = 8.7 Hz, 2 H), 7.77 (d, J = 7.9 Hz, 1 H), 7.83 (t,
J = 1.5 Hz, 1 H). 4’-Chlorobiphenyl-4-carbonitrile (11a´´): Rf = 0.5 (hexane/EtOAc = 4:1)
[UV]; 1H NMR (600 MHz, CDCl3) δ 7.45 (d, J = 8.7 Hz, 2 H), 7.52 (d, J = 8.8 Hz, 2 H), 7.65
(d, J = 8.7 Hz, 2 H), 7.73 (d, J = 8.7 Hz, 2 H); 13C NMR (91 MHz, CDCl3) δ 111.3 (Cq), 118.7
(Cq), 127.6 (2 × CH), 128.5 (2 × CH), 129.3 (2 × CH), 132.7 (2 × CH), 134.9 (Cq), 137.6 (Cq),
146.1 (Cq). The spectral data obtained are in agreement with those reported in literature.43,44
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4’ꢀChloroꢀ5ꢀfluorobiphenylꢀ2ꢀcarbonitrile
(11b)
and
4’ꢀchloroꢀ6ꢀfluorobiphenylꢀ3ꢀ
carbonitrile (11b´) were prepared under the conditions A, B and C. Purification by column
chromatography (hexane/EtOAc = 10:1) gave a mixture of 11b and 11b´. 4’-Chloro-5-
1
fluorobiphenyl-2-carbonitrile (11b): Rf = 0.6 (Hexan/EtOAc = 4:1) [UV]; H NMR (600
MHz, CDCl3) δ 7.16 (ddd, J = 2.6 Hz, JHF = 7.8 Hz, J = 8.6 Hz, 1 H), 7.19 (dd, J = 2.6 Hz,
JHF = 9.5 Hz, 1 H), 7.46ꢀ7.50 (m, 4 H), 7.77 (dd, JHF = 5.5 Hz, J = 8.6 Hz, 1 H); DEPTQ (151
MHz, CDCl3) δ 107.3 (Cq), 115.5 (d, JCF = 22.5 Hz, CH), 117.2 (d, JCF = 23.2 Hz, CH), 117.
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(Cq), 129.2 (2 × CH), 129.9 (2 × CH), 135.5 (d, JCF = 1.6 Hz, Cq), 135.6 (Cq), 136.2 (d,
JCF = 9.7 Hz, Cq), 147.2 (d, JCF = 9.1 Hz, Cq), 164.8 (d, JCF = 257.4 Hz, Cq); GCꢀMS (EI)
m/z: 233 (37ClꢀM+), 231 (35ClꢀM+), 196, 176, 169, 149, 97; HRMS (EI) calcd for
C13H7ClFNNa: 254.0143, found: 254.0148. 4’-Chloro-6-fluorobiphenyl-3-carbonitrile (11b´):
Rf = 0.6 (Hexan/EtOAc = 4:1) [UV]; 1H NMR (600 MHz, CDCl3) δ 7.26 (m, 1 H), 7.43ꢀ7.45
(m, 4 H), 7.64 (ddd, J = 2.2 Hz, JHF = 4.5 Hz, J = 8.5 Hz, 1 H), 7.73 (dd, JHF = 2.1 Hz,
J = 7.1 Hz, 2 H).
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4'ꢀChloroꢀ2ꢀnitrobiphenyl (12a), 4'ꢀchloroꢀ3ꢀnitrobiphenyl (12a´) and 4’ꢀchloroꢀ4ꢀ
nitrobiphenyl (12a´´) were prepared under the conditions A, B and C. Purification by column
chromatography (hexane/EtOAc = 15:1) gave a mixture of 12a, 12a´ and 12a´´. 4'-Chloro-2-
1
nitrobiphenyl (12a): Rf = 0.6 (hexane/EtOAc = 4:1) [UV]; H NMR (600 MHz, CDCl3) δ
7.16–7.19 (m, 2 H), 7.31–7.34 (m, 3 H), 7.43 (dt, J = 1.2 Hz, J = 8.0 Hz, 1 H), 7.54 (td,
J = 1.2 Hz, J = 7.6 Hz 1 H), 7.80 (dd, J = 1.2 Hz, J = 8.0 Hz 1 H). 4'-Chloro-3-nitrobiphenyl
1
(12a´): Rf = 0.6 (hexane/EtOAc = 4:1) [UV]; H NMR (600 MHz, CDCl3) δ 7.45 (d,
J = 7.6 Hz, 2 H), 7.55 (d, J = 7.6 Hz, 2 H), 7.61 (t, J = 8.6 Hz, 1 H), 7.87 (d, J = 7.6 Hz,
1 H), 8.20 (m, 1 H), 8.39 (t, 1 H). 4’-Chloro-4-nitrobiphenyl (12a´´): Rf = 0.6 (hexane/EtOAc
1
= 4:1) [UV]; H NMR (600 MHz, CDCl3) δ 77.47 (d, J = 8.4 Hz, 2 H), 7.55 (d, J = 8.4 Hz,
2 H), 7.70 (d, J = 8.4 Hz, 2 H), 8.29 (d, J = 8.4 Hz, 2 H); 13C NMR (91 MHz, CDCl3) δ 124.2
(2 × CH), 127.6 (2 × CH), 128.6 (2 × CH), 129.4 (2 × CH), 135.3 (Cq), 137.2 (Cq), 146.3 (Cq),
147.3 (Cq). The spectral data obtained are in agreement with those reported in literature.44ꢀ46
Acknowledgment. The authors would like to thank the Deutsche Forschungsgemeinschaft for
financial support within the projects HE5413/2ꢀ2 and GRK 1910/A6 and B3.
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Supporting Information Available. Computational results of the densityꢀfunctional
calculations, tables of atom coordinates and absolute energies, NMR spectra of biaryl
compounds and GC chromatograms of biaryl compounds 10b and 10b’. This material is
available free of charge via the Internet at http://pubs.acs.org.
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