Through-Space Activation Can Override Substituent Effects in Electrophilic Aromatic Substitution

Article abstract of DOI:10.1021/jacs.7b09792

Electrophilic aromatic substitution (EAS) represents one of the most important classes of reactions in all of chemistry. One of the "iron laws" of EAS is that an electron-rich aromatic ring will react more rapidly than an electron-poor ring with suitable electrophiles. In this report, we present unique examples of electron-deficient arenes instead undergoing preferential substitution in intramolecular competition with more electron-rich rings. These results were made possible by exploiting the heretofore unknown propensity of a hydrogen-bonding OH-arene interaction to switch to the alternative HO-arene interaction in order to provide activation. In an extreme case, this through-space HO-arene activation is demonstrated to overcome the deactivating effect of a trifluoromethyl substituent, making an otherwise highly electron-deficient ring the site of exclusive reactivity in competition experiments. Additionally, the HO-arene activation promotes tetrabromination of an increasingly more electron-deficient arene before the unactivated "control" ring undergoes monobromination. It is our hope that these results will shed light on biological interactions as well as provide new strategies for the electrophilic substitution of aromatic rings.

Full text of DOI:10.1021/jacs.7b09792

Subscriber access provided by LAURENTIAN UNIV
Communication
Through-space Activation can Override Substituent
Effects in Electrophilic Aromatic Substitution
Liangyu Guan, Maxwell Gargiulo Holl, Cody Ross Pitts,
Mark D Struble, Maxime A. Siegler, and Thomas Lectka
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b09792 • Publication Date (Web): 09 Oct 2017
Downloaded from http://pubs.acs.org on October 13, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Through-space Activation Can Override Substituent
Effects in Electrophilic Aromatic Substitution
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Liangyu Guan, Maxwell Gargiulo Holl, Cody Ross Pitts, Mark D. Struble, Maxime A. Siegler, and
Thomas Lectka*
Department of Chemistry, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA
electron-deficient arene ring in space, its lone pair of
electrons should stabilize a Meisenheimer-like transition
state7 8 and thus alter its reactivity toward EAS (Figure 1).9
Abstract: Electrophilic aromatic substitution, or EAS,
represents one of the most important classes of reactions in
all of chemistry. One of the "iron laws" of EAS is that an
electron-rich aromatic ring will react more rapidly than an
electron-poor ring with suitable electrophiles. In this
report, we present unique examples of electron-deficient
arenes instead undergoing preferential substitution in
intramolecular competition with more electron-rich rings.
These results were made possible by exploiting the
heretofore unknown propensity of a hydrogen-bonding
OH—arene interaction to switch to the alternative HO—
arene interaction in order to provide activation. In an
extreme case, this through-space HO—arene activation is
demonstrated to overcome the deactivating effect of a
trifluoromethyl substituent, making an otherwise highly
electron-deficient ring the site of exclusive reactivity in
competition experiments. Additionally, the HO—arene
activation promotes tetrabromination of an increasingly
more electron-deficient arene before the unactivated
"control" ring undergoes monobromination. It is our hope
that these results will shed light on biological interactions,
as well as provide new strategies for the electrophilic
substitution of aromatic rings.
,
Figure 1. Switchable OH/HO—arene interaction guides non-
traditional
electrophilic
aromatic
substitution
reactivity/selectivity.
R
R
R
through-space
effect
(this work)
substituent
effect
OH
(traditional)
linker
X
switchable
HO-arene interaction
OH-arene interaction
O
H-bonding
linker
lone pair donation
linker
H
OH
X
X
X
+
+
E
E
OH
OH
linker
linker
X
E
E
observed in reaction chemistry for X = H, Br, CF3
and also applicable to polyfunctionalization
Herein, we present examples of electron-deficient arene
rings that undergo preferential substitution in competition
with relatively electron-rich rings, whereby through-space
interactions override traditional substituent effects.
Furthermore, we exploit the heretofore-unknown
propensity of a hydrogen-bonding OH—arene interaction
to switch to the alternative HO—arene interaction in order
to provide the basis for activation. We recently reported an
F—arene interaction that achieves through-space EAS
activation; we believed the phenomenon would be much
stronger with an oxygen atom incorporated in a similar
molecular scaffold, thus allowing traditional reactivity
patterns to be reversed.10
To test our initial hypothesis, we chose target molecule
1, which contains a hydroxyl group poised directly over an
aromatic ring (Scheme 1); we envisioned this could assist
with EAS through a Meisenheimer-like interaction. The
synthesis of 1 is shown in Scheme 1. First, benzylation of
previously reported alcohol 2,10 followed by saponification
and anhydride ring formation, affords alkene 3 (29% yield
over three steps). To establish the 'probe' and 'control'
Electrophilic aromatic substitution (EAS) is one of the
most fundamentally important reactions in the science of
chemistry.1 2 In the classroom setting, students are taught at
length about how EAS reactions are governed by
"substituent effects" in terms of relative reaction rates and
,
selectivity.3 For instance, imagine that a molecule with two
different aromatic rings, separated by a linker, is subjected
to an EAS reaction. In principle, substitution will occur at
the more electron-rich ring, assuming that other factors be
equal. This deactivating effect on EAS reactions by
electron withdrawing groups is well established, and it is a
fundamental concept in textbook organic chemistry. On
the other hand, what if a traditionally deactivated ring were
to experience an external source of activation that would
compensate for its inherent unreactivity? This situation is
reminiscent of Meisenheimer complexes - anionic σ-
adducts formed from the interaction of highly electron-
, ,
deficient arenes with alkoxide nucleophiles.4 5 6 With that
in mind, it stands to reason that if an oxygen-based
functional group is poised, at very close distance, to an
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
anthracene with 1-trifluoromethylanthracene28 as the diene.
rings, a Diels-Alder reaction of anthracene with 3 (160 °C,
1
2
3
4
5
6
7
8
sealed tube), followed by debenzylation (H2, Pd/C),
provides alcohol 4 (43% yield over two steps). Finally,
epimerization of the hydroxyl group in 4 (PCC oxidation,
then LiAlH4 reduction) yields the desired alcohol 1 (64%
yield over two steps).
The OH stretching frequencies of 5 and 6 are nearly
identical to each other, and to that of nonsubstituted out-
OH 4, suggesting that, in contrast to 1, the hydrogen atom
of the OH group of 6 is not hydrogen bound to the arene (a
statement that is supported by DFT calculations: see Figure
S4). In terms of NMR analysis, the OH in 6 is less
shielded than 1 by 0.39 ppm. Since the hydrogen atom is
facing outward, it is further from the ring and less affected
by ring currents.
Scheme 1. Synthesis of the probe molecules 1 and 6.
9
i. anthracene, 160 °C
ii. H2, Pd/C
(43% overall)
OBn
H
OH
H
i. benzyl-2,2,2-
trichloroacetimidate,
cat. TfOH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
The OH—arene interaction is expected to be deactivating
in an electrophilic aromatic substitution, whereas the HO—
arene interaction should be activating. Which effect would
dominate in EAS? Monobromination of 1 (Br2, MeCN,
room temperature) forms product 7 exclusively and under
mild conditions, confirming that the ring perturbed by the
or
MeO2C
O
i. 1-trifluoromethyl-
anthracene, 160 °C
ii. H2, Pd/C
ii. LiOH, H2O/THF
iii. TFAA
3
MeO2C
2
O
(29% overall)
(61% overall)
1.2:1 5:5-down
Y
Y
i. PCC, CH2Cl2
HO
OH
H
H
O
,
hydroxyl group is activated (Scheme 2).29 30 Bromine is a
X
X
ii. LiAlH4
(1: 64% overall)
(6: 61% overall)
O
moderate electron-withdrawing group that slows the rate of
aromatic substitution by about two orders of magnitude.31
Can the HO—arene interaction override bromine's
deactivation? We were gratified to find that nitration of 7
also proceeds exclusively on the brominated ring (in
addition to nitrate ester formation: Figure S2) (8).32,33 In
fact, we found that the nitrate ester forms prior to arene
nitration (see SI). It is noteworthy that an electron deficient
oxygen atom, as part of a nitrate ester, can direct EAS.
When 1 was subjected to more forceful bromination
conditions (excess Br2, Fe metal, CH2Cl2), we monitored
the reaction and observed tetrabromination of the top ring 9
before evidence of bottom ring bromination (Scheme 2 and
O
O
4: X = Y = H
5: X = H, Y = CF3
5-down: X = CF3, Y = H
1: X = Y = H
6: X = H, Y = CF3
O
O
6-down: X = CF3, Y = H
The OH—arene interaction of 1 is revealed by a red-
shifted OH stretch (32 cm-1) in the IR spectrum in
chloroform when compared to the out-diastereomer 4
(Table S1). In the NMR spectrum (CDCl3), the oxygen-
bound proton is shielded (-0.21 ppm) and sharp in
comparison to the broader resonance of the OH group in 4,
which is comparatively deshielded (1.16 ppm). Thus, it
appears that intramolecular hydrogen bonding to the arene
dominates in 1, similar to interactions observed between
,
Figure S3 show the crystal structure of 9).34 35
OH groups and non-conjugated C=C bonds.11
The OH—arene hydrogen bond can be categorized, as a
We then sought a stronger electron-withdrawing group
that would afford a more dramatic demonstration of the
external activating effect of the hydroxyl group. One of the
most potent deactivators is the trifluoromethyl group,
which reduces the relative reactivity of an arene ring by
type of cation-π interaction.
It has been observed
biologically; for example, the OH group of a threonine
residue is positioned above the π-cloud of tyrosine in the
enzyme glutathione transferase when complexed with
more than 40,000 fold.36 This significant deceleration also
means that any other electron-rich aromatic rings present in
a typical synthetic sequence will undergo preferential
aromatic substitution under most conditions. When 6 is
subjected to standard bromination conditions at room
temperature (Scheme 2) product 10 is obtained (57%
yield). The mass balance is composed of starting material
and a mixture of polybrominated products. No hint of
monobromination on the other aromatic ring was observed,
thus demonstrating the hydroxyl group's ability to override
one of the strongest deactivating substituents. In order to
attribute these non-traditional substitution patterns to the
HO—arene interaction, several control experiments were
conducted (Scheme 3). 37 The simplest comparison is
between benzene (11) and trifluorotoluene (12), as no
through-space rigid atom—arene interaction would be
present.
-
15
glutathione. 12
Additionally, a water—phenylalanine
interaction is featured in the complex of the anti-
Alzheimer's drug donepezil with its target
,
acetylcholinesterase.16 17 In the case of small molecules,
although a number of well-documented examples exist in
the literature,18242526 many aspects of the interaction remain
unexplored. In terms of intermolecular interactions, OH—
arene hydrogen bonding plays an important role in the
formation of 1,1,2-triphenylethanol dimers in the solid
phase.27
Upon examining an X-ray crystal structure of 1, we
noticed another interesting feature (Figure S1). The
oxygen-bound hydrogen atom is disordered over two
orientations: the in-form is bound to the arene and the out-
form is involved in a hydrogen bond with the oxygen of an
adjacent molecule. Note that the out-form can be described
as a dominant HO—arene interaction, between the lone
pairs on oxygen and the arene ring, instead of an OH—
arene interaction. In order to study this HO—arene
interaction in solution, we envisioned that a more electron
deficient arene ring would decrease the favorability of
OH—arene hydrogen bonding, so we synthesized 5 and 6
in an analogous fashion to 1 and 4 (Scheme 1), replacing
In an intermolecular competitive bromination experiment
(with benzene and trifluorotoluene in great excess of other
reagents), bromobenzene (13) was the only product
observed upon complete consumption of Br2. To illustrate
further the relative reaction rates, benzene and
trifluorotoluene were subjected to the same bromination
conditions in separate vessels.
The initial rate of
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
bromobenzene formation was monitored over 140 min. to the inward hydroxide in 1 or the hydrogen in 17).
1
2
3
4
5
6
7
8
6% conversion, while no brominated trifluorotoluene
isomers were observed after 15 days. However, criticism
of these control experiments may come from the rigidity
and substitution pattern of our probe molecule - are there
unforeseen features of the framework that prevent
functionalization of the bottom ring (or otherwise activate
the top ring)? Thus, we synthesized 14 (see Scheme 3 and
S1),38 with the hydroxyl group replaced by a less (but still
slightly activating) hydrogen atom as an intramolecular
control experiment. We also employed out-OH 5 as
another control. At room temperature, no bromination was
observed after multiple attempts, thus providing initial
support for the necessity of the HO—arene activation.
Upon refluxing the reaction mixture, bromination was
observed exclusively on the bottom ring at the two distal
positions in ~1:1 ratio (15-16a:15-16b). Therefore, the
HO—arene activation is crucial in dictating both reactivity
and selectivity with regard to this control.
Bromination of 19 resulted in a ~1:1 ratio of top ring to
bottom ring products (Scheme 3).
The observed selectivity was further corroborated by
DFT calculations. We calculated the relative energies of
various σ-complexes leading to potential brominated
products of 1, 6, and 14 (Table S2). In the case of 1, the
isomer with bromine on the top ring is more stable than that
on the bottom ring by 9.0 kcal (ωB97XD/6-311++G**; exo
bromo slightly more stable than endo epimer). This large
difference would explain the preferential substitution on the
top ring. In the case of 6, the top ring complex is favored
by a lesser amount (3.8 kcal) than in 1, whereas in the case
of 14, the bottom ring complex is favored by 5.2 kcal.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Control reactions confirming role of HO—arene
interaction in through-space activation.
intermolecular competition
relative rates (separate reaction vessels)
Br
Br2, Fe
DCM, rt
Br
11
Br2, Fe
Scheme 2. Reactions of 1, 6, and 7. Bottom right: Ball and stick
model of 9 from crystallographic coordinates. Note that there is
an i-Pr2O solvent molecule in the asymmetric unit.
6% conversion
after 140 min.
+
DCM, rt
CF3
CF3
13
Br2, Fe
no reaction
after 15 days
only product observed
DCM, rt
12
intramolecular competition
Br
Br
CF3
H
CF3
CF3
O2N
NO2
H
R
H
R
R
H
O
H
O
H
HO
H
Br
Br2, Fe
+
O
O
NH4NO3, TFAA
MeCN, rt
Br2, Fe
O
O
O
DCM, reflux
O
Br
DCM, rt
O
O
14 R = H
5 R = OH
O
O
O
O
O
15a R = H
15b R = H
O
~ 1
: 1
O
O
1
7
8
O
O
16a R = OH
16b R = OH
Br
R = H, OH exclusively bottom ring bromination observed
tetrabromination
observed
Br
Br
Br
before
bottom ring
bromination
H
O
H
HO
H
H
H
H
H
H
H
Br
excess
Br2, Fe
Br2, Fe
O
+
O
O
O
O
DCM, rt
DCM, reflux
Br
O
O
1
O
9
O
O
O
O
17
18a
18b
O
O
O
Br
CF3
~6 : 1
CF3
H
Br
H
O
H
O
H
O
O
O
Br2, Fe
O
O
DCM, rt
Br2, Fe
+
O
O
O
O
O
10
6
O
DCM, reflux
O
Br
20a
~1 : 1
exclusive monbrominated product
19
O
O
O
20b
O
O
O
We employed another control molecule, 17,10 where
there is equal substitution on the aromatic rings, and the
hydroxyl group is again replaced with a hydrogen atom
(Scheme 3). Bromination of this compound resulted in a
mixture of monobromides on the top ring and the bottom
ring in a 6:1 ratio. This suggests that the inherent
difference in reactivity between the two rings is fairly small
on this compound, but that the top ring is still slightly
activated by the inward facing hydrogen atom. We would
expect this theoretically and in analogy to the profusion of
Is the activation truly "Meisenheimer like," i.e., is there a
developing covalent bond between oxygen and an arene
carbon in the transition state? DFT calculations can shed
light on this question using 6 as the model. At ωB97XD/6-
311+G**, the σ-complex intermediate 6A for bromination
of 6 was optimized with an explicit solvent molecule
(dichloromethane). The oxygen atom in the optimized
structure is in close proximity (1.57 Å) to the carbon ortho
to the trifluoromethyl group and para to the complexed
bromine (Figure 2). There clearly is a covalent bond
between oxygen and the arene carbon atom, which serves
to explain the relative stability of this σ-complex compared
to those that lead to other products. In addition, an AIM
(atoms in molecules) analysis shows the existence of a
bond critical point between the oxygen and carbon (Figure
39
"hydrido-bridged" structures in organic chemistry.
Additionally, a slight inherent deactivation of the bottom
ring may contribute as well, but the effect is evidently
small. This result is in rough accord with previous
investigations (nitration of this compound gives a 2:1 ratio
of top ring to bottom ring substitution).10 As a final
control, we employed ketone 19, which contains no
activating atom (the carbonyl is farther from the arene than
S5).40 Finally, if 6 undergoes exclusive bromination on the
top ring (with the trifluoromethyl substituent), is the top
ring still considered the more electron-deficient ring in the
ACS Paragon Plus Environment

Journal of the American Chemical Society
ground state? Natural bond orbital (NBO) analyses of the
Page 4 of 5
1
2
3
4
5
6
7
8
9 Murphy, K. E.; Bocanegra, J. L.; Liu, X.; Chau, H.-Y. K.; Lee, P.
carbon atoms on the aromatic rings show more positive
charge character on the trifluoromethylated ring regardless
of the presence (6) or absence (14) of the hydroxyl group
(Table S3). Thus, the HO—arene activation must be more
influential during the formation of the σ-complex.
C.; Li, J.; Schneebeli, S. T. Nature Commun. 2017, 8, 14840.
10 Holl, M. G.; Struble, M. D.; Singal, P.; Siegler, M. A.; Lectka, T.
Angew. Chem. Int. Ed. 2016, 55, 8266-8269.
11 Struble, M. D.; Holl, M. G.; Coombs, G.; Siegler, M.; Lectka, T. J.
Org. Chem. 2015, 80, 4803−4807.
12 Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew. Chem. Int.
Ed. 2003, 42, 1210-1250.
13 Ji, X.; Zhang, P.; Armstrong, R. N.; Gilliland, G. L. Biochemistry
1992, 31, 10169-10184.
Figure 2.
Optimized structure of 6A, the σ-complex
intermediate for endo-bromination of 6, at ωB97XD/6-
311+G**.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Br
H
14 Xiao, G.; Liu, S.; Ji, X.; Johnson, W. W.; Chen, J.; Parons, J. F.;
Stevens, W. J.; Gilliland, G. L.; Armstrong, R. N. Biochemistry 1996,
35, 4753-4765.
H
Cl
H
Cl
H
d(C1-O)
d(C2-O)
=
=
1.47 A
1.57 A
O
H
CF3
C1
C2
15 Sulpizi, M.; Carloni, P. J. Phys. Chem. B. 2000, 104, 10087-10091.
16 Kryger, G.; Silman, I.; Sussman, J. L. Structure 1999, 7, 297-307.
17 Kryger, G.; Silman, I.; Sussman, J. L. J. Phisiol. Paris 1992, 92,
191-194.
18 Banerjee, P.; Chakraborty, T. J. Phys. Chem. A 2014, 118, 7074−
7084.
O
O
6A
O
In conclusion, we demonstrated that the HO—aryl
interaction dramatically increases an aromatic ring's
reactivity with electrophiles such that this phenomenon
may override the influence of deactivating substituents. In
19 Malenov, D. P.; Janjic, G. V.; Veljkovic, D. Z.; Zaric, S. D. Comp.
Theor. Chem. 2013, 1018, 59−65.
20 Saggu, M.; Levinson, N. M.; Boxer, S. G. J. Am. Chem. Soc. 2011,
133, 17414−17419.
particular, preferential EAS on
a
trifluoromethyl-
21
Mohan, N.; Vijayalakshmi, K. P.; Koga, N.; Suresh, C. H. J.
substituted ring over a comparable unsubstituted aromatic
ring is a testament to the strength of this interaction. Not
only does this expand the selectivity "rules" of EAS in
chemical synthesis based on substituent effects, but it
should also draw attention to interactions in, for instance,
enzyme active sites where forced HO—arene interactions
are plausible.
Comput. Chem. 2010, 31, 2874−2882.
22 Toth, G.; Bowers, S. G.; Truong, A. P.; Probst, G. Curr. Pharm.
Des. 2007, 13, 3476−3493.
23 Motherwell, W. B.; Moïse, J.; Aliev, A. E.; Nič, M.; Coles, S. J.;
Horton, P. N.; Hursthouse, M. B.; Chessari, G.; Hunter, C. A.; Vinger,
J. G. Angew. Chem. Int. Ed. 2007, 46, 7823 –7826.
24 Aliev, A. E.; Arendorf, J. R. T.; Pavlakos, I.; Moreno, R. B.; Porter,
M. J.; Rzepa, H. S.; Motherwell, W. B. Angew. Chem. Int. Ed. 2015,
54, 551-555.
25 Paruch, K.; Vyklický, L.; Wang, D. Z.; Katz, T. J.; Incarvito, C.;
Zakharov, L.; Rheingold, A. L. J. Org. Chem. 2003, 68, 8539-8544.
Supporting Information. General experimental procedures
and characterization data can be found therein. CCDC
1545393, 1547865, and 1547866 contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic
Data Centre.
26
Hong, J.; Yang, G.; Duan, C.; Guo, Z.; Zhu, L. Inorg. Chem.
Commun. 2005, 8, 988-991.
27 Ferguson, G.; Gallagher, J. F. Acta Cryst. 1994, 50, 70-73.
28 Carr, G. E.; Chambers, R. D.; Holmes, T. F. J. Chem. Soc. Perkin
Trans. 1 1988, 1, 921-926.
AUTHOR INFORMATION
29 Gustafson, J. L.; Lim, D.; Miller, S. J. Science 2010, 328, 1251-
1255.
30 Pathak, T. P.; Miller, S. J. J. Am. Chem. Soc. 2012, 134, 6120-6123.
31 Rosenthal, J.; Schuster, D. I. J. Chem. Educ. 2003, 80, 679-690.
The authors declare no competing financial interests.
Correspondence and requests for materials should be
addressed to lectka@jhu.edu.
32 Roberts, J. D.; Sanford, J. K.; Sixma, F. L. J.; Cerfontain, H.; Zagt,
ACKNOWLEDGMENTS
T.L. thanks the NSF (CHE 1465131) for financial support.
R. J. Am. Chem. Soc. 1954, 76, 4525-4534.
33 Nieves-Quinones, Y.; Singleton, D. J. Am. Chem. Soc. 2016, 138,
15167-15176.
REFERENCES
34 Reich, H. J.; Cram, D. J. J. Am. Chem. Soc. 1969, 91, 3505-3516.
35 Bondarenko, L.; Kampf, J. W.; Lahann, J. Eur. J. Org. Chem. 2006,
1 Ferguson, L. N. Chem. Rev. 1952, 50, 47-67.
2 Galabov, B.; Nalbantova, D.; Schleyer, P. v. R.; Schaefer III, H. F.
Acc. Chem. Res. 2016, 49, 1191-1199.
24, 5499-5504.
36 Carey, F. A. Organic Chemistry, 4th ed.; McGraw Hill: New York,
2000.
37 The O-methylated derivatives of 1 and 6 brominate preferentially
on the top ring, consistent with activation by the O-atom. See SI for
details.
3 Gilow, H. J. Chem. Ed. 1977, 54, 450-452.
4 Pollit, R. J.; Saunders, B. C. J. Chem. Soc. 1964, 1132-1135.
5 Ueda, H.; Sakabe, N.; Tanaka, J.; Furusaki, A. Bull. Chem. Soc. Jpn.
1968, 41, 2866-2871.
38 Diels, O.; Alder, K. Liebigs Ann. Chem. 1931, 490, 236−242.
39 McMurry, J. E.; Lectka, T. Acc. Chem. Res.
40 Bader, R. F. W. Acc. Chem. Res. 1985, 18, 9-15.
6
1992, 25, 47-53.
Chiavarino, B.; Crestoni, M. E.; Fornarini, S.; Lanucara, F.;
Lemaire, J.; Maître, P. Angew. Chem. Int. Ed. 2007, 46, 1995-1998.
7 Glukhovtsev, M. N.; Bach, R. D.; Laiter, S. J. Org. Chem. 1997, 62,
4036-4046.
8 Giroldo, T.; Xavier, L. A.; Riveros, J. M. Angew. Chem. Int. Ed.
2004, 43, 3588-3590.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
EWG
EWG
governed by substituent effects
classical EAS
linker
E
EWG
linker
9
preferred site
for EAS
deactivated
this work
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
E
linker
reversal by through-space activation
ACS Paragon Plus Environment