Iron-catalyzed directed alkylation of aromatic and olefinic carboxamides with primary and secondary alkyl tosylates, mesylates, and halides

Article abstract of DOI:10.1021/ja5066015

Alkenes, arenes, and heteroarenes possessing an 8-quinolylamide group as the directing group are alkylated with primary and secondary alkyl tosylates, mesylate, and halides in the presence of Fe(acac) ₃/ diphosphine as a catalyst and ArZnBr as a base. The reaction proceeds stereospeci fically for alkene substrates and takes place without loss of regiochemical integrity of the starting secondary tosylate, but with loss of the stereochemistry of the chiral center.

Full text of DOI:10.1021/ja5066015

Communication
pubs.acs.org/JACS
Iron-Catalyzed Directed Alkylation of Aromatic and Olefinic
Carboxamides with Primary and Secondary Alkyl Tosylates,
Mesylates, and Halides
Laurean Ilies,* Tatsuaki Matsubara, Saki Ichikawa, Sobi Asako,† and Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
bis(diphenylphosphino)ethylene (dppen, 10 mol %) in THF
ABSTRACT: Alkenes, arenes, and heteroarenes possess-
ing an 8-quinolylamide group as the directing group are
alkylated with primary and secondary alkyl tosylates,
mesylate, and halides in the presence of Fe(acac)3/
diphosphine as a catalyst and ArZnBr as a base. The
reaction proceeds stereospecifically for alkene substrates
and takes place without loss of regiochemical integrity of
the starting secondary tosylate, but with loss of the
stereochemistry of the chiral center.
were added sequentially, and the reaction mixture was stirred at
70 °C for 9 h. Aqueous workup followed by silica-gel
chromatography afforded the desired β-alkylated amide 2 in
71% yield together with a Z-arylated product11 3 in 21% yield (on
a 0.4 mmol scale), both as a single isomer (eq 1). Addition of dry
NaI to the reaction suppresses the arylation (13%) and afforded 2
in 85% yield. The reaction using 1.00 g of 1 gave 2 in 75% isolated
yield. p-AnisMgBr was used to facilitate chromatographic
removal of 3 and can be replaced with PhMgBr.
The use of p-anisylzinc bromide12 generated from p-AnisMgBr
and ZnBr2 was found to effect cleanly 100% stereoselective
coupling with phenethyl tosylate to afford 2. This catalytic
system utilizes 2.5 equiv of p-AnisMgBr and 1.5 equiv of ZnBr2·
TMEDA, where 2 equiv of the p-anisyl group are consumed to
remove two hydrogens atoms from 1, leaving 0.5 equiv of the p-
anisyl moiety, probably staying as a stationary ligand on the iron
atom. These conditions almost entirely suppress two undesirable
side reactions of the aryl Grignard reaction: the Negishi-type
cross-coupling with the tosylate (or halide)13 to give 4-
phenethylanisole and the homocoupling of the aryl group14 to
give 4,4′-bianisyl. The use of a slight excess of p-AnisMgBr (3
equiv, together with 2 equiv of ZnBr2·TMEDA, as in eq 1) was
often necessary to ensure reproducibility of the reaction because
the p-anisyl group is partially consumed for the formation of 3
(which consumes 3 equiv/mol of the anisyl group).11
fter extensive developments in the use of alkenes1 and
A
alkylmetal reagents2 for directed C(sp2)−H functionaliza-
tion of alkenes and arenes,3 alkyl halides are receiving increasing
attention as an alkyl donor4 under palladium5 and ruthenium
catalysis,6 and more recently under 3d-block transition metals,
such as cobalt7 and nickel.8 However, the synthetic versatility of
the alkyl halide approach is still limited9 because of stereo-
isomerization of the olefins in the product,8a and the limitation of
the alkyl donor mainly to alkyl halides. The use of alkanol
derivatives as an alkyl donor has been illustrated only for the
coupling of octyl tosylate with an acetophenone imine under
cobalt catalysis.7b We report here that, under iron catalysis, alkyl
tosylates, mesylate, and halides serve as effective alkyl donors for
the alkylation of alkenes, arenes, and heteroarenes possessing an
8-aminoquinolyl carboxamide directing group10 (eq 1). The
The effects of the directing group and the ligand are
summarized in Figure 1 for alkylation of 3-methylbenzamide or
tiglamide 1 with phenethyl tosylate. The 8-aminoquinoline
directing group was essential, and a 2-methyl-8-aminoquinoline
group was entirely ineffective, indicating sensitivity to steric
hindrance. N-Phenylamide and pyridine directing groups
resulted in recovery of the starting material. The reaction is
also sensitive to the ligand, as shown in Figure 1b. The reaction
took place most smoothly with a diphosphine possessing a π-
bridge such as dppen and dppbz, but not with 1,2-ethyl-
enediphosphine (dppe) lacking the π-bridge. Monophosphine
and bipyridine ligands are ineffective.
Table 1 illustrates the stereospecific alkylation of α,β-
unsaturated amides with alkyl tosylates and halides. All reactions
resulted in quantitative conversion of the starting amide,
accompanying the formation of 10−20% of the arylated product
3 (or congener). In no cases did we observe the homocoupling
iron-catalyzed reaction of secondary alkyl tosylates proceeds with
retention of regiochemical integrity,8b but with loss of the
stereochemistry of the chiral center. The reaction tolerates the
presence of a variety of functional groups, such as alkyl chloride,
aryl halide, and ester, and can utilize an alcohol as an alkyl donor
after in situ conversion into the corresponding mesylate (eq 2).
A typical reaction protocol is described first (eq 1): a solution
of p-anisylmagnesium bromide (p-AnisMgBr) in THF (3 equiv)
was added dropwise to a solution of the tiglamide 1 and ZnBr2·
TMEDA (2 equiv). Next, 2-phenethyl tosylate (1.2−l.5 equiv) in
THF and a mixture of Fe(acac)3 (10 mol %) and cis-1,2-
Received: July 1, 2014
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
Table 1. Iron-Catalyzed Reaction of Alkene Carboxamides
with Various Primary and Secondary Alkyl Tosylates and
a
Halides
Figure 1. Effect of directing group and ligand. (a) Effects examined for
the reaction of a benzamide substrate with phenethyl tosylate. R =
CH2CH2Ph refers to the yield of the desired product, R = Ph refers to
the arylation side product (cf. 3 in eq 1), and R = H refers to the starting
material. (b) Effects examined for alkene substrate 1 in eq 1.
product of p-AnisMgBr.14 Functionalization of olefinic C−H
substrates with alkyl halides has so far been reported for the
nickel-catalyzed reaction of an α,β-unsaturated amide with alkyl
bromide or chloride8 that occurred with degradation of the
olefin’s stereochemistry.8a The 100% Z-stereoselective introduc-
tion of a hexyl group at the β-position was achieved by the use of
1-hexyl tosylate, and iodide, bromide, and chloride also reacted
with equal ease (entries 1, 4−6). The reaction took place much
faster at the tosyloxy group than at an alkyl chloride moiety
(entry 7). Ester (entry 8), aryl chloride (entry 9), and aryl
bromide (entry 10) groups remained entirely unaffected. The
reaction of 5-hexenyl tosylate took place in 79% yield to give
mainly a cyclized product (entry 13) without the olefin
isomerization that was observed in cobalt catalysis,7b suggesting
that metal hydride species are not involved. Cyclopropylmethyl
bromide and tosylate reacted with complete opening of the
cyclopropyl ring (entries 14 and 15), indicating that the alkyliron
intermediate has a radical-like character.
The examples after entry 16 depict the reaction of alkenyl C−
H substrates with secondary alkyl tosylatesan illustration of
the advantage of iron catalysis over other catalytic systems so far
reported. Cyclopentyl tosylate and tetrahydropyranyl tosylate
reacted in modest to good yield (entries 16 and 17). 2-Butyl
tosylate gave a 2-butylated product exclusively, and none of a 1-
butylated product (entry 18).7
The stereochemistry of trans-4-tert-butylcyclohexyl tosylate
decreased to 72:28 during the reaction (entry 19), while the cis-
isomer gave none of the desired product, probably because of
competitive β-eliminative loss of the axial tosyloxy group.13e The
observed loss of the stereochemistry at the sp3 center connected
to the tosyloxy group suggests a radical-like character of the C−
Fe bond in an intermediate that forms prior to the C−C bond
formation.13e Exo-norbornyl bromide gave the less hindered exo
product selectively (entry 20). Under these reaction conditions,
tertiary alkyl halides such as tert-butyl bromide or chloride and
adamantyl bromide did not produce the alkylated product at all,
and the starting alkenecarboxamide was recovered together with
20%−30% of an arylated product (congener of 3).
Trisubstituted acyclic or cyclic alkene substrates such as
tiglamide (entries 1, 7, 8, 10−15), 3-ethyl-2-methylacrylamide
(entry 2), cyclohexenamide (entries 4−6, 9, 16−20), or
dihydropyranamide (entry 3) reacted well. By contrast, the
reaction of acrylamide (entry 21) gave the desired (Z)-3-hexyl
product only in 12% yield, giving predominantly a (Z)-3-
anisylated product11,15 (congener of 3, 81% yield). A similar
result was obtained for 2-methylacrylamide (Supporting
a
The reaction was carried out using 0.4 mmol of amide, 3 equiv of p-
AnisMgBr, 2 equiv of ZnBr2·TMEDA, 1.2−1.5 equiv of an alkyl donor,
Fe(acac)3 (10 mol %) and dppen (10 mol %), and NaI (1.5 equiv) at
50−70 °C for 9−12 h in THF, as described in the text. The yield is
based on a pure isolated product obtained by silica-gel chromatog-
raphy, except in entries 4−6 and 15, where the yield was determined
B
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Journal of the American Chemical Society
Communication
implying that both alkyl and aryl groups are attached to a high-
valent iron intermediate responsible for C−H activation and/or
C−C bond formation. These data also illustrate the functional
group tolerance of the reaction. Secondary tosylates reacted
cleanly, and 2-butyl tosylate gave a 2-butylated product
uncontaminated by a 1-butylated product (entry 8). A 2-
substituted amide reacted slower than the 3-substituted analogue
and with much lower alkylation/arylation selectivity (entry 9).
Indolecarboxamide (entry 10) gave the desired alkylated product
in 81% yield, whereas thiophenecarboxamide (entry 11) gave a
mixture of the alkylated and the arylated products in 41% and
35% yield, respectively. Phenethyl chloride and bromide served
as a good alkyl donor (entries 12 and 13).
Table 1. continued
1
by GC or H NMR using an internal standard. The yields in brackets
are for the reaction performed in the absence of NaI. See the
Supporting Information for details. All reactions formed an arylation
b
side product (an analogue of 3) in 10−20% yield. Ratio determined
c
1
by H NMR. The reaction produced 100% 2-butylated product and
d
none of the 1-butylated product. A 3-p-anisyl product was obtained in
81% yield.
Information (SI)). This competition between the two pathways
suggests that a reactive iron intermediate bears both the alkyl and
aryl groups on the iron atom.
In Table 2, we summarize the alkylation of aromatic and
heteroaromatic carboxamides with alkyl tosylates and halides.
For all substrates examined, the combined yield of the alkylation
and arylation (p-anisylation) product was 80%−90%. A notable
trend found in entries 1−6 for the reaction of 3-substituted
benzamide with 2-phenethyl tosylate is that the yield of the
alkylation decreases while that of the arylation increases,
We can use an alcohol directly for the alkylation of the
alkenecarboxamide 1 via one-pot in situ mesylation.16 The
reaction proceeded well to give the desired product 2 in 68%
yield (eq 2).17
Table 2. Iron-Catalyzed Alkylation of Aromatic and
Heteroaromatic Carboxamides with Phenethyl, Cyclopentyl
(entry 7), and 2-Butyl Tosylates (entry 8) and Phenethyl
a
Halides (entries 12 and 13)
Several pieces of information relevant to the mechanism are
summarized here. The present reaction retains the regiochemical
integrity of a secondary tosylate (e.g., 2-butyl tosylate) as
opposed to the cobalt-catalyzed reaction of alkyl halides,7
indicating that β-elimination of an iron hydride does not interfere
with the reaction. In addition to the data reported in the
foregoing paragraphs, the ability of TEMPO to completely stop
the reaction (Scheme S3 in SI) provides further support for the
radical character of the organoiron intermediates.
The persistent formation of the p-anisyl side products suggests
that an organoiron intermediate preceding the C−C bond
formation carries both an alkyl group from alkyl-X and the p-
anisyl group from p-AnisZnX and that there is a general
preference for the alkyl group transfer except in Table 1, entry 21
where the p-anisyl transfer predominates. To further test this
hypothesis, we reacted the benzamide 4 with hexyl iodide in the
presence of MeZnX and obtained the hexylated (5) and the
methylated products (6) in an almost 1:1 ratio (eq 3).
Competition experiments using the standard p-AnisMgBr/
ZnBr2·TMEDA conditions showed that the order of reactivity for
the leaving group is I > Br > OTs ≫ Cl (Scheme S4) and that a
rapid conversion of the tosylate into the corresponding bromide
occurs. The exchange of tosylate with bromide is faster than that
with the iodide of NaI, in both the presence and absence of a
substrate (Scheme S5). On the other hand, the use of a
combination of PhMgCl and ZnCl2·TMEDA for the reaction of
hexyl tosylate and chloride gave the desired product in a much
lower yield (21% and 31% yield, respectively, Scheme S6). We
thus conclude that the halide groups on the magnesium and zinc
atoms are active participants in the reaction.
a
The reactions were performed under the same reaction conditions as
b
used in Table 1. See the Supporting Information for details. Yield (%)
of the alkylation product is based on the isolated product, except
entries 12 and 13, where it was determined by H NMR using an
internal standard. Yields of the arylation product (introduction of the
p-anisyl group) and recovery are based on either isolated product or
GC. Not determined. The reaction produced 100% 2-butylated
product and none of the 1-butylated product. Phenethyl bromide was
used as the starting material. Phenethyl chloride was used as the
1
c
d
e
In conclusion, we have developed a new protocol for coupling
between an alkyl electrophile with alkene, arene, and heteroarene
carboxamides under iron catalysis. Despite a variety of precious
f
starting material.
C
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Journal of the American Chemical Society
Communication
R. Org. Lett. 2011, 13, 1875−1877. (d) Hofmann, N.; Ackermann, L. J.
Am. Chem. Soc. 2013, 135, 5877−5884.
(7) (a) Chen, Q.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2011, 133,
428−429. (b) Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 9279−
9282. (c) Song, W.; Ackermann, L. Angew. Chem., Int. Ed. 2012, 51,
8251−8254.
(8) (a) Chatani, N.; Aihara, Y. J. Am. Chem. Soc. 2013, 135, 5308−5311.
(b) Song, W.; Lackner, S.; Ackermann, L. Angew. Chem., Int. Ed. 2014,
53, 2477−2480.
metal catalysts for C−H functionalization, the present method
provides unique synthetic examples for the utilization of an
alcohol and the corresponding tosylate and mesylate as an
electrophile. Another feature of the reaction is the lack of
regioisomerization in the reaction of a secondary tosylate and the
lack of stereoisomerization of olefins in the product. Although
the interest in iron catalysis18,19 has so far been driven largely by
its economic and environmental merits,20 the present results
suggest that iron catalysis may become more synthetically
versatile than precious metal catalysis.21
(9) Heck-type reactions: (a) Firmansjah, L.; Fu, G. C. J. Am. Chem. Soc.
2007, 129, 11340−11341. (b) Liu, C.; Tang, S.; Liu, D.; Yuan, J.; Zheng,
L.; Meng, L.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 3638−3641.
(c) Nishikata, T.; Noda, Y.; Fujimoto, R.; Sakashita, T. J. Am. Chem. Soc.
2013, 135, 16372−16375. (d) Harris, M. R.; Konev, M. O.; Jarvo, E. R. J.
Am. Chem. Soc. 2014, 136, 7825−7828. (e) McMahon, C. M.; Alexanian,
E. J. Angew. Chem., Int. Ed. 2014, 53, 5974−5977. (f) Zou, Y.; Zhou, J.
Chem. Commun. 2014, 50, 3725−3728.
(10) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154−13155. (b) Rouquet, G.; Chatani, N. Angew. Chem.,
Int. Ed. 2013, 52, 11726−11743. (c) Shang, R.; Ilies, L.; Matsumoto, A.;
Nakamura, E. J. Am. Chem. Soc. 2013, 135, 6030−6032.
(11) Ilies, L.; Asako, S.; Nakamura, E. J. Am. Chem. Soc. 2011, 133,
7672−7675.
(12) (a) Asako, S.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2013, 135,
17755−17757. (b) Asako, S.; Norinder, J.; Ilies, L.; Yoshikai, N.;
Nakamura, E. Adv. Synth. Catal. 2014, 356, 1481−1485.
(13) Selected examples: (a) Tamura, M.; Kochi, J. K. J. Organomet.
Chem. 1971, 31, 289−309. (b) Nakamura, M.; Matsuo, K.; Ito, S.;
Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686−3687. (c) Nagano, T.;
Hayashi, T. Org. Lett. 2004, 6, 1297−1299. (d) Nakamura, M.; Ito, S.;
Matsuo, K.; Nakamura, E. Synlett 2005, 1794−1798. (e) Ito, S.;
Fujiwara, Y.-I.; Nakamura, E.; Nakamura, M. Org. Lett. 2009, 11, 4306−
4309.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and physical properties of the
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
laur@chem.s.u-tokyo.ac.jp
nakamura@chem.s.u-tokyo.ac.jp
Present Address
†Division of Chemistry and Biotechnology, Graduate School of
Natural Science and Technology, Okayama University, 3-1-1
Tsushimanaka, Kita-ku, Okayama 700-8530, Japan.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(14) (a) Cahiez, G.; Chaboche, C.; Mahuteau-Betzer, F.; Ahr, M. Org.
Lett. 2005, 7, 1943−1946. (b) Nagano, T.; Hayashi, T. Org. Lett. 2005, 7,
491−493.
■
We thank MEXT for financial support (KAKENHI No.
22000008 to E.N. and Grant-in-Aid for Scientific Research on
Innovative Areas No. 25105711 and Grant-in-Aid for Young
Scientists (A) No. 26708011 for to L.I.). T.M. and S.A. thank the
Japan Society for the Promotion of Science for Young Scientists
for a Research Fellowship (No. 26-11422 and No. 23-8207,
respectively). T.M. was supported by the Japan Society for the
Promotion of Science through Program for Leading Graduate
Schools (MERIT).
(15) (a) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E. J.
Am. Chem. Soc. 2008, 130, 5858−5859. (b) Yoshikai, N.; Matsumoto,
A.; Norinder, J.; Nakamura, E. Angew. Chem., Int. Ed. 2009, 48, 2925−
2928. (c) Yoshikai, N.; Asako, S.; Yamakawa, T.; Ilies, L.; Nakamura, E.
Chem.Asian J. 2011, 6, 3059−3065. (d) Ilies, L.; Konno, E.; Chen, Q.;
Nakamura, E. Asian J. Org. Chem. 2012, 1, 142−145.
(16) Do, H.-Q.; Chandrashekar, E. R. R.; Fu, G. C. J. Am. Chem. Soc.
2013, 135, 16288−16291.
(17) We thank a reviewer for suggesting this reaction to us.
(18) Selected reviews: (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L.
Chem. Rev. 2004, 104, 6217−6254. (b) Plietker, B., Ed.; Iron Catalysis in
Organic Chemistry; Wiley-VCH: Weinheim, Germany, 2008. (c) En-
thaler, S.; Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2008, 47, 3317−
REFERENCES
■
(1) (a) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826−834.
(b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110,
624−655. (c) Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2011, 133, 400−
402. (d) Ilies, L.; Chen, Q.; Zeng, S.; Nakamura, E. J. Am. Chem. Soc.
2011, 133, 5221−5223.
3321. (d) Sherry, B. D.; Furstner, A. Acc. Chem. Res. 2008, 41, 1500−
̈
1511. (e) Czaplik, W. M.; Mayer, M.; Cvengros, J.; Jacobi von Wangelin,
A. ChemSusChem 2009, 2, 396−417. (f) Sun, C.-L.; Li, B.-J.; Shi, Z.-J.
Chem. Rev. 2011, 111, 1293−1314.
(2) (a) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46, 677−
685. (b) Li, B.-J.; Shi, Z.-J. Chem. Soc. Rev. 2012, 41, 5588−5598.
(c) Giri, R.; Thapa, S.; Kafle, A. Adv. Synth. Catal. 2014, 356, 1395−
1411. (d) Chen, Q.; Ilies, L.; Yoshikai, N.; Nakamura, E. Org. Lett. 2011,
13, 3232−3234.
(19) (a) Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010, 75, 6061−
6067. (b) Ilies, L.; Nakamura, E. Iron-Catalyzed Cross-Coupling
Reactions. In The Chemistry of Organoiron Compounds; Marek, I.,
Rappoport, Z., Eds.; John Wiley & Sons, Ltd.: Chichester, U.K., 2014.
(c) Nakamura, E.; Hatakeyama, T.; Ito, S.; Ishizuka, K.; Ilies, L.;
Nakamura, M. Iron-Catalyzed Cross-Coupling Reactions. In Organic
Reactions; Denmark, S. E., Ed.; Vol. 83; John Wiley & Sons: 2014.
(20) Nakamura, E.; Sato, K. Nat. Mater. 2011, 10, 158−161.
(21) Matsubara, T.; Asako, S.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc.
2014, 136, 646−649.
(3) Dyker, G., Ed.; Handbook of C−H Transformations; Wiley-VCH:
Weinheim, Germany, 2005.
(4) Ackermann, L. Chem. Commun. 2010, 46, 4866−4877.
(5) (a) Tremont, S. J. J. Am. Chem. Soc. 1984, 106, 5759−5760.
(b) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48,
6097−6100. (c) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010,
132, 3965−3972. (d) Nadres, E. T.; Santos, G. I. F.; Shabashov, D.;
Daugulis, O. J. Org. Chem. 2013, 78, 9689−9714. (e) Zhao, Y.; Chen, G.
Org. Lett. 2011, 13, 4850−4853. (f) Xiao, B.; Liu, Z.-J.; Liu, L.; Fu, Y. J.
Am. Chem. Soc. 2013, 135, 616−619.
(6) (a) Ackermann, L.; Novak
Chem., Int. Ed. 2009, 48, 6045−6048. (b) Ackermann, L.; Novak
Lett. 2009, 11, 4966−4969. (c) Ackermann, L.; Hofmann, N.; Vicente,
́
, P.; Vicente, R.; Hofmann, N. Angew.
́
, P. Org.
D
dx.doi.org/10.1021/ja5066015 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX