Condensed Fukui function predicts innate C-H radical functionalization sites on multi-nitrogen containing fused arenes

Article abstract of DOI:10.1039/c4ra01853b

The condensed Fukui function could be correlated with the reported innate C-H radical functionalization sites on some heterocycles. This computational method was further extended to predict the innate C-H functionalization sites on multi-nitrogen containi

Full text of DOI:10.1039/c4ra01853b

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Condensed Fukui function predicts innate C–H
radical functionalization sites on multi-nitrogen
containing fused arenes†
Cite this: RSC Adv., 2014, 4, 17262
Received 3rd March 2014
Accepted 24th March 2014
a
ab
b
a
a
Yuchi Ma,‡ Jin Liang,‡ Dongmei Zhao, Yue-Lei Chen,* Jingkang Shen*
a
and Bing Xiong*
DOI: 10.1039/c4ra01853b
www.rsc.org/advances
The condensed Fukui function could be correlated with the reported hampered by the high nitrogen content and fused structures.
innate C–H radical functionalization sites on some heterocycles. This Furthermore, it is difficult to apply Baran's empirical rules on
computational method was further extended to predict the innate C– such complex systems to predict the innate C–H functional-
H functionalization sites on multi-nitrogen containing fused arenes, ization sites.
and the calculated results were validated by experimental outcomes.
In past decades, the condensed Fukui function (eqn (1)) was
utilized to rationalize and predict the reactivities of various
organic reaction systems. As shown in eqn (1), the condensed
4
Due to the peculiar electronic character of many nitrogen-con-
taining arenes, harsh reaction conditions or guided function-
Fukui functions are calculated based on atomic charges
obtained from electron density population analysis. Inspired by
the previous studies, which indicated that the innate C–H
functionalization of heterocycles was strongly related to their
1
alization are oen required for a successful modication.
These methods either reduce functional group tolerance or add
synthetic steps. To avoid these problems, philosophically, it is
intriguing to follow and make use of the native reactivity of
these heterocycles. However, only recently has this philosophy
been reincarnated by the radical-generating sulnates.
According to recent progress made by Baran et al., innate C–H
functionalization has become a powerful strategy for hetero-
3
intrinsic electronic properties and reactivities, we proposed
that this inexpensive computational method could be used in
parallel with Baran's empirical prediction rules to understand
and predict the innate C–H functionalization. Thus, we proved
that the condensed Fukui functions could be correlated with the
innate C–H functionalization sites reported by Baran et al. More
importantly, we performed experiments to verify that this
inexpensive computational method could be extended to
predict the innate C–H radical alkylation sites on multi-nitrogen
containing fused arenes.
2
arene functionalization. Along this line, Baran et al. further
established empirical rules for the prediction of innate C–H
radical functionalization site on some nitrogen-containing
3
heteroarenes.
Multi-nitrogen containing fused arenes are important
scaffolds in medicinal chemistry and drug discovery. Direct
functionalization on these ring systems is very useful for
diversication and proprietary purposes. On the basis of
preliminary study, we found that the radical-generating sul-
þ
ꢀ
A
¼ q ꢀ q
N
A
Nþ1
Nucleophilic attack : f
A
A
A
Electrophilic attack : f
A
¼ qNꢀ1 ꢀ q
(1)
ꢀ
N
0
A
Nꢀ1
A
Radical attack : f
A
¼ ðq
ꢀ q Þ 2
Nþ1
A
N
The denition of condensed Fukui functions: q
partial charge of atom A in the molecule with N electrons, while
Nꢀ1 and qN+1 are partial charges of atom A in the molecule with
is the

nate salt chemistry works well on such systems. However,
NMR characterization of this type of product was oen
A
A
q
N ꢀ 1 electrons and N + 1 electrons, respectively.
Initially, we assessed the correlation between condensed
Fukui functions and the previous experimental results of Baran
a
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi
Road, Shanghai 201203, P. R. China. E-mail: chenyuelei@gmail.com; bxiong@simm.
ac.cn
b
et al. Seven representative molecules (1 through 6, and
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 protonated 3) were selected from the vast collection and sub-
3
Wenhua Road, Shenyang 100016, P. R. China
jected to computation. For the rst step, the molecules with N
†
Electronic supplementary information (ESI) available: Experimental details,
crystallographic data, and copies of NMR spectra. CCDC 979231, 979233,
79222 and 979230. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4ra01853b
electrons were subjected to geometry optimization at B3LYP/6-
5
31+G** level along with the solvent (DMSO) continuum model.
9
Concerning the atomic charge calculation for Fukui function
6
analysis, previous studies demonstrated that the Hirshfeld
‡
These authors contributed equally to this work.
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population analysis serves as a good candidate for condensed
Fukui function calculation, since it constantly gives the positive
Fukui function values and shows better accuracy in predicting
the reactive sites. Thus, as the second step, the geometry opti-
mized structures were modied to yield new molecules with N +
1
and N ꢀ 1 electrons, which were subjected to single point
calculation to yield the Hirshfeld charges and then the three f
values in eqn (1). We immediately found that the condensed
A
0
7
Fukui function for radical attack (f
A
value) could not be
associated with the experimentally validated reaction sites.
However, we were surprised to see that the condensed Fukui
+
function of nucleophilic attack (fA value) correlated well with
the reported reaction sites, as the reaction site had the largest
+
A
Fig. 2 Calculated f
of carbon atoms on multi-nitrogen containing
+
3
+
f
A
A
value in all the molecules. Higher f values on selected fused arenes.
molecules from Baran's work are illustrated in Fig. 1. For
+
compound 1, C5 with the highest f
A
value was characterized as
multi-nitrogen containing fused arenes (compounds 7–14) that
are frequently encountered scaffolds in medicinal chemistry,
and calculated the corresponding condensed Fukui function.
Solely based on Baran's empirical rules, it is not straightforward
the major isopropylation site, while C4 with the second highest
fA value was also functionalized, albeit to a lesser extent. For
+
compound 2, the observed single isopropylation site again
+
corresponded to C5 with the highest f value. For compound 3,
A
+
to predict the reaction site of these compounds. However, with
the f
A
values of C2 and C3 were quite close, rendering the
+
the condensed Fukui function method, the f
rapidly obtained. Higher f
A
values were
prediction rather difficult. Experimentally, the slightly higher
C3 (0.087) was demonstrated to be more functionalized. On
protonated 3, the preferred isopropylation site was reverted
dramatically according to Barran et al., and our calculation
+
A
values are displayed for the eight
substrates in Fig. 2.
Meanwhile, to verify the computational results in Fig. 2, we
devised radical isopropylation on compounds 7–14. Although it
is convenient to follow Baran's protocol (Zn(i-PrSO ) , TBHP,
+
agreed with this nding by a signicant elevation of the fA
2
2
value on C2. On bis-nitrogenated mono rings 4 and 5, the
ꢁ
3
DMSO, 50 C), such radical alkylation on multi-nitrogen con-
taining arenes was surprisingly rare. The difficulties in product
isolation and structure elucidation might account for this
scarcity. Nevertheless, with careful experimentation, we were
able to separate and characterize the major isopropylation
products (15–22) on all eight starting materials. Due to multi-
nitrogen substitutions present in the ring system, NMR analysis
of the isopropylation sites became rather complicated and less
reliable. We managed to obtain single crystals of compounds
calculation indicated a large gap between the rst and the
+
second highest f
A
values. As anticipated, for both compounds,
experimentation found only single isopropylation on the site
+
with the highest f
A
value. Compound 6 is a system of signicant
complexity. The condensed Fukui function predicted C9 as a
major site for modication, and this has been proved by the
reported results (90% isopropylation on C9). However, it should
be noted that the minor isopropylation (10%) site was observed
on C2, which could not be forecasted by the calculation.
7
+
A
16, 18, 20, and 22, and the corresponding XRD data further
corroborated the NMR analysis. The reagents and reaction
conditions are shown in Scheme 1.
Generally, it was fair to conclude that our calculated f
value
showed good agreement with the experimental isopropylation
sites found by Baran et al.
Encouraged by the good consistency between the experi-
mental and computational results, we further selected eight
+
A
Fig. 1 Calculated f
of carbon atoms on representative nitrogen
2 2
containing arenes (highest value in red, second highest in blue) and the Scheme 1 ꢁReagents and reaction conditions: (a) Zn(i-PrSO ) , TBHP,
reported radical alkylation sites with ratio or yield.
DMSO, 50 C.
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As indicated in Fig. 2 and Scheme 1, compounds 7–11 were
exclusively functionalized on the sites with the highest fA values
to yield the mono isopropyl derivatives 15–19. On compounds 12,
Chemistry, Blackwell Science Ltd, 4th edn, 2000; (c)
T. Br u¨ ckl, R. D. Baxter, Y. Ishihara and P. S. Baran, Acc.
Chem. Res., 2012, 45, 826–839.
+
13, and 14, double isopropylation products (20, 21 and 22) were 2 (a) Y. Fujiwara, V. Domingo, I. B. Seiple, R. Gianatassio,
experimentally identied and the substitution positions were
M. D. Bel and P. S. Baran, J. Am. Chem. Soc., 2011, 133,
3292–3295; (b) Y. Ji, T. Brueckl, R. D. Baxter, Y. Fujiwara,
I. B. Seiple, S. Su, D. G. Blackmond and P. S. Baran, Proc.
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Y. Fujiwara, J. A. Dixon, F. O'Hara, E. D. Funder,
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2012, 492, 95–99; (d) Y. Fujiwara, J. A. Dixon,
R. A. Rodriguez, R. D. Baxter, D. D. Dixon, M. R. Collins,
D. G. Blackmond and P. S. Baran, J. Am. Chem. Soc., 2012,
134, 1494–1497; (e) Q. Zhou, J. Gui, C. M. Pan, E. Albone,
X. Cheng, E. M. Suh, L. Grasso, Y. Ishihara and P. S. Baran,
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A. Ruffoni, R. Gianatassio, Y. Fujiwara, E. Sella, D. Shabat
and P. S. Baran, Angew. Chem., Int. Ed., 2013, 52, 3949–3952.
+
again consistent with the rst and the second highest f
A
values
of each starting material. From these examples, we also noticed
that compound 9 with a small gap between the rst and the
+
A
second highest f
values yielded only mono isopropylated
product 17, while the large gap on compound 14 did not prevent
the formation of double functionalization product 22. It was,
therefore, reasonable to suggest that the gap value was not
signicantly relevant to the number of isopropylation sites.
Nevertheless, from the above-described results, several general
trends can be identied: (1) at least on typical mono- or multi-
nitrogen containing single or fused rings, it was possible to use the
+
f
A
values from the condensed Fukui function to predict the
radical alkylation sites with Baran's synthetic method; (2) on
multi-nitrogen containing fused arenes, if mono alkylation is
observed on MS or NMR spectra, the reaction site would likely be 3 F. O'Hara, D. G. Blackmond and P. S. Baran, J. Am. Chem. Soc.,
+
A
the one with the highest f
value; (3) on multi-nitrogen containing
2013, 135, 12122–12134.
fused arenes, if double alkylation is found experimentally, the sites 4 (a) P. W. Ayers, W. Yang and L. J. Bartolotti, Fukui Function,
+
with the top two f
A
values would probably be involved.
in Chemical Reactivity Theory: A Density Functional View, ed. P.
K. Chattaraj, CRC Press, 2009, ch. 18, pp. 255–267; (b)
R. K. Roy, J. Phys. Chem. A, 2004, 108, 4934–4939; (c)
M. H. Cohen and A. Wasserman, J. Phys. Chem. A, 2007,
111, 2229–2242.
Conclusions
In conclusion, we utilized the inexpensive condensed Fukui
function method to generate a map of f
+
A
values on typical 5 (a) C. Lee, W. Yang and R. G. Parr, Phys. Rev. B: Condens.
mono- or multi-nitrogen containing single or fused rings. We
also carried out radical alkylation on multi-nitrogen containing
arenes with alkylsulnate salts, and unambiguously character-
Matter Mater. Phys., 1988, 37, 785–789; (b) J. Tomasi,
B. Mennucci and R. Cammi, Chem. Rev., 2005, 105, 2999–
3093.
ized the products using MS, NMR and XRD methods. It was 6 (a) W. Tiznado, E. Chamorro, R. Contreras and P. Fuentealba,
found that the experimental innate radical alkylation sites
J. Phys. Chem. A, 2005, 109, 3220–3224; (b) F. D. Pro,
C. V. Alsenoy, A. Peeters, W. Langenaeker and P. Geerlings,
J. Comput. Chem., 2002, 23, 1198–1209; (c) B. Pint ´e r,
F. D. Pro, T. Veszpr ´e mi and P. Geerlings, J. Org. Chem.,
2008, 73, 1243–1252; (d) P. P ´e rez, A. Aizman and
validated by Baran et al. and our group could be well correlated
+
A
with the position of high f
values. Therefore, we believe that,
in a limited, but highly important, subset of multi-nitrogen
containing arenes, the condensed Fukui function method could
assist the understanding of Baran's innate radical C–H
functionalization.
R. Contreras, J. Phys. Chem. A, 2002, 106, 3964–3966; (e)
C. Frontana, A´ . V ´a zquez-Mayagoitia, J. Garza, R. Vargas and
I. Gonz ´a lez, J. Phys. Chem. A, 2006, 110, 9411–9419.
See ESI† for details.
7
Notes and references
1
(a) T. L. Gilchrist, Heterocyclic Chemistry, Prentice Hall, 3rd
edn, 1997; (b) J. A. Joule and K. Mills, Heterocyclic
17264 | RSC Adv., 2014, 4, 17262–17264
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