Synthesis and intramolecular hydrogen bonding networks of 2,4,6-Tri (o-hydroxyaryl)-1,3,5-Triazines

Article abstract of DOI:10.1021/ol201946f

Functionalized, triaryl substituted triazines were synthesized via the Friedel-Crafts arylation reaction. These conjugated triazines possess unique, intramolecular hydrogen bonding motifs, which provide tunable planarity.

Full text of DOI:10.1021/ol201946f

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5080–5083
Synthesis and Intramolecular Hydrogen
Bonding Networks of 2,4,6-Tri
(o-hydroxyaryl)-1,3,5-Triazines
Gregory Conn and Sara Eisler*
Department of Chemistry, University of New Brunswick, P.O. Box 4400, Fredericton,
New Brunswick, E3B 5A3, Canada
seisler@unb.ca
Received July 19, 2011
ABSTRACT
Functionalized, triaryl substituted triazines were synthesized via the FriedelꢀCrafts arylation reaction. These conjugated triazines possess
unique, intramolecular hydrogen bonding motifs, which provide tunable planarity.
The value of highly conjugated carbon-rich molecules
such as polycyclic aromatic hydrocarbons (PAHs) and
other nanographenes toward the formation of advanced
materials is well established.1 Recent work has shown that
a variety of carbon-rich, atomically precise graphene
derivatives can be synthesized, where size and edge struc-
ture are programmable.2 Their unique structural and
electronic properties are enhanced by their ability to self-
assemble, often resulting in the formation of liquid crystal-
line phases and supramolecular architectures.3
Figure 1. Hydrogen bonding motif of planar, triaryl triazines.
Extended graphene-based nanomaterials containing het-
eroatoms, however, are more rare than the primarily carbon
Maintaining conjugation in heteroatom-containing na-
nographenes is possible by connecting aryl subunits through
both covalent and hydrogen bonds, a strategy that allows
for design flexibility while maintaining or enhancing elec-
tronic properties.5 s-Triazines are a convenient subunit for
this purpose; they possess interesting electronic properties
and are able to form multiple hydrogen bonds.6,7
based systems mentioned above, even though including
atoms other than carbon presents an opportunity to vary
the electronic and physical properties of the resulting graphi-
tic structures.4
€
(1) Wu, J.; Pisula, W.; Mullen, K. Chem. Rev. 2007, 107, 718–747.
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Am. Chem. Soc. 2002, 124, 9121–9128. (c) Wasserfallen, D.; Kastler, M.;
For example, as shown in Figure 1, placement of ortho-
hydroxy substituted aryl groups in the 2,4,6 positions of
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r
10.1021/ol201946f
Published on Web 08/26/2011
2011 American Chemical Society

Scheme 1
1,3,5-triazine allows for the formation of intramolecular
hydrogen bonds between the nitrogen of the central tri-
azine and the hydroxy group of the attached aryl groups.8
These hydroxy groups allow for conjugation between the
triazine ring and the pendant aryl groups, while also
providing a handle for fine-tuning the degree of planarity
in the system, a variable that is known to have a strong
effect on the physical and electronic properties of
molecules,9 oligomers and polymers.10 Although planar,
aryl-substituted triazine systems are known and utilized
frequently as structural units in coordination cages,11 the
highly functionalized, symmetrical structures as proposed
in Figure 1 have yet to be synthesized. We present herein
the synthesis and the physical and electronic properties of
symmetrical, crowded, planar triazines bearing unique
hydrogen bonded networks.
There are a number of established methods to form aryl-
substituted 1,3,5-triazines. Suzuki cross-coupling and ni-
trile trimerization have both been used to form triaryl
triazines.11ꢀ13 The sterically hindered triazine derivatives
of the type in Figure 1, where R ¼ H, are almost non-
existent in the literature, and these aforementioned meth-
ods were ineffective at forming the desired triazines.14
A
variety of organometallic reagents have also been used in
the literature to produce symmetrical and unsymmetrical
triazines,15 although for our targets, the use of Grignard
and organolithium reagents resulted only in the produc-
tion of mono- and diaryl-substituted triazines.16
The FriedelꢀCrafts arylation reaction is the method of
choice for appending bulky aryl substituents to the triazine
core, Scheme 1.14 Readily available starting materials can
be used to obtain the desired products, column chromato-
graphy is not necessary for purification, and high yields are
generally obtained.17,18
As shown in Scheme 1, O-methylated 5 was initially
targeted to provide a derivative that is not capable of
forming intramolecular hydrogen bonds with the triazine
nitrogens. Molecule 5 can be formed in one step from
compound 1 in 70% yield through reaction with AlCl3 and
(8) (a) Stueber, G. J.; Kieninger, M.; Schettler, H.; Busch, W.;
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Phys. Chem. B 1998, 102, 6975–6985. (c) Elbe, F.; Keck, J.; Fluegge,
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Kaim, W.; Ketterle, M. J. Phys. Chem. A 2000, 104, 8296–8306.
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(15) Peng, Z.; Haag, B. A.; Knochel, P. Org. Lett. 2010, 12,
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Chem.;Eur. J. 2010, 16, 50–54. (b) Ciana, C.-L.; Phipps, R. J.; Brandt,
J. R.; Meyer, F.-M.; Gaunt, M. J. Angew. Chem., Int. Ed. 2011, 50,
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work on curved aromatics, see: Steinberg, B. D.; Jackson, E. A.; Filatov,
A. S.; Wakamiya, A.; Petrukhina, M. A.; Scott, L. T. J. Am. Chem. Soc.
2009, 131, 10537–10545. Zhang, B.; Manning, G. P.; Dobrowolski,
M. A.; Cyranski, M. K.; Bodwell, G. J. Org. Lett. 2008, 10, 273–276.
(10) (a) Castelaın, M.; Salavagione, H. J.; Gomez, R.; Segura, J. L.
Chem. Commun. 2011, 47, 7677–7679. (b) Banerjee, M.; Shukla, R.;
Rathore, R. J. Am. Chem. Soc. 2009, 131, 1780–1786. (c) Wijsboom,
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Am. Chem. Soc. 2010, 132, 15553–15555.
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S. K.-H.; Zeng, L.; Chen, S. H. Chem. Mater. 2006, 18, 204–213. (c)
Su, S.-J.; Sasabe, H.; Pu, Y.-J.; Nakayama, K.-i.; Kido, J. Adv. Mater.
2010, 22, 3311–3316.
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Org. Lett., Vol. 13, No. 19, 2011
5081

cyanuric chloride in monochlorobenzene. Purification by
recrystallization provided pure product. Encouraged by
this result, nonaol 6, which can form a petal-shaped
network of hydrogen bonds around the triazine core
consisting of six ꢀOH N interactions, was targeted.
3 3 3
Phloroglucinol 2 was treated to very similar conditions as
methylated 1, although due to the low solubility of the
starting material 2, the reaction was carried out in a
mixture of DCM and ether. Upon workup, triazine 6, with
a total of 9 hydroxy groups, was isolated in 96% yield in
one step. Despite the low solubility of this very polar
compound in most solvents, purification was easily per-
formed via a centrifuge wash process.
Derivatives 7 and 8 were synthesized to determine the
effect of altering the substitution at the ortho position on
the hydrogen-bonding system around the triazine core.
Selective methylation of phloroglucinol provided disubsti-
tuted phenol 3 in good yields.19 Treatment with AlCl3 and
cyanuric chloride in 1,2-dichloroethane then provided the
Figure 2. Absorption properties of compounds 2, 5, 6, and 7 in
acetonitrile.
hexamethoxy derivative 7, with only three OH N inter-
3 3 3
actions. As one would predict, molecule 7 was one of
several products formed in this reaction as other less
symmetrical triazine derivatives were also produced. How-
ever, triol derivative 7 could be obtained pure from the
crude reaction mixture through a series of washes and
extractions in19% yield. Compound 8, with a hydroxyand
a hydrogen in the ortho positions, was synthesized accord-
ing to literature procedure from resorcinol.20
The UVꢀvisible spectra of compounds 5, 6, and 7 are
presented to demonstrate the degree of planarity in these
compounds, Figure 2. Nonplanar, fully methylated deri-
vative 5 has a λmax of 297 nm; the conjugation is limited by
the bulky ortho substituents. The nonaol 6 displays a
significantly red-shifted band, λmax at 331 nm, indicating
increased conjugation and therefore increased planarity
between the phloroglucinol aryl groups and the triazine
ring in comparison to methyl-protected derivative 5. In
addition, triazine 7, with 3 methoxy groups in the ortho
positions, alsopossessesabandat335 nm. Presumably, the
phenolic OH groups in 7 are forming a hydrogen-bonded
network with the triazine nitrogens despite the added bulk
of the methoxy groups. In fact, the increase in intensity of
the absorption band of 7 over 6, in addition to the slight
red-shift of 7, both indicate slightly more conjugation than
in 6.21
peak at 12.84 ppm is assigned as the ortho-hydroxy that is
forming a hydrogen bond with the triazine. Similar peaks
are observed for nonaol 6 at 12.28 ppm for the ortho-
hydroxy groups, and at 10.12 ppm for the para-hydroxy
group.22 The downfield position of the ortho peak in
comparison to the para-hydroxy group in 6 indicates that
intramolecular hydrogen bonds are formed between the
ortho-hydroxy moieties and the triazine ring, despite the
steric bulk present at the ortho positions. However, the
broadness of the ortho-hydroxy peak of 6 and the fact that
it is upfield in comparison to the equivalent peak in 8
indicate that while still providing conjugation, the three-
centered hydrogen bonding network is weaker in the more
symmetrical nonaol 6 than in 8.23
Replacing one of the ortho-hydroxy groups of 6 with a
methoxy group as in compound 7 resulted, surprisingly, in
the formation of what appears to be a much stronger
hydrogen bonded network. The intramolecular OH
N
3 3 3
hydrogen-bond of 7 appears at 14.97 ppm, 2.69 ppm
downfield from 6 and 2.13 ppm downfield from 8 (in fact,
1.13 ppm downfield of any comparable molecule in the
literature).24 The methoxy groups supply minimal bulki-
ness as they can flip away from the nitrogen without
disturbing the conjugation between the triazine and the
pendant rings. The strong hydrogen bond network ob-
served in 7 is likely due in part to the lone pair on the
methoxy oxygen, allowing the formation of a threeꢀcenter,
bifurcated hydrogen bond.
1H NMR spectroscopy gives some insight into the
hydrogen bonding pattern at the core of these molecules
and their spectra in d6-DMSO are compared in Figure 3.
Hexaol 8 has two downfield OH peaks; the peak at 10.45
ppm is assigned to the para-hydroxy and the downfield
The effect of concentration on compounds 6 and 7 was
explored to determine if the intramolecularly hydrogen
bonded network around the triazine core was available for
(19) Gallardo-Goday, A.; Fierro, A.; McLean, T. H.; Castillo, M.;
Cassels, B. K.; Reyes-Parada, M.; Nichols, D. E. J. Med. Chem. 2005, 48,
2407–2419.
(22) Integrations support this assignment.
(20) (a) Zan, S.; Jiang, W.; Shao, Y. Jingxi Huagong 2007, 24, 1106–
1108. (b) Harda, W. B.; Milionis, J. P.; Pinto, F. F. US Patent 3,268,474;
American Cyanamid Co.: Princeton, NJ, 1966.
(21) Two bands appear in the UVꢀvisible spectrum of compound 8
corresponding to ππ* and CT bands, an electronic feature observed in 8
due to the possession of fewer OR groups than 5, 6, and 7. As such, a
useful comparison cannot be made with 8 in this study. See ref 8c.
(23) Diyabalanage, H. V. K.; Ganguly, K.; Ehler, D. S.; Collis, G. E.;
Scott, B. L.; Chaudhary, A.; Burrell, A. K.; McCleskey, T. M. Angew.
Chem., Int. Ed. 2008, 47, 7332–7334.
(24) As measured in CDCl3 for comparison with literature values.
See: Sosnovskikh, V.; Usachev, B. I.; Sizov, A. Y.; Vorontsov, I. I.;
Shklyaev, Y. V. Org. Lett. 2003, 5, 3123–3126.
5082
Org. Lett., Vol. 13, No. 19, 2011

However, triol 7 was not observed to undergo exchange
with H2O in either the NOESY or saturation transfer
experments, indicating that the exchange rate was below
the limit of detection in this tightly bound system on the
NMR time scale.
Calculations have provided some insight into the struc-
tural differences between structures 6, 7 and 8, Figure 4.27
The results indicate that while triol 7 and hexaol 8 possess
very planar structures with average dihedral angles of 3°
and 7°, respectively, and possess near perfect bond angles
for the intramolecular hydrogen bond, nonaol 6 is at its
lowest energy conformation when the pendant phloroglu-
cinyl arms are twisted by approximately 20° from the
central triazine ring. As can be seen in Figure 4a, the
ortho-hydroxy groups are pointed in toward the triazine
nitrogens to form weak hydrogen bonds with the lone pairs.
1
Combined with the H NMR data, the calculations in-
Figure 3. 1H NMR spectra in d6-DMSO at 298 K of nonaol 6,
hexaol 8, and triol 7.
dicate that this nonaol system of compound 6 is dynamic,
with the phloroglucinyl arms rotating back and forth
around the triazine core.
intermolecular interactions.25 The ortho and para phenol
peaks of 6 are clearly observable at 12.28 and 10.12 ppm,
respectively, at low concentration. The resonance corre-
sponding to the ortho-hydroxy resonance broadens signifi-
cantly as the solution is concentrated, while the para peak
remains at the same position. At the final concentration of
52 mM, the ortho peak disappears completely into the
baseline, indicating that exchange of these protons is faster
at higher concentration. It is likely that compound 6 loosely
associates at high concentrations and the ortho-hydroxy
groups undergo exchange with adjacent molecules. Presum-
ably, the para-hydroxy is hydrogen bonded to the DMSO
solvent at all concentrations, hence the lack of concentration
dependence. A concentration experiment was also per-
formed on triol 7, with different results. No broadening or
shifting of the ortho-hydroxy peak was observed at all,
indicating that the strong intramolecular bonds formed in
7 successfully maintain planarity as concentration is
In conclusion, we have successfully synthesized new,
crowded, triazine based aromatic compounds. These
highly conjugated structures possess interesting hydrogen
bonding patterns that allow for fine-tuning of planarity.
Figure 4. Minimized structures for triazines: (a) nonaol 6, (b)
hexaol 8, and (c) triol 7. Geometry optimization was undertaken
at the B3LYP/6-31G* level.
This feature will be exploited in the future through the
synthesis of extended, conjugated networks containing
these monomer units.
1
increased.26 This result supports the H NMR and the
UVꢀvisible spectroscopic data presented above, indicating
that the ortho-OH groups on 6 are available for exchange
with adjacent molecules and are in fact capable of partici-
pating in both intra- and intermolecular interactions. In
contrast, for molecule 7 no visible change with concentra-
tion is observed, indicating that the ortho-OH is strongly
held in the intramolecular hydrogen bond and is not avail-
able for facile exchange. A series of NOESY and saturation
transfer experiments were performed on samples of com-
pounds 6ꢀ8 to probe this feature. 2-D NOESY experiments
revealed that the ortho- and para-hydroxy groups of nonaol
6 undergo rapid exchange with each other and with water,
while hexaol 8 did not appear to undergo exchange with
H2O. A more sensitive 1-D NOESY indicated that com-
pound 8 does in fact undergo medium-slow exchange.
Acknowledgments. This work was supported by NSERC
and the New Brunswick Innovation Foundation. The
advice of Dr. Fritz Grein (UNB) is gratefully acknowl-
edged, and we thank Dr. Larry A. Calhoun (UNB) whole-
heartedly for NMR experiments and analysis.
Supporting Information Available. Synthetic procedures,
1
characterization data, and H and 13C NMR spectro-
scopic data (including NOESY experiments) for com-
pounds 5ꢀ8. This material is available free of charge via
the Internet at http://pubs.acs.org.
(26) Due to the low solubility of compound 7 in DMSO, the
concentration dependence experiment of triol 7 could only be performed
in the lower concentration range. This concentration experiment for 7
was therefore also repeated in CDCl3 and is reproduced in the Support-
ing Information.
(25) Concentration experiment for compound 6 is reproduced in the
Supporting Information.
(27) Spartan ’10; Wavefunction, Inc.: Irvine, CA, 2010.
Org. Lett., Vol. 13, No. 19, 2011
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