Synthetic duplex oligomers: Optimizing interstrand affinity through the use of a noncovalent constraint

Article abstract of DOI:10.1016/S0040-4020(01)01090-0

The covalent casting of a one-dimensional hydrogen-bonding motif permits the design of oligomers possessing a predetermined duplex mode of aggregation. In this account, studies on the hydrogen bond mediated self-assembly of dimeric duplex oligomers 2 in s

Full text of DOI:10.1016/S0040-4020(01)01090-0

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 721±725
Synthetic duplex oligomers: optimizing interstrand af®nity
through the use of a noncovalent constraint
Eric A. Archer, David F. Cauble, Jr., Vincent Lynch and Michael J. Krischep
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA
Received 28 May 2001; revised 21 August 2001; accepted 22 August 2001
AbstractÐThe covalent casting of a one-dimensional hydrogen-bonding motif permits the design of oligomers possessing a predetermined
duplex mode of aggregation. In this account, studies on the hydrogen bond mediated self-assembly of dimeric duplex oligomers 2 in solution
are described. Two-fold self-association in solution is established by 1H NMR, and the intended mode of assembly is further corroborated via
X-ray crystallographic analysis. An increase in interstrand af®nity of over three orders of magnitude is observed upon substitution of nitrogen
for oxygen in the oligomer backbone, owing to preorganization of the molecular strand in the binding effective conformation as directed by
the formation of an internal hydrogen bond. These data provide insight into the structural and interactional features of the oligomers required
for high af®nity/speci®city binding in organic media. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Here, we explore the structural and interactional features of
synthetic duplex oligomers required for high af®nity/
speci®city binding. We begin by optimizing the self-
association of the simplest oligomer, duplex dimer 2, in
solution. These studies reveal that an ostensibly modest
structural modi®cation of the oligomer backbone, the substi-
tution of oxygen for nitrogen, produces an increase in inter-
strand af®nity of greater than three orders of magnitude.
This effect owes to preorganization of the oligo-amino-
triazine in the form of an internal hydrogen bond.
In nature, functional nanostructures are assembled from
biomacromolecular precursors such as proteins and DNA.
Such biomacromolecules possess exceptional mechanical
properties (e.g. arachnid silk ®bers),1 remarkable catalytic
functions (e.g. cytochrome-p450),2 and high-density infor-
mation storage capabilities (e.g. CD-ROM technology
,108 bits/cm2 versus DNA ,1021 bits/cm3).3 With such
inspiration from nature, it is not surprising that a broad
goal of modern research relates to understanding the key
factors that govern self-assembly events. Such studies
have primarily focused on the assembly of small molecular
precursors.4 In contrast, few rational approaches to the
directed organization of oligomeric precursors have been
forthcoming.5,6,7 As part of a general investigation into the
assembly of molecular strands, we have introduced the
`covalent casting' of one-dimensional hydrogen-bonded
superstructures as a general strategy toward oligomers of
predetermined topography, speci®cally a duplex mode of
aggregation.6,8 By developing technologies for the induction
of prede®ned higher order structural motifs via self-
assembly of oligomeric and polymeric precursors, steps
are taken toward the de®nition of a platform for the de
novo design of abiotic polymer-based devices of nanometric
dimensions, which, upon suf®cient development, may
embody capabilities beyond those displayed by their natural
counterparts.
2. Results and discussion
In order to selectively direct the aggregation of polyvalent
oligomers, subtle manipulation of the myriad weak forces
contributing to the overall binding event is required. For the
design of topographically de®ned molecular strands, we
make use of the noncovalent connectivities de®ned by
known one-dimensional hydrogen bonding motifs as `blue-
prints' for the introduction of commensurate covalent
scaffolding.6 For example, in the solid state, 2-amino-4,6-
dichlorotriazine yields a ribbon I comprised of hydrogen-
Ê
bonded dimers. An inter-chlorine distance of ca 3.3 A
between alternate triazines of ribbon I was obtained from
X-ray crystallographic data.8 The supramolecular frame-
work may be `covalently cast' by connecting alternate
aminotriazines with 1,3-diol or 1,3-aminoalcohol linkages.
In this way, covalent strands III are devised, which are
structurally encoded with a highly selective interactional
algorithm, i.e. the expression of the duplex superstructure
II (Scheme 1).
Keywords: hydrogen bonding; self-assembly; foldamer; polymer structure;
duplex oligomer.
Corresponding author. Tel.: 11-512-232-5892; fax: 11-512-471-8696;
e-mail: mkrische@mail.utexas.edu
p
Optimum interstrand af®nity requires engineering structural
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)01090-0

722
E. A. Archer et al. / Tetrahedron 58 (2002) 721±725
Scheme 1. Covalent casting of the one-dimensional H-bonding motif I obtained upon self-assembly of 2-amino-4,6-dichlorotriazine through the introduction
of linking groups. The resulting duplex strand II exists in equilibrium with the single-stranded oligomer III.
For the synthesis of the dimeric duplex oligomers 2a±2c, it
was desirable to develop a convergent, modular sequence
that would allow access to a series of analogues in prepara-
tive quantities. The diol-linked bis-aminotriazines 2a and 2b
were prepared using our previously described synthetic
protocol.8 Thus, 1,3-diols 1a and 1b, obtained via alkylation
of diethyl malonate followed by LiAlH4 reduction, were
exposed to cyanuric chloride. Aminolysis of the resulting
triazinylated diols provides 2a and 2b. The preparation of
Figure 1. An internal NH´´´OH-bond preorganizes aminoalcohol-linked
the aminoalcohol-linked bis-aminotriazine 2c requires
oligotriazines.
sequential triazinylation of the BOC-protected amino-
alcohol 1c, which is prepared via alkylation of ethyl cyano-
acetate followed by LiAlH4 reduction and, ®nally,
N-protection. Treatment of 1c with cyanuric chloride
followed by exposure to ammonia gives the mono-amino-
triazine 1d. Removal of the BOC-group unmasks the latent
amine nucleophile, which upon exposure to 2-amino-4,6-
dichlorotriazine yields 2c (Scheme 2).
features of the oligomer backbone to enhance the population
of binding-effective conformers. Geminal substitution of the
inter-triazine linking group should promote adoption of the
requisite syn-periplanar geometry via Thorpe±Ingold
effect.9 However, in the case of 1,3-diol linking groups, a
syn-periplanar arrangement elicits unfavorable steric and
electrostatic interactions due to eclipsed C±O bonds. The
nonbonded interactions evident in the diol-linked dimers 2a
and 2b may be transformed into bonded interactions through
the utilization of an aminoalcohol linking group as in 2c,
which embodies an intramolecular NH´´´O hydrogen bond
(Fig. 1).
The interstrand af®nity of aminotriazine oligomers may be
estimated by the determination of association constants via
1H NMR dilution studies (see Fig. 3 for a representative 1H
NMR dilution plot).10,11 For the diol-linked bis-amino-
triazine 2a, self-association occurs through the action of
Scheme 2. Synthesis of diol-and aminoalcohol-linked aminotriazine dimers 2a±2c. Reagents: (a) cyanuric chloride, 2,6-lutidine, DCM, re¯ux (b) anhydrous
NH3, 258C (c) HCl, 1,4-dioxane, CH2Cl2, 258C (d) 2-amino-4,6-dichloro-[1,3,5]triazine, iPr2NEt, CHCl3, re¯ux.
Scheme 3. Self-assembly of monomer 1e and dimers 2a and 2c.

E. A. Archer et al. / Tetrahedron 58 (2002) 721±725
723
1
Table 1. Association constants (M21) determined by H NMR
Compound
Percent d6-DMSO in CDCl3 (v:v)
0%
5%
10%
1e
2a
2c
2.9
100
NDa
±
9.2
28,000
±
2.0
1100
a
1
Dissociation was not observed within the detection limits of H NMR.
six hydrogen bonds (Scheme 3). Dilution studies performed
at room temperature ®t a two-fold self-association model
with low error, yielding the following dimerization constant
in neat CDCl3: log(K1)ˆ2.0^0.10 (K1ˆ100 M21) (Table 1).
The intended duplex mode of assembly was corroborated
via X-ray crystallographic analysis of the structurally
related 2,2-dibenzyl-1,3-diol-linked species 2b (Fig. 2).
This association constant is relatively low for a complex
bound by six hydrogen bonds. To con®rm that 2a was not
aggregating through the formation of only two hydrogen
bonds, dilution studies were performed on mono-triazine
1e. An association constant of log(K1)ˆ0.46^0.026
(K1ˆ2.9 M21) was obtained in the same medium (Table
1). The disparity between association constants obtained
for 1c and 2a, in addition to the crystal structure of 2a,
support the proposed mode of assembly. While an asso-
ciation constant corresponding to the oligomerization of
(2a)2 to yield [(2a)2]n (i.e. K2) could not be extracted from
the dilution data, compound 1c may also serve as a model
for the estimation of K2.
Figure 3. A representative 1H NMR dilution plot. Chemical shift values of
the methylene protons adjacent to the oxygen atom in the linker or amino-
alcohol-linked dimer 2c were monitored as a function of [2c] in 5%
d6-DMSO/CDCl3 (v:v). The curved line represents the calculated ®t of
the experimental data points.
ment. In order to witness dissociation of the duplex in a
concentration range suitable for NMR studies, a more
competitive medium was required. Therefore, dilution
studies were performed in d6-DMSO/CDCl3.14 For the
aminoalcohol-linked dimer 2c, dilution in 5% d6-DMSO/
CDCl3 (v:v) yielded an association constant of log(K1)ˆ
4.45^0.56 (K1ˆ28,000 M21). This value is more than
three orders of magnitude greater than that observed for
the analogous diol-linked dimer 2a in the same medium,
log(K1)ˆ0.96^0.06 (K1ˆ9.2 M21). Dilution studies per-
formed on 2c in 10% d6-DMSO/CDCl3 (v:v) yielded an
association constant of log(K1)ˆ3.1^0.20 (K1ˆ
1100 M21), whereas the diol-linked species 2a yielded an
association constant of log(K1)ˆ0.32^0.02 (K1ˆ2.0 M21).
In this case, aminoalcohol-linked bis-aminotriazine 2c
exhibits an association constant more than two orders of
magnitude greater than the diol-linked species 2a (Fig. 3).
In principle, the low binding constant observed for 2a might
stem from unfavorable secondary electrostatic interactions
between adjacent hydrogen bond donor±acceptor pairs12
and sub-optimal pKa matching.13 However, as previously
outlined, diminished interstrand af®nity was anticipated
for 2a on the basis of steric and electrostatic repulsion
between oxygen atoms incurred upon adoption of the
binding-effective conformation. For aminoalcohol-linked
dimer 2c, nonbonded interactions evident in 2a are
exchanged for bonded interactions. Consequently, higher
binding af®nities should result. Upon dilution in neat
CDCl3, negligible changes in chemical shift for all signals
of 2c were observed, suggesting the persistence of the
The profound increase in interstrand af®nity observed for
aminoalcohol-linked bis-aminotriazine 2c deserves some
comment. For 2c, preorganization of the binding residues
is induced through the action of a noncovalent constraint.
For covalently constrained systems, the reduction of
entropic terms is offset by an enthalpic penalty if the binding
sites are restricted to a sub-optimal geometry.15 Non-
covalent interactions are weak and, hence, are amenable
to considerable distortion accompanied by minimal loss in
energy.16 As such, noncovalent constraints should allow for
an `induced ®t' between binding residues. While we have
yet to compare 2c to a covalently constrained analogue, an
induced ®t between strands may account for the dramatic
increase in interstrand af®nity.
1
duplex (2c)2 at the detection limits of the H NMR experi-
3. Conclusion and outlook
The covalent casting of one-dimensional hydrogen bonding
motifs represents an effective and rational strategy toward
molecular strands that embody prede®ned modes of
assembly. Here, we establish duplex formation in solution
and demonstrate that ®ne-tuning of the structural and inter-
actional features of the oligomer backbone can produce
profound increases in complex stability. Through the
covalent casting of alternative one-dimensional hydrogen
bonding motifs, it should be possible to design a diverse set
of duplex oligomers that assemble via mutually orthogonal
Figure 2. X-Ray crystal structure of 2b revealing the encoded duplex mode
of association. Top: view orthogonal to the plane of the H-bonded tape.
Bottom: view along the plane de®ned by the H-bonded tape revealing the
eclipsed C±O bonds of the diol linkage.

724
E. A. Archer et al. / Tetrahedron 58 (2002) 721±725
modes of recognition. Ultimately, conjugation of
`orthogonal' strand segments will enable the creation of
information-rich oligomers capable of sequence speci®c
hybridization.
benzyl)-3-(3,5-bis-decyloxy-phenyl)-2-hydroxymethyl-
propyl]-carbamic acid tert-butyl ester 1c18 (4.00 g,
4.08 mmol, 100 mol%) in toluene (100 mL, 0.04 M) was
added 2,6-lutidine (0.83 mL, 7.12 mmol, 175 mol%)
followed by cyanuric chloride (1.20 g, 6.51 mmol, 160
mol%). The resulting orange mixture was stirred and heated
to 808C under N2 for 18 h. The mixture was then diluted
with toluene and washed with citric acid (15% aqueous
solution) and brine. The organic layer was treated with
activated charcoal, dried over Na2SO4 and was ®ltered
through celite and concentrated in vacuo, yielding an
amber oil (5.90 g). The oily residue was dissolved in
CH2Cl2 (50 mL) and treated with NH3 (2.0 M solution in
iPrOH, 8 mL, 16.0 mmol, 400 mol%). After 3 h stirring at
ambient temperature, the mixture was diluted with dichloro-
methane and washed with H2O and brine, then dried with
Na2SO4, ®ltered, and concentrated in vacuo. The resulting
amber oil was puri®ed by column chromatography (SiO2:
10% ethyl acetate in hexanes). Evaporation of the pure frac-
tions yielded 1d as a waxy solid (2.29 g, 51%). Rfˆ0.65
(25% ethyl acetate in hexanes). 1H NMR: (d, ppm,
CDCl3) 0.85 (t, Jˆ6.6 Hz, 12H), 1.24±1.4 (m, 66H), 1.40
(s), 1.70 (quintet, Jˆ6.4 Hz, 8H), 2.67 (A part of AB
system, Jˆ13.8 Hz, 2H), 2.74 (B part of AB system, Jˆ
13.8 Hz, 2H), 3.17 (d, Jˆ4.9 Hz, 2H), 3.82 (t, Jˆ6.7 Hz,
8H), 4.05 (s, 2H), 4.65 (br s, 1H), 6.25 (s, 4H), 6.29 (s,
2H); 13C NMR: (d, ppm, CDCl3) 14.1, 22.7, 26.0, 28.3,
29.2, 29.3, 29.4, 29.5, 29.6, 31.9, 40.8, 42.3, 43.0, 68.0,
79.4, 99.7, 108.9, 115.9, 138.7, 156.0, 160.1, 168.1, 170.8;
HRMS: calcd for C65H111N5O7Cl: 1108.8172, found:
1108.8165; FT-IR: (neat, cm21) 3327, 3210, 2920, 2846,
1704, 1649, 1600, 1563, 1532, 1464, 1415, 1371, 1297,
4. Experimental
4.1. General
Tetrahydrofuran (THF) was distilled from sodium-benzo-
phenone ketyl prior to use. Dichloromethane was distilled
from P2O5 prior to use as a reaction medium. Deuterated
solvents were used as received from Cambridge Isotope
Laboratories.
Analytical TLC was performed on EM Reagents 0.25 mm
silica gel 60-F plates, and visualized under UV light. Flash
chromatography was performed on silica gel 60 (200±400
mesh). NMR spectra were recorded on a Varian UNITY1
300 spectrometer. 1H and 13C NMR spectra were obtained at
300 and 75 MHz, respectively. FT-IR spectra were taken on
a Nicolet Impact 410 spectrometer. Melting points were
obtained on a Thomas±Hoover Unimelt apparatus and are
uncorrected.
4.1.1. 4-(3,5-Bis-decyloxy-benzyloxy)-6-chloro-[1,3,5]tri-
azin-2-ylamine (1e). (3,5-Bis-decyloxy-phenyl)-methanol17
(3.57 g, 8.49 mmol, 100 mol%), cyanuric chloride (1.96 g,
10.6 mmol, 125 mol%), and iPr2NEt (2.19 g, 16.9 mmol,
200 mol%) were dissolved in CH2Cl2 (80 mL, 0.11 M),
and the mixture was stirred at ambient temperature for
6 h. The reaction mixture was then washed with brine,
dried over Na2SO4, evaporated onto silica gel, and puri®ed
chromatographically (SiO2: 5% ethyl acetate in hexanes) to
provide 2-(3,5-bis-decyloxy-benzyloxy)-4,6-dichloro-[1,3,5]-
1248, 1155, 1063, 1014, 939, 902, 835, 804, 717 cm21
;
mp 46±508C.
4.1.3. 1,3-Bis-(4-amino-6-chloro-[1,3,5]triazin-2-yloxy)-
2,2-bis-(3,5-bis-decyloxy-benzyl)-propane (2a). Prepared
in 41% overall yield from 2,2-bis-(3,5-bis-decyloxy-
benzyl)-propane-1,3-diol 1a19 as described for 2b. The
title compound was obtained as an oil. Rfˆ0.2 (20% ethyl
1
triazine (2.50 g, 52%). H NMR: (d, ppm, CDCl3) 0.86 (t,
Jˆ6.6 Hz, 6H), 1.21±1.43 (m, 30H), 1.74 (quintet, Jˆ
6.6 Hz, 4H), 3.90 (t, Jˆ6.7 Hz, 4H), 5.41(s, 2H), 6.41(m,
1H), 6.53 (m, 2H); 13C NMR: (d, ppm, CDCl3) 14.4, 20.3,
22.9, 26.3, 29.4, 29.6, 29.7, 29.8, 29.9, 32.1, 68.4, 71.9,
102.0, 106.9, 135.9, 160.8, 171.1, 172.8; HRMS: calcd for
C30H47N3O3Cl2: 567.2994, found 567.2988. To a solution of
2-(3,5-bis-decyloxy-benzyloxy)-4,6-dichloro-[1,3,5]triazine
(1.00 g, 1.76 mmol, 100 mol%) in Et2O (20 mL, 0.088 M)
was added a solution of NH3 (2 M in iPrOH, 2.00 mL,
4.00 mmol, 220 mol%), and the mixture stirred at ambient
temperature for 30 min. The reaction mixture was washed
with H2O and brine, dried over Na2SO4, ®ltered, and evapo-
rated to dryness, to afford 1e as a white solid (0.869 g, 90%).
1H NMR: (d, ppm, CDCl3) 0.86 (t, Jˆ6.6 Hz, 6H), 1.25±
1.45 (m, 28H), 1.73 (quintet, Jˆ6.6 Hz, 4H), 3.90 (t, Jˆ
6.6 Hz, 4H), 5.29 (s, 2H), 5.95 (br s, 1H), 6.38 (m, 1H),
6.51(m, 2H); 13C NMR: (d, ppm, CDCl3) 14.1, 22.6,
25.9, 29.1, 29.2, 29.3, 29.5, 29.6, 31.8, 68.0, 69.7, 101.2,
106.2, 137.1, 160.4, 168.2, 170.7, 171.2; FT-IR (neat,
cm21): 3506, 3324, 3188, 2922, 2844, 1662, 1604, 1565,
1533, 1468, 1422, 1344, 1305, 1247, 1156, 1059, 1000,
935, 812, 728, 676; mp 71±748C.
1
acetate in hexanes); H NMR: (d, ppm, CDCl3) 0.85 (t,
Jˆ6.6 Hz, 12H), 1.23±1.40 (m, 60H), 1.70 (quintet, Jˆ
6.6 Hz, 8H), 2.79 (s, 4H), 3.81(t, Jˆ6.4 Hz, 8H), 4.31(s,
4H), 6.24 (m, 4H), 6.30 (m, 2H), 7.22 (br s, 2H), 8.12 (br s,
2H); 13C NMR: (d, ppm, CDCl3) 14.1, 22.7, 26.0, 29.2, 29.3,
29.4, 29.6, 31.9, 41.6, 68.0, 108.9, 137.9, 160.1, 167.9,
170.5, 171.1; HRMS: calcd for C63H103N8O6Cl2:
1137.7378, found: 1137.7373; FT-IR: (neat, cm21) 3582,
3222, 2920, 2836, 1679, 1596, 1512, 1467, 1416, 1358,
1313, 1249, 1152, 1062, 998, 934, 812 cm21
.
4.1.4. 1,3-Bis-(4-amino-6-chloro-[1,3,5]triazin-2-yloxy)-
2,2-dibenzyl-propane (2b). Cyanuric chloride (14.4 g,
77.9 mmol, 400 mol%) was added to a solution of
2,2-dibenzyl-propane-1,3-diol 1b19 (5.00 g, 19.5 mmol,
100 mol%) and 2,6-lutidine (8.36 g, 78.0 mmol, 400
mol%) in CH2Cl2 (100 mL, 0.2 M). The red±orange mixture
was stirred at re¯ux under N2 for 15 h, then washed with
brine, dried over MgSO4, ®ltered and concentrated to
dryness in vacuo. The residue was puri®ed by column
chromatography (SiO2: 25% hexanes in CH2Cl2) to afford
1,3-bis-(4,6-dichloro-[1,3,5]triazin-2-yloxy)-2,2-dibenzyl-
propane as a yellow solid (9.40 g, 87%). Rfˆ0.6 (25% ethyl
4.1.2. [3-(4-Amino-6-chloro-[1,3,5]triazin-2-yloxy)-2,2-
bis-(3,5-bis-decyloxy-benzyl)-propyl]-carbamic acid tert-
butyl ester (1d). To a solution of [2-(3,5-bis-decyloxy-

E. A. Archer et al. / Tetrahedron 58 (2002) 721±725
725
acetate in hexanes); 1H NMR: (d, ppm, CDCl3) 3.04 (s, 4H),
4.28 (s, 4H), 7.15 (m, 4H), 7.28 (m, 6H); 13C NMR: (d, ppm,
CDCl3) 38.3, 42.3, 70.2, 127.0, 128.6, 130.4, 135.5, 170.6,
172.7; HRMS: calcd for C23H19N6O2Cl4: 551.0323, found:
551.0320; FT-IR: (neat, cm21) 3125, 3055, 2913, 2836,
2354, 1711, 1544, 1506, 1441, 1384, 1313, 1261, 1178,
1062, 857, 812, 741, 696 cm21; mp 148±1578C. Ammonia
(0.5 M in 1,4-dioxane, 130 mL, 65 mmol, 400 mol%) was
added to a solution of 1,3-bis-(4,6-dichloro-[1,3,5]triazin-2-
yloxy)-2,2-dibenzyl-propane (8.9 g, 16.1 mmol, 100 mol%)
in Et2O (50 mL, 0.32 M). The mixture was stirred for
45 min at which point the reaction was washed with water
and brine. The organic phase was dried (Na2SO4), ®ltered
and concentrated in vacuo to ca. 20 mL. The gradual
addition of hexanes produced a white precipitate, which
was collected by suction ®ltration to yield pure 2b (4.08 g,
J. Am. Chem. Soc. 2000, 122, 5014. For a review, see:
(b) Deming, T. J. Adv. Mater. 1997, 9, 299.
2. For a review, see: Loew, G. H.; Harris, D. L. Chem. Rev. 2000,
100, 407.
3. Martin, P. J. Photochromism. In Introduction to Molecular
Electronics, Petty, M. C., Bryce, M. R., Bloor, D., Eds.;
Oxford University: New York, 1995; pp. 114±117.
4. For selected reviews, see: (a) Philp, D.; Stoddart, J. F. Angew.
Chem. Int. Ed. 1996, 35, 1155. (b) Lawrence, D. S.; Jiang, T.;
Levett, M. Chem. Rev. 1995, 95, 2229. (c) Langford, S. J.;
Stoddart, J. F. Pure Appl. Chem. 1996, 68, 1255. (d) Fuhrhop,
J.-H.; Rosengarten, B. Synlett 1997, 1015. (e) Krische, M. J.;
Lehn, J.-M. Struct. Bonding 2000, 94, 3. (f) Zimmerman, S. C.;
Corbin, P. S. Struct. Bonding 2000, 94, 63.
5. For reviews, see: (a) Gellman, S. H. Acc. Chem. Res. 1998, 31,
173. (b) Moore, J. Acc. Chem. Res. 1997, 30, 402. (c) Archer,
E. A.; Gong, H.; Krische, M. J. Tetrahedron 2000, 57, 1139.
6. Archer, E. A.; Sochia, A. E. Krische. Chem. Eur. J. 2001, 10,
2059.
1
49%). H NMR: (d, ppm, DMSO-d6) 2.85 (s, 4H), 3.92 (s,
4H), 7.07±7.28 (m, 10H), 8.00 (s, 2H), 8.05 (s, 2H); 13C
NMR: (d, ppm, DMSO-d6) 38.4, 41.8, 66.4, 67.6, 126.6,
128.4, 130.3, 136.2, 168.0, 169.9, 170.1; HRMS: calcd for
C23H23N8O2Cl2: 513.1231, found: 513.1317; FT-IR: (neat,
cm21) 3350, 3286, 3183, 3132, 2367, 2328, 1750, 1679,
1634, 1512, 1403, 1294, 1242, 1139, 1069, 979, 921, 754,
702, 664, 587 cm21; mp 210±2148C.
7. For duplex oligomers reported from other labs, see: (a) Bisson,
A. P.; Carver, F. J.; Eggleston, D. S.; Haltiwanger, R. C.;
Hunter, C. A.; Livingstone, D. L.; McCabe, J. F.; Rotger,
C.; Rowan, A. E. J. Am. Chem. Soc. 2000, 122, 8856.
(b) Corbin, P. S.; Zimmerman, S. C. J. Am. Chem. Soc.
2000, 122, 3779. (c) Zeng, H.; Miller, R. S.; Flowers, R. A.;
Gong, B. J. Am. Chem. Soc. 2000, 122, 2635.
4.1.5. 1-(4-Amino-6-chloro-[1,3,5]triazin-2-yloxy)-2,2-
bis(3,5-bis-decyloxy-benzyl)-3-(4-amino-6-chloro-[1,3,5]-
triazin-2-ylamino)-propane (2c). A solution of hydrogen
chloride (4.0 M in 1,4-dioxane, 1.35 mL, 5.40 mmol,
400 mol%) was added under N2 to a solution of 1d
(1.50 g, 1.35 mmol, 100 mol%) in CH2Cl2 (50 mL, 0.027
M). After 6 h, the volatiles were removed under reduced
pressure and the residue was maintained on a vacuum line
for 30 min. The white solid residue was dissolved in DMF
(20 mL) and 2-amino-4,6-dichloro-[1,3,5]triazine (0.445 g,
2.70 mmol, 200 mol%) was added, followed by iPr2NEt
(1.17 mL, 6.75 mmol, 500 mol%). After heating to 608C
under N2 for 1h, the mixture was allowed to cool spon-
taneously to ambient temperature and stirred for an
additional 15 h. The reaction mixture was poured into H2O
to give a precipitate that was extracted into Et2O. The
combined organic phases were washed with brine, dried
over Na2SO4, ®ltered, and concentrated to dryness in
vacuo to yield a waxy solid (1.46 g). Chromatographic
puri®cation (SiO2: 1 0%iPrOH in hexanes) yielded 2c
(0.82 g, 54%) along with several mixed fractions. Rfˆ0.4
8. Archer, E. A.; Goldberg, N. T.; Lynch, V.; Krische, M. J.
J. Am. Chem. Soc. 2000, 122, 5006.
9. (a) Schleyer, P. V. R. J. Am. Chem. Soc. 1961, 83, 1368.
(b) Jung, M. E. Synlett 1999, 843.
10. (a) Chen, J.-S.; Shirts, R. B. J. Phys. Chem. 1985, 89, 1643.
(b) Chen, J.-S.; Rosenberger, F. Tetrahedron Lett. 1990, 31,
3975.
11. Dimerization constants were obtained from 1H NMR dilution
data using the computer program CHEMEQUI developed by
Dr Vitaly Solov'ev. For a detailed description, see: Solov'ev,
V. P.; Baulin, V. E.; Strakhova, N. N.; Kazachenko, V. P.;
Belsky, V. K.; Varnek, A. A.; Volkova, T. A.; Wipff, G.
J. Chem. Soc., Perkin Trans. 2 1998, 1489.
12. (a) Pranata, J.; Wierschke, S. G.; Jorgensen, W. L. J. Am.
Chem. Soc. 1991, 113, 2810. (b) Jorgensen, W. L.; Pranata,
J. J. Am. Chem. Soc. 1990, 112, 2008.
13. (a) Garcia-Viloca, M.; Gonzalez-Lafont, A.; Lluch, J. M.
J. Phys. Chem. A 1997, 101, 3880. (b) Chen, J.; McAllister,
M. A.; Lee, J. K.; Houk, K. N. J. Org. Chem. 1998, 63, 4611.
14. Mammen, M.; Simanek, E. E.; Whitesides, G. M. J. Am.
Chem. Soc. 1996, 118, 12614.
1
(10% iPrOH in hexanes). H NMR: (d, ppm, 7.9 mM in
CDCl3) 0.85 (t, Jˆ6.9 Hz, 12H), 1.23±1.39 (m, 57H), 1.72
(m, 8H), 2.60 (A part of AB system, Jˆ13.5 Hz, 2H), 2.72
(B part of AB system, Jˆ13.5 Hz, 2H), 3.52 (br s, 0.5H),
3.62 (br s, 1.4H), 3.84 (br s, 8H), 4.12 (br s, 0.3H), 4.38 (br s,
1.4H), 5.82 (br s, 1H), 6.19 (s, 4H), 6.32 (s, 2.5H); 13C NMR:
(d, ppm, CDCl3) 14.1, 22.7, 26.0, 29.3, 29.5, 29.6, 31.9,
40.4, 68.0, 99.7, 109.1, 137.9, 160.1; HRMS: calcd for
C63H104N9O5Cl2: 1136.7537, found: 1136.7565; FT-IR:
(neat, cm21) 3444, 3302, 3136, 2926, 2846, 2636, 2365,
2136, 1890, 1692, 1643, 1587, 1464, 1415, 1353, 1303,
1155, 1063, 939, 841, 798 cm21; mp 140±1458C.
15. Sharp, K. Prot. Sci. 2001, 10, 661and references therein.
16. (a) Taylor, R.; Kennard, O. Acc. Chem. Res. 1984, 17, 320.
(b) Scheiner, S. Acc. Chem. Res. 1994, 27, 402.
17. Prepared in analogy to a published procedure: Johansson, G.;
Percec, V.; Ungar, G.; Abramic, D. J. Chem. Soc. Perkin
Trans. 1 1994, 447.
18. Prepared in analogy to a published procedure: Varie, D. L.;
Shih, C.; Hay, D. A.; Andis, S. L.; Corbett, T. H.; Gossett,
L. S.; Janisse, S. K.; Martinelli, M. J.; Moher, E. D.; Schultz,
R. M.; Toth, J. E. Bioorg. Med. Chem. Lett. 1999, 9 (3), 369.
19. Prepared in analogy to a published procedure: Czech, B. P.;
Zazulak, W.; Kumar, A.; Dalley, N. K.; Weiming, J.; Bartsch,
R. A. J. Heterocycl. Chem. 1991, 28, 1387.
References
1. (a) Qu, Y.; Payne, S. C.; Apkarian, R. P.; Conticello, V. P.