Toward poly(aminophthalimide), structures of dimers and trimers

Article abstract of DOI:10.1016/j.tet.2007.04.002

Poly(aminophthalimide) (PAP) dimers and trimers have been synthesized by palladium-catalyzed cross-coupling reactions of 3-aminophthalimides with 3-chloro- and 3,6-dichlorophthalimide, respectively. When Pd(OAc)₂, XPhos (2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), and K₃PO₄ are used, the C-N bond-forming reactions proceed quantitatively. The structures of those oligomers are examined by experimental and theoretical techniques including NMR, IR, single-crystal X-ray diffraction, and DFT calculations. The strong preference for cisoid structure of the diphthalimidylamine unit bearing a bifurcate hydrogen bonding is disclosed. Therefore, the aminophthalimide backbone is a highly promising candidate for the construction of a dynamically ordered helical structure.

Full text of DOI:10.1016/j.tet.2007.04.002

Tetrahedron 63 (2007) 6642–6653
Toward poly(aminophthalimide), structures of dimers and trimers
Hiroyuki Katayama,a Tom F. A. de Greef,a Huub Kooijman,b Anthony L. Spek,b
Jef A. J. M. Vekemansa and E. W. Meijera,
*
aLaboratory of Macromolecular and Organic Chemistry, Department of Chemistry, Eindhoven University of Technology,
PO Box 513, 5600 MB Eindhoven, The Netherlands
bBijvoet Center for Biomolecular Research, Crystal and Structural Chemistry, Utrecht University, Padualaan 8,
3584 CH Utrecht, The Netherlands
Received 17 January 2007; revised 30 March 2007; accepted 2 April 2007
Available online 6 April 2007
Abstract—Poly(aminophthalimide) (PAP) dimers and trimers have been synthesized by palladium-catalyzed cross-coupling reactions of
3-aminophthalimides with 3-chloro- and 3,6-dichlorophthalimide, respectively. When Pd(OAc)2, XPhos (2-dicyclohexylphosphino-
20,40,60-triisopropylbiphenyl), and K3PO4 are used, the C–N bond-forming reactions proceed quantitatively. The structures of those oligomers
are examined by experimental and theoretical techniques including NMR, IR, single-crystal X-ray diffraction, and DFT calculations. The
strong preference for cisoid structure of the diphthalimidylamine unit bearing a bifurcate hydrogen bonding is disclosed. Therefore, the
aminophthalimide backbone is a highly promising candidate for the construction of a dynamically ordered helical structure.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
more complex folding behavior of proteins as foldamers
are composed of a single monomer.
The design of synthetic oligomers characterized by ordered
solution conformations has recently attracted intense interest
from different scientific areas. Considerable effort from
numerous groups1 has resulted in a wealth of synthetic
non-natural oligomers capable of adopting one preferred
backbone conformation out of a large number of accessible
conformations. Foldamers2 represent a subclass of oligomers
in which the restricted backbone conformation is caused
by non-covalent interactions between adjacent and non-
adjacent monomeric units. Hydrogen bonding,3–9 solvopho-
bic,10–14 aromatic donor–acceptor,15,16 metal–ligand,17 and
anion–hydrogen bond18 interactions have all been utilized
as driving forces for the cooperative transition of random
coiled backbones into well defined helical architectures.19
Due to their compact and ordered conformations, foldamers
have found use as protein mimics competing with a variety of
protein–protein,20 protein–membrane,21 and protein–sugar22
interactions. Furthermore, foldamers present an inner-void,
which can be used to create stimuli-responsive materials
upon binding of a specific guest with an affinity for the
interior. Examples are binding of mercury ions to helical
oligomeric cholates23 and the induction of helicity in oligo-
(meta-ethynylpyridine)s upon binding of saccharides.24
From a fundamental point of view, the intrinsic folding dy-
namics25 of these molecules can provide insight into the
Recently, we reported a new class of poly(ureidophthal-
imides) (PUP, 1) illustrated in Figure 1, which was shown
to fold in apolar and polar media25–27 depending on the
nature of the R* group. The NH-groups of the ureas, which
are positioned at the 3,6-positions of phthalimide ring, pref-
erentially adopt a conformation in which intramolecular
hydrogen bonding of the NH protons with the adjacent imide
oxygens is operational. In case of a cisoid urea conforma-
tion, the consecutive monomer units lead to a curvature in the
backbone and this may induce folding, probably with the aid
of interlayer p–p stacking. Furthermore, a small perturba-
tion by chiral groups (R*) on the periphery28 can bias the
twist sense of the helical structure.
In order to gain more insight into the thermodynamics and
kinetics of folding of phthalimide based foldamers we
have turned our focus on the design of a new foldamer in
which the conformational lock of the subunit, caused by
the strong intramolecular hydrogen bond, is loosened as
compared to our previous PUP foldamer. By loosening the
conformational lock we hope to achieve that the number of
torsionally accessible conformations of a given oligomer
will increase slightly, thereby increasing the effect of config-
urational entropy on the folding process. Changes in the
configurational entropy of the folding process will lead to
a foldamer with a significantly different free energy land-
scape29 as compared to PUP foldamers. Moreover, by
* Corresponding author. E-mail: e.w.meijer@tue.nl
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.002

H. Katayama et al. / Tetrahedron 63 (2007) 6642–6653
6643
R
N
R
N
O
O
H
N
H
N
O
O
H
H
N
O
N
H
O
H
N
O
O
N
R*
N
R*
N
O
R
N
R
O
O
O
O
N
O
+
O
N
OCN
NCO
H
H2N
NH2
O
N
H
O
N
H
N
H
O
O
O
O
O
N
N
N
R
R
N
H
N
H
O
N
H
R
N
H
O
O
O
O
N
R
1
Figure 1. Tentative helical structure of poly(ureidophthalimide) (PUP) foldamer 1 obtained by polymerization of the corresponding di-isocyanato and di-amino
phthalimide monomers. The number of units per helical turn has been estimated to be >7.25,27
focusing our attention on stronger interactions between non-
adjacent units, oligomers with a true cooperative transition
between extended and folded conformations are envisioned.
The resulting helix will display a smaller inner-void due to
the decrease in the number of linking atoms as compared
to the ureido counterpart. Presumably, steric repulsion be-
tween the ortho protons may occur giving rise to a smaller
number of units per helix turn. This may induce stronger in-
teractions between non-adjacent units within a given oligo-
mer, for example, by an increase in the strength of p–p
interactions due to a shorter distance between the overlap-
ping units in the folded conformation.
We therefore turned our attention on the introduction of
amine (NH) linkage instead of a urea linkage. As shown by
poly(aminophthalimide) (PAP, 2) in Figure 2, the amine hy-
drogen would form a hydrogen bond in a six-membered ring
giving rise to a curved backbone, in a way similar to the ure-
idophthalimide. It is hypothesized that the resulting NH pro-
ton will still be a good proton donor as the electron accepting
carbonyl substituents will increase its acidity considerably.
Furthermore, due to its polyaniline-based backbone, these
structures can serve as p-conjugated polymers with appeal-
ing electronic properties.30 By incorporating electron-donat-
ing monomers bearing hydrogen bond acceptor units, low
band-gap polymers with highly ordered structures can be
envisioned.31
R*
N
O
O
O
N
H
H
O
N
O
N
N
R*
R*
N
H
N
H
N
Palladium-catalyzed C–N bond formation has been envis-
aged as one of the most practical and straightforward ways
to construct a phthalimide–amine sequence in 2. This metho-
dology has become a widely used practical method of syn-
thesizing diarylamines.32,33 As for the aminophthalimide
synthesis, Buchwald and Hennessy reported a synthetic
route to 4,5-dianilinophthalimides that employs the palla-
dium-catalyzed amination as the key bond-forming step.34
More recently, catalytic polycondensation between 3,6-di-
bromophthalimide and 1,4-phenylenediamine to afford a
O
O
O
O
O
N
N
R*
R*
R*
N
H
N
H
O
O
O
O
N
R*
2
hybrid polymer of polyaniline and phthalimide dyes was
€
reported by Mullen and co-workers.
35
R
R
N
O
O
N
H
N
R
O
O
In this paper, we demonstrate the Pd(OAc)2/XPhos-cata-
lyzed system (XPhos¼2-dicyclohexylphosphino-20,40,60-
triisopropylbiphenyl), which was originally developed by
the Buchwald group, to be effective in synthesizing 3,6-
linked aminophthalimide scaffolds by illustrating the
segmental PAP dimer (3) and trimer (4) formations. The ex-
perimental and theoretical studies on the structures of those
oligomers show that they nicely fit into the designed archi-
tecture of 2.
N
O
O
O
H
N
H
N
O
3
R
R
N
N
O
O
4
Figure 2. Tentative helical structure of poly(aminophthalimide) (PAP)
foldamer 2 and structures of dimer 3 and trimer 4.

6644
H. Katayama et al. / Tetrahedron 63 (2007) 6642–6653
2. Results and discussion
the product were highly expected to take place spontaneously
after the [4+2] cycloaddition.38 Indeed, heating a mixture of
15 and 13b or 13c in DMF at 130 ꢀC for 18–22 h gave the cor-
responding 3,6-diiodophthalimides 17b,c, albeit in rather
low yields. 3,6-Dibromo-N-trialkoxyphenylphthalimide 16c
could be also prepared by this method. Finally, synthesis of
ditriflates 19 was accomplished by imidation of 3,6-dihy-
droxyphthalic anhydride followed by esterification of the
resulting dihydroxyphthalimide 18 with triflic anhydride
(Scheme 2). Compounds 19a,b were substantially mois-
ture-stable allowing the purification by silica gel column
chromatography.
2.1. Synthesis of 3-aminophthalimides
Three kinds of 3-amino-N-arylphthalimides 9a–c for the
building blocks of 3 and 4 were prepared in four steps ac-
cording to Scheme 1. Dehydration of 3-nitrophthalic acid
followed by catalytic reduction/acetylation of the resulting
nitro compound 5 yielded 3-acetylaminophthalic anhydride
(6).36 Subsequent reaction of 6 with primary aromatic
amines 7a–c in acetic acid or 1,4-dioxane at 100 ꢀC afforded
3-acetylamino-N-arylphthalimides 8a–c, which were then
treated with aq HCl to give 9a–c in a total yield of 46–
84% in two steps. Compounds 9a–c were obtained as yellow
crystalline solids that are air-stable and can be safely stored
under ambient conditions for months. Condensation of 5
with 7 followed by nitro group reduction could also provide
9 in a one step less procedure. In this case, however, lower
appreciated reactivity of 5 toward the imidation reduced
the overall yields, especially for gallic derivative 9c.26
R1
R2
R2
O
O
O
7a-c
AcOH or 1,4-dioxane
N
X1
X2
O
O
Δ
X1
X1 = Cl, X2 = H
X2
O
O
O
R1 = R2 = H (a)
R
R
10a: 77%, 10b: 69%, 10c: 65%
O
O
O
HO2C
CO2H
NO2
1 = I, X2 = H
11a: 46%, 11b: 67%
1 = X2 = Cl
1 = OC8H17, R2 = H (b)
1 = R2 = OC12H25 (c)
(b)
X
X
(a)
H
N
NO2
CH3
12a: 62%, 12b: 50%, 12c: 65%
O
5
6
ð1Þ
R1
R2
R2
R1
N
R1
R2
R2
O
R2
O
R2
R1
N
R1
R2
O
R2
NH2
R2
O
R2
(d)
7a-c
N
O
DMF, 130 °C
O
(c)
+
X
X
S
H
N
O
X
O2
N
NH2
O
X = Br (14)
X = I (15)
CH3
X
O
13b,c
R1 = R2 = H (a)
8a: 79%
8b: 68%
8c: 98%
9a: 58%
9b: 76%
9c: 86%
X = Br
R1 = OC8H17, R2 = H (b)
R1 = R2 = OC12H25 (c)
16c: 22%
R1 = OC8H17, R2 = H (b)
X = I
17b: 33%, 17c: 34%
R
1 = R2 = OC12H25 (c)
Scheme 1. Synthesis of 3-amino-N-arylphthalimides (9a–c). (a) Ac2O,
reflux. (b) (i) H2, Pd/C, (ii) Ac2O, 100 ꢀC. (c) AcOH or 1,4-dioxane,
100 ꢀC. (d) (i) aq HCl, 1,4-dioxane, 100 ꢀC, (ii) NH3 (aq).
ð2Þ
R1
2.2. Synthesis of phthalimidyl halides and triflates
R2
O
R2
O
O
O
To systematically investigate the effect of various phthal-
imide electrophiles on the C–N coupling, a series of the
halides and triflates were synthesized. 3-Chloro- (10a–c),
3-iodo- (11a,b), and 3,6-dichlorophthalimides (12a–c)
were readily accessible from the corresponding anhydrides
(Eq. 1). On the other hand, the same strategy was not applied
to synthesize 3,6-diiodophthalimides (17) because of the in-
accessibility of the starting anhydride. For example, attempts
to prepare such anhydride by direct or palladium-catalyzed
iodination of phthalic anhydride and permanganate oxidation
of 3,6-diiodo-o-xylene were all unsuccessful. A Diels–Alder
approach was then examined (Eq. 2). N-Arylmaleimides
13b,c were prepared by a two-step imidation of maleic anhy-
dride with 7b,c according to the literature.37 2,5-Diiodothio-
phene-1,1-dioxide (15) was selected as a diene substrate
because elimination of sulfur dioxide from the Diels–Alder
adduct and the subsequent aerobic oxidation to aromatize
(a)
N
O
HO
OH
HO
OH
18a: 73%, 18b: 60%
R1
N
R2
O
R2
O
(b)
R1 = R2 = H (a)
TfO
OTf
R1 = OC8H17, R2 = H (b)
19a: 85%, 19b: 90%
Scheme 2. Synthesis of phthalimidyl triflates (19a,b). (a) 7a,b, AcOH,
100 ꢀC. (b) Tf2O, pyridine, toluene, 0 ꢀC to rt.

H. Katayama et al. / Tetrahedron 63 (2007) 6642–6653
6645
Table 1. Synthesis of PAP trimer 4ca
2.3. Palladium-catalyzed C–N coupling reaction
+
2 9c
12c, 16c, or 17c
Taking the generally accepted reactivity order of cross-cou-
pling substrates into account, an initial attempt to synthesize
PAP dimer 3 was made on 3-iodophthalimide 11 (Eq. 3). The
reaction of 11b with an equimolar amount of 3-aminophthal-
imide 9b completed at 100 ꢀC within 6 h in the presence of
Pd(dba)2 (2 mol %), Xantphos (4,5-bis(diphenylphosphino)-
9,9-dimethylxanthene) (4 mol %), and Cs2CO3 (1.5 equiv)
to give an orange solid of PAP dimer bearing octyloxy tails
3b in 85% isolated yield. Under similar conditions PAP
dimer 3a was obtained as a yellow solid in 91% yield.
Pd cat.
L
toluene
100 °C
24 h
base
OC12H25
OC12H25
C12H25
O
OC12H25
OC12H25
OC12H25
N
O
O
C
12H25
C12H25
O
O
O
H
N
H
N
O
N
O
N
OC12H25
R1
R2
N
R2
N
R1
O
Pd(dba)2
Xantphos
Cs2CO3
R2
R2
4c
9a,b
+
O
O
H
N
1,4-dioxane
100 °C, 6 h
11a,b
ð3Þ
O
O
PCy2
i
i
Pr
Pr
O
R1 = R2 = H (a)
3a: 91%
3b: 85%
PPh2
PPh2
R
1 = OC8H17, R2 = H (b)
Xantphos
i
Pr
Gratified with these results, we next performed the reaction
of 9b with 3,6-diiodophthalimide 17b with the aim of syn-
thesizing PAP trimer 4b. However, H NMR and MALDI-
XPhos
Run 3,6-Dihalophthalimide Pd cat.
(X)
L
Base
Yieldb (%)
1
TOF-MS analyses of the crude reaction mixture indicated
the formation of only w20% 4b along with a number of
unidentified products. The reactions using 3,6-ditriflates
19a,b gave somewhat better results (45% yield for 4a, 30%
yield for 4b), but were still unsatisfactory when considering
future higher oligomer synthesis. To establish more effective
conditions, the reactions between 9c and 3,6-dihalophthal-
imides (12c, 16c, 17c) were examined with varying palla-
dium source, ligand, and base (Table 1). The use of XPhos
instead of Xantphos slightly improved the yield of 4c (runs
1 and 2). Regarding the effect of the sort of halogen atoms
in 3,6-dihalophthalimides, interestingly, the yield increased
in the order 17c (X¼I)<16c (X¼Br)<12c (X¼Cl) (runs 2–
4), which is rather unusual in cross-coupling chemistry. It
should be mentioned that no significant by-product was
detected in the reaction of dichlorophthalimide 12c (run 4).
Potassium phosphate was the base of choice among those
tested (runs 4–6). A dramatic rate increase was observed
when the palladium source Pd2(dba)3 was replaced by
Pd(OAc)2 (run 7). In this case the C–N bond formation
proceeded quantitatively, and the trimer 4c was isolated as
an orange sticky solid in 97% yield.
1c 17c (I)
Pd2(dba)3 Xantphos Cs2CO3 27
2
3
4
5
6
7
17c (I)
Pd2(dba)3 XPhos
Pd2(dba)3 XPhos
Pd2(dba)3 XPhos
Pd2(dba)3 XPhos
Pd2(dba)3 XPhos
Pd(OAc)2 XPhos
K3PO4 35
K3PO4 43
K3PO4 76 (59)
Cs2CO3 64
K2CO3 17
16c (Br)
12c (Cl)
12c (Cl)
12c (Cl)
12c (Cl)
K3PO4 >99 (97)
a
All reactions were carried out with 3,6-dihalophthalimide (25 mM), 9c
(2.2 equiv), Pd cat. (1–2 mol %), Pd/L¼1/2, and base (3 equiv) in toluene
at 100 ꢀC for 24 h, unless otherwise noted.
NMR yield using C6Me6 as an internal standard. The number in paren-
theses is isolated yield after column chromatography.
The reaction was run in 1,4-dioxane.
b
c
analysis. Furthermore, because PAP trimer 4c is the longest
monodisperse oligomer in our hands, all resonances were
unambiguously assigned by 1H and 13C NMR spectros-
copies with 1H–1H correlation spectroscopy (gCOSY,
TOCSY) and gradient enhanced heteronuclear multiple
quantum coherence (gHMQC). The key spectroscopic fea-
1
tures are summarized in Table 2. The H signals of phthal-
imide ring protons (Ha–g) were assigned based on the mutual
coupling patterns and constants. Figure 3 depicts the ex-
panded 1H NMR spectra of 3c and 4c in CDCl3. Also shown
are the spectra of 8c, 9c, and PUP dimer 20b, which has been
prepared by catalytic C–N coupling of 11b and urea,39 for
comparison. While the NH proton signal of amine 9c is ob-
served at ordinary position (5.30 ppm), those of PAP, PUP,
and acetylamino compounds appears considerably down-
field (>9.3 ppm). This shift is attributed to intramolecular
hydrogen bonding with the imide oxygen. Appearance of
the NH proton signal of 3c and 4c at a more downfield posi-
tion than that of 20b presumably implies the bifurcate nature
of the hydrogen bonding of PAP compounds. The intramo-
lecular fashion was demonstrated by the fact that the signals
of NH and Ha–g were independent on sample concentration
With these optimized conditions (Pd(OAc)2/XPhos/K3PO4)
in hand, the syntheses of PAP dimers 3a–c and PAP trimers
4a,b were re-examined using chlorophthalimides 10a–c and
12a,b, respectively, instead of the corresponding iodide 9.
Consequently, nearly quantitative conversion was attained
in each case, giving the desired PAP oligomers in 91%
isolated yield.
2.4. Structural identification of PAP dimers 3 and
trimers 4
All the PAP oligomers thus obtained were characterized by
1H and 13C NMR, IR, MALDI-TOF-MS, and elemental

6646
H. Katayama et al. / Tetrahedron 63 (2007) 6642–6653
Table 2. Selected 1H NMR and IR data for 3a–c and 4a–c
indicating that the trimer adopts the expected syn conforma-
tion in solution. Furthermore, a weak NOE contact is ob-
0
served between the NH proton and Ha proton consistent
with the larger distance between these two protons in the
syn conformation. In combination with the large downfield
shift of the NH proton as compared to the NH resonances
in other aniline oligomers bearing electron withdrawing
groups,41 these results imply the existence of an intramolec-
ularly H-bonded six-membered ring and the preferred syn–
syn conformation adopted by the phthalimide groups.
R
R
R
N
O
O
O
O
N
N
H
N
O
H
H
O
O
O
N
N
R
R
N
N
γ
α
α
γ
α' α'
α
α
β
β
O
O
3a-c
γ
γ
β
β
4a-c
Compound
1H NMRa
Ha
IRb
0
NH
Ha
Hb
Hg
nNH
To evaluate the extent of hydrogen bonding of PAP and PUP
compounds, variable temperature H NMR measurements
1
3a
3b
3c
4a
4b
4c
10.15
10.11
10.00
10.00
9.80
7.86
7.84
7.83
7.78
7.64
7.75
7.71
7.70
7.69
7.69
7.53
7.67
7.54
7.53
7.51
7.51
7.36
7.49
3303
3282
3293
3298
3314
3317
on 3b and 20b in 1,1,2,2-tetrachloroethane-d2 were per-
formed. Upfield shifts of the NH and Ha–g proton resonances
were observed with increasing temperature in each case,
whereas other signals such as OCH2 resonances remained
unchanged. This result implies that the extent of hydrogen
bonding is reduced at higher temperatures due to the in-
creased population of less favored conformers. Figure 4
shows the chemical shifts of the NH and Ha proton signals
as a function of temperature. The changes in Dd/DT for 3b
(2.2ꢁ10ꢂ3 for NH, 1.1ꢁ10ꢂ3 for Ha) are larger than those
for 20b (1.1ꢁ10ꢂ3 for NH, 0.56ꢁ10ꢂ3 for Ha). Based on
these values it can be concluded that in PAP dimers, less fa-
vorable conformers lacking hydrogen bonding are populated
at lower temperatures compared to PUP dimers. However, it
should be mentioned that the hydrogen bond in 3c does not
collapse even at 140 ꢀC, while 20b starts thermal decompo-
sition at this temperature.
7.87
7.75
7.83
9.85
a
In CDCl3 at 20 ꢀC.
Neat.
b
in the range from 0.2 to 25 mM in CDCl3. The signal of Ha
protons of phthalimide ring in 8c and 20b shows a remark-
ably downfield shift (8.8–8.7 ppm) compared to the other
ring protons (7.8–7.6 ppm), which is due to the anisotropic
deshielding effect by the proximal carbonyl double bond.
R1
R1
O
O
N
N
H
N
H
N
The N–H stretching vibration of the IR spectra was indica-
tive of hydrogen bonding in the solid state. Compound 9c
showed two absorptions at 3472 and 3350 cmꢂ1, the former
of which can be attributed to the free amino group, and the
latter to the hydrogen-bonded N–H group arising from a
restricted rotation of phthalimide–NH2 bond in the solid
state. In the lower wavenumber region the N–H stretching
vibrations appear in the order: 4c (3317 cmꢂ1)>3c
(3293 cmꢂ1). This reflects the fact that the 6-aminophthal-
imide substituent is a weaker electron acceptor than
O
O
O
R1 = H (20a)
R1 = OC8H17 (20b)
2D NOESY experiments on PAP trimer 4c in CDCl3 were
performed to confirm its crescent shape in solution. A strong
NOE contact40 (Fig. 3) can be observed between Ha and Ha
0
Figure 3. (a) Expanded 1H NMR spectra of PAP dimer 3c, trimer 4c, 3-acetylaminophthalimide 8c, 3-aminophthalimide 9c, and PUP dimer 20b in CDCl3.
Arrows mark the signal of NH proton. (b) 2D NOESY spectrum of trimer 4c in CDCl3 (298 K, mixing time 0.1 s).

H. Katayama et al. / Tetrahedron 63 (2007) 6642–6653
6647
each compound. The hydrogen bond distances of PAP di-
˚
mers 3a,b are 0.15–0.35 A longer than that of PUP dimer
20a. The two phthalimide units (A and B) in 3a,b are mutu-
ally tilted by 35–41ꢀ to avoid a steric (and possibly electro-
static) repulsion between the aromatic ortho protons. It
seems that the tilt angle is influenced by substitution on
the phenyl rings, when one compares 3a and 3b. Unlike 3,
20a features a nearly planar structure, in which the urea
oxygen and the phthalimide Ha protons are also located in
the range of hydrogen bond distances. This fact may ratio-
nalize the downfield shift of the signal of Ha in the 1H NMR
spectrum of 20b (Fig. 3).
2.5. Computational investigation and comparison with
X-ray structures
Density functional theory (DFT) was used to study the con-
formational preference of PUP dimers and PAP dimers in
more detail. DFT, as introduced by Kohn and Sham,42 is
a computationally very effective method that includes elec-
tron correlation effects. DFT has been used to accurately de-
scribe hydrogen bonding in DNA base pairs,43 quadruple
hydrogen-bonded dimers,44 and to study the effect of hydro-
gen bonding on the conformational preference of pyrimi-
dine-4,6-dicarboxamide based foldamers.45
Figure 4. Temperature dependence of 1H NMR signals of NH and Ha pro-
tons of 3b and 20b in 1,1,2,2-tetrachloroethane-d2.
a phthalimide substituent. Hence, the N–H function in the
dimer is more acidic than the N–H functions in the trimer
resulting in a stronger hydrogen bonding of the former.
Calculations were performed on small model molecules,
PUP dimer 22 and PAP dimer 23 (Fig. 6) in which the phenyl
group was replaced by a methyl group. Geometries were op-
timized using the hybrid B3LYP46 density functional using
a 6-311G triple split valence basis sets47 and polarization
functions48 (B3LYP/6-311G(d,p)). The final geometries
were re-optimized using additional diffuse functions49
(B3LYP/6-311+G(d,p)) on C, N, and O. The latter basis
The structures of 3a, 3b, and 20a in the solid state were un-
ambiguously determined by single-crystal X-ray diffraction
analysis. Their molecular structures are illustrated in
Figure 5. Table 3 lists the selected bond distances and dihe-
dral angles. As expected from the spectroscopic studies
described above, an intramolecular hydrogen bonding be-
tween the NH proton and the imide oxygen is present in
Figure 5. Single-crystal X-ray structures of 3a, 3b, and 20a. Solvent molecule THF is omitted for 3a.

6648
H. Katayama et al. / Tetrahedron 63 (2007) 6642–6653
ꢀ
ꢀ
˚
Table 3. Selected bond distances (A) and angles ( ) and dihedral angles ( ) for 3a, 3b, and 20a
3a 3b
20a
N(1)–C(1)
N(1)–C(15)
N(1)–H(1)
H(1)/O(2)
H(1)/O(4)
1.3898(17)
1.3841(18)
0.877(18)
2.404(18)
2.374(17)
N(1)–C(1)
N(1)–C(23)
N(1)–H(1)
H(1)/O(2)
H(1)/O(5)
1.379(2)
1.386(2)
0.870(18)
2.362(18)
2.211(18)
N(1)–C(3)
1.391(3)
1.390(3)
0.95(3)
0.95(3)
2.03(3)
2.06(3)
N(3)–C(17)
N(1)–H(1)
N(3)–H(10)
H(1)/O(3)
H(10)/O(5)
N(1)–H(1)/O(2)
N(1)–H(1)/O(4)
126.1(14)
124.6(14)
N(1)–H(1)/O(2)
N(1)–H(1)/O(5)
127.2(16)
136.1(16)
N(1)–H(1)/O(3)
N(3)–H(10)/O(5)
144(2)
141(2)
C(16)–C(15)–N(1)–C(1)
C(2)–C(1)–N(1)–C(15)
22.5(2)
26.4(2)
C(2)–C(1)–(N1)–C(23)
C(24)–C(23)–N(1)–C(1)
25.9(3)
18.2(3)
H(10)–N(3)–C(17)–C(18)
H(2)–O(1)–C(29)–H(11)
178.3(17)
173.7(9)
Estimated standard deviation in parentheses.
Figure 6. Relative energies of PAP dimer and PUP dimer conformers.
set has sufficient diffuseness and angular flexibility to pro-
vide a reasonable description of strong intramolecular sec-
ondary interactions.
distance between H(2) and H(16) are almost similar in crys-
˚
tal structure 3a (2.22 A) and the calculated geometry
˚
(2.20 A). Comparison of other important dihedral angles
shows that DFT accurately predicts both the C(2)–C(1)–
N(1)–C(15) and C(16)–C(15)–N(1)–C(1) dihedral angles
(Table S3).
Results from the gas-phase calculations suggest that the syn–
syn conformation of PAP dimer 22a is energetically favored
over the syn–anti conformation 22b by approximately
3 kcal/mol. Compared to the crystal structure, the bond
lengths of the DFT optimized structure of 22a are similar
The transoid–transoid conformation of PUP dimer as repre-
sented by 23a is 5 kcal/mol more stable than the correspond-
ing transoid–cisoid conformer. This value is somewhat
larger compared to the value reported by Gong and co-
workers7f for ortho ester substituted aromatic ureas using
the same B3LYP functional and basis set. This difference
is most probably the result of the enforced planarity of the
imide carbonyl resulting in a maximum strength of the hy-
drogen bonds. However, it must be noted that depending
on the method of calculation,53 large differences between
the relative stabilities of the cisoid and transoid conformers
of phenylurea have been found. Without considering the N–
H bond lengths, the absolute deviations found for bond
lengths between 23a and 20a are small (between 0.001
˚
(deviations between 0.001 and 0.01 A) except for the N–H
bond length, which is overestimated by DFT (Table S2).
The length of the intramolecular hydrogen bond, repre-
˚
sented by H(1)/O(2) in 22a is 2.31 A, which is shorter
50
˚
than in the crystal structure (2.39 A). Previous studies on
neutral intermolecular hydrogen-bonded complexes have
shown that B3LYP tends to underestimate hydrogen bond
strengths and provides incorrect H-bond distances compared
to MP2 as a result of an incorrect description of dispersion
energy51 by current DFT methods. As expected, the error
in the H-bond length is larger for the geometry optimized
˚
without additional diffuse functions (2.29 A). It must be
˚
noted, however, that the uncertainty regarding the location
of the H atom in N–H/O hydrogen bonds, obtained through
X-ray diffraction experiments has been documented52 and
therefore direct comparison of the hydrogen bond lengths
in the X-ray structure and the B3LYP optimized geometry
is troublesome. On the other hand, DFT correctly predicts
the non-planarity of the backbone of 22a and good agree-
ment is found between the dihedral angles when compared
to the angles in crystal structure 3a (Fig. 7). For example,
the (pseudo)torsional angle C(16)–C(25)–C(1)–C(2) defin-
ing the angle between the two phthalimide plains are
40.78ꢀ in 3a and 38.58ꢀ in 22a, reflecting the excellent
agreement between theory and experiment. The distances
between the two phthalimide units, represented by the
and 0.01 A). In contrast to PAP dimer 3a, the deviations be-
tween the dihedral angles of 23a and 20a are considerable.
For example, DFT predicts the C(29)–N(1)–C(3)–C(4) dihe-
dral angle to be 0ꢀ (resulting in a planar conformation) while
it is ꢂ8.8ꢀꢃ3ꢀ in the crystal structure (Table S5). Any at-
tempts to minimize a non-planar transoid–transoid starting
geometry resulted in a planar optimized geometry indicating
that the planar geometry is indeed the global minimum using
the current computational method. The discussed divergence
may rely on two factors. First, it can be due to the larger ste-
ric hindrance of the phenyl groups in 20a as compared to the
methyl groups in 23a thereby forcing the phthalimide units
out of plane. Second, Bickelhaupt and co-workers54 showed
that the molecular environment in the unit cell may cause

H. Katayama et al. / Tetrahedron 63 (2007) 6642–6653
6649
Figure 7. Comparison of C(16)–C(25)–C(1)–C(2) dihedral angle and distances between H(2) and H(16) in crystal structure 3a and B3LYP optimized structure
22a.
significant deviation between theoretical results and the
experimentally determined X-ray structure.
of physical and chemical properties of the resulting PAP
foldamers. Synthesis of discrete oligomers and folding be-
havior of PAP is now under investigation.
Although a direct comparison is difficult to make due to the
absence of solvent effects in the gas-phase calculations, it is
striking that the same order of stability between the PUP and
PAP dimers was also observed in the analysis of the temper-
ature dependence of 1H NMR signals of NH and Ha protons
of 3b and 20b in 1,1,2,2-tetrachloroethane-d2.
4. Experimental section
4.1. General
All chemicals were purchased from Aldrich or Acros and
were used as received unless stated otherwise. Dioxane
˚
was freshly distilled from 4 A molecular sieves, toluene
3. Conclusion
˚
was freshly distilled from Na; CDCl3 was dried over 4 A mo-
˚
lecular sieves and THF was distilled from 4 A molecular
sieves.
The synthesis of PAP dimers 3 and trimers 4 has been suc-
cessfully performed by Buchwald–Hartwig amination. The
use of chlorophthalimide as a coupling partner, Pd(OAc)2/
XPhos as a catalyst system, and K3PO4 as a base is of partic-
ular importance to reach a selective and quantitative conver-
sion. The structural analysis of 3 and 4 in solution as well as
in the solid state points to bifurcated hydrogen bonding
between the amine protons and the adjacent imide oxygens,
which is responsible for locking the conformation of the
phthalimide backbone. The DFT calculations are indicative
that the syn–syn conformation of diphthalimidylamine unit
is energetically more stable than the syn–anti conformer.
Taking all these data as well as our previous findings on
PUP foldamers into account, it is strongly expected that
the aminophthalimide backbone is capable of adopting
a folded conformation with a smaller number of repeating
units as compared to PUP. Furthermore, both temperature
dependent 1H NMR and DFT studies suggest that the confor-
mational lock in PAP dimers is significantly loosened com-
pared to PUP dimers. It is expected that such a design will
lead to foldamers with a significantly more dynamical fold-
ing character as compared to PUP oligomers due to loosen-
ing of the conformational lock.
The coupling reactions were carried out under dry argon. All
reactions were followed by thin-layer chromatography (pre-
coated 0.25 mm silica gel plates from Merck), and silica gel
column chromatography was carried out with silica gel 60
1
(mesh 70–230). H and 13C NMR spectra were recorded
1
on a 400 MHz NMR (Varian Mercury, 400 MHz for H
NMR and 100 MHz for 13C NMR), a 300 MHz NMR (Var-
1
ian Gemini, 300 MHz for H NMR and 75 MHz for 13C
NMR), or 500 MHz NMR (Varian Unity Inova, 500 MHz
for 1H NMR and 125 MHz for 13C NMR). Proton chemical
shifts are reported in parts per million downfield from tetra-
methylsilane (TMS) and the coupling constant, J, is reported
in hertz (Hz). The following splitting patterns are designated
as s, singlet; d, doublet; t, triplet; q, quartet; br, broad; m,
multiplet. Carbon chemical shifts are reported downfield
from TMS using the resonance of the deuterated solvent
as the internal standard. Temperature calibration for VT
NMR was achieved by observing the temperature dependent
chemical-shift separation between the OH resonances and
CHn resonances in ethylene glycol. Matrix assisted laser
desorption/ionization mass-time of flight (MALDI-TOF)
was obtained using a PerSeptive Biosystems Voyager-DE
PRO spectrometer. Infrared (IR) spectra were recorded on
a Perkin–Elmer Spectrum One FTIR spectrometer with
Also noteworthy is that the aminophthalimide compound is
thermally and chemically more stable than the correspond-
ing ureidophthalimide, which would allow in-depth study

6650
H. Katayama et al. / Tetrahedron 63 (2007) 6642–6653
a Universal ATR sampling accessory. Elemental analysis
was performed on a Perkin–Elmer 2400 series II CHNS/O
€
Analyzer. Melting points were determined on a Buchi Melt-
ing Point B-540 apparatus.
(71.1 mg, 0.389 mmol) and 7c (304 mg, 0.471 mmol) in ace-
tic acid (1.5 mL) was refluxed at 135 ꢀC for 1 h with stirring.
The mixturewas cooled to room temperature, and then the re-
sulting gray suspension was extracted with CHCl3 and water.
The combined organic layers were dried over MgSO4. The
drying agent was filtered off, and the filtrate was evaporated
to give a pale brown solid, which was purified by flash
column chromatography on silica gel eluted with CH2Cl2/
heptane (1/1) to give 10c as a white solid (0.206 g, 65%
yield). 1H NMR (CDCl3): d 7.88–7.84 (m, 1H, H6 of
C6H3), 7.73–7.68 (m, 2H, H4,5 of C6H3), 6.60 (s, 2H, C6H2),
3.99 (t, J¼6.6 Hz, 2H, 4-OCH2), 3.96 (t, J¼6.6 Hz, 4H, 3,5-
OCH2), 1.83–1.72 (m, 6H, OCH2CH2), 1.52–1.42, 1.38–1.20
(each m, 54H, CH2), 0.90–0.86 (m, 9H, CH3). 13C{1H} NMR
(CDCl3): d 166.0, 165.0 (each C]O), 153.3 (C3,5 of C6H2),
138.1 (C1 of C6H2), 136.1, 135.2 (each C4 or 5 of C6H3), 133.9
(C1 of C6H3), 131.9 (C2 of C6H3), 127.4 (C3 of C6H3), 126.2
(C4 of C6H2), 122.2 (C6 of C6H3), 105.4 (C2,6 of C6H2), 73.5
(4-OCH2), 69.2 (3,5-OCH2), 31.9, 30.4, 29.8, 29.7, 29.7,
29.6, 29.4, 29.4, 29.3, 26.1, 26.1, 22.7 (each CH2), 14.1
(CH3). IR (ATR): 2920, 2849, 1769, 1714, 1601, 1506,
1465, 1437, 1396, 1356, 1308, 1241, 1116, 891, 772,
741 cmꢂ1. Anal. Calcd for C22H24ClNO3: C, 68.48; H,
6.27; N, 3.63. Found: C, 68.59; H, 6.27; N, 3.69.
4.1.1. 3-Acetylamino-N-(3,4,5-tridodecyloxyphenyl)-
phthalimide (8c). A solution of 3-acetylaminophthalic
anhydride (6) (0.541 g, 2.64 mmol) and 3,4,5-tridodecyl-
oxyaniline (7c) (2.05 g, 3.17 mmol) in acetic acid (26 mL)
was stirred at 100 ꢀC for 12 h. The resulting black suspension
was cooled to room temperature and then evaporated. The
residue was purified by flash column chromatography on sil-
ica gel, eluted with CH2Cl2 to give 8c as a pale brown solid
(2.15 g, 98% yield). 1H NMR (CDCl3): d 9.64 (s, 1H, NH),
8.84 (d, J¼8.4 Hz, 1H, H4 of C6H3), 7.74 (dd, J¼8.4,
7.3 Hz, 1H, H5 of C6H3), 7.60 (d, J¼7.3 Hz, 1H, H6 of
C6H3), 6.57 (s, 2H, H2,6 of C6H2), 4.01–3.95 (m, 6H,
OCH2), 2.27 (s, 3H, COCH3), 1.84–1.73 (m, 6H, OCH2CH2),
1.52–1.21 (m, 54H, CH2), 0.93–0.86 (m, 9H, CH3). 13C{1H}
NMR (CDCl3): d 169.4 (C]O), 169.2 (NHCO), 166.8
(C]O), 153.3 (C3,5 of C6H2), 138.1 (C3 of C6H3), 137.7
(C4 of C6H2), 136.3 (C5 of C6H3), 131.1 (C1 of C6H3),
125.9 (C1 of C6H2), 125.0 (C4 of C6H3), 118.3 (C6 of
C6H3), 115.2 (C2 of C6H3), 105.3 (C2,6 of C6H2), 73.5 (4-
OCH2), 69.2 (3,5-OCH2), 32.0, 31.9, 30.3, 29.8, 29.7, 29.6,
29.4, 29.3, 26.1, 26.0, 25.0, 22.6 (each CH2), 14.1 (CH3).
IR (ATR): 3361, 2919, 2851, 1764, 1698, 1621, 1597,
1533, 1505, 1481, 1468, 1437, 1413, 1390, 1377, 1307,
1260, 1233, 1180, 1118, 1016, 903, 868, 798, 747, 720,
684 cmꢂ1. Anal. Calcd for C52H84N2O6: C, 74.96; H,
10.16; N, 3.36. Found: C, 74.99; H, 10.20; N, 3.29.
4.1.4. 3,6-Dichloro-N-(3,4,5-tridodecyloxyphenyl)phthal-
imide (12c). A mixture of 3,6-dichlorophthalic anhydride
(1.40 g, 6.45 mmol) and 7c (5.01 g, 7.75 mmol) in acetic
acid (26 mL) was refluxed at 135 ꢀC for 1 h with stirring.
The mixture was cooled to room temperature, and then the
resulting gray suspension was extracted with CHCl3 and
water. The combined organic layers were dried over
MgSO4. The drying agent was filtered off, and the filtrate
was evaporated to give a brown solid, which was purified
by flash column chromatography on silica gel, eluted with
CHCl3/hexane (1/1) to give 12c as a pale orange solid
4.1.2. 3-Amino-N-(3,4,5-tridodecyloxyphenyl)phthal-
imide (9c). To a solution of 8c (2.10 g, 2.52 mmol) in 1,4-di-
oxane (80 mL) was added 37% aq HCl (7.1 mL), and the
mixturewas stirred at 100 ꢀC for 4 h. The mixturewas cooled
to room temperature and then neutralized with 25% aq NH3.
The mixture was extracted with CH2Cl2, washed with brine,
and dried over MgSO4. After removal of the drying agent the
filtrate was evaporated to give a yellow solid, which was
purified by flash column chromatography on silica gel eluted
with CH2Cl2/hexane (6/1) to give 9c as yellow crystals
1
(3.54 g, 65%). H NMR (CDCl3): d 7.63 (s, 2H, C6H2Cl2),
6.60 (s, 2H, C6H2(OC12H25)3), 3.99 (t, J¼6.6 Hz, 2H, 4-
OCH2), 3.96 (t, J¼6.6 Hz, 4H, 3,5-OCH2), 1.83–1.73 (m,
6H, OCH2CH2), 1.52–1.20 (m, 54H, CH2), 0.92–0.85 (m,
9H, CH3). 13C{1H} NMR (CDCl3): d 163.7 (C]O), 153.3
(C3,5 of C6H2(OR)3), 138.2 (C1 of C6H2(OR)3), 136.9 (C4,5
of C6H2Cl2), 130.4 (C3,6 of C6H2Cl2), 128.8 (C1,2 of
C6H2Cl2), 125.9 (C4 of C6H2(OR)3), 105.3 (C2,6 of
C6H2(OR)3), 73.5 (4-OCH2), 69.2 (3,5-OCH2), 31.9, 30.4,
29.8, 29.7, 29.7, 29.6, 29.4, 29.4, 29.3, 26.1, 26.1, 22.7
(each CH2), 14.1 (CH3). IR (ATR): 2953, 2919, 2848,
1788, 1766, 1714, 1601, 1506, 1466, 1454, 1438, 1393,
1353, 1306, 1240, 1180, 1130, 1115, 889, 830, 755, 723,
693, 668 cmꢂ1. Anal. Calcd for C50H79Cl2NO5: C, 71.06;
H, 9.42; N, 1.66. Found: C, 70.82; H, 9.44; N, 1.63.
1
(1.61 g, 81% yield). H NMR (CDCl3): d 7.47 (dd, J¼8.4,
7.3 Hz, 1H, H5 of C6H3), 7.23 (d, J¼7.3 Hz, 1H, H6 of
C6H3), 6.90 (d, J¼8.4 Hz, 1H, H4 of C6H3), 6.59 (s, 2H,
C6H2), 5.30 (br s, 2H, NH2), 3.99–3.95 (m, 6H, OCH2),
1.83–1.72 (m, 6H, OCH2CH2), 1.53–1.20 (m, 54H, CH2),
0.90–0.86 (m, 9H, CH3). 13C{1H} NMR (CDCl3): d 169.3,
167.7 (each C]O), 153.2 (C3,5 of C6H2), 145.6 (C3 of
C6H3), 137.8 (C1 of C6H2), 135.5 (C5 of C6H3), 132.4 (C1
of C6H3), 126.7 (C4 of C6H2), 121.2 (C4 of C6H3), 113.1
(C6 of C6H3), 110.9 (C2 of C6H3), 105.4 (C2,6 of C6H2),
73.5 (4-OCH2), 69.1 (3,5-OCH2), 32.0, 31.9, 30.4, 29.8,
29.8, 29.7, 29.7, 29.7, 29.4, 29.4, 29.3, 26.1, 26.1, 22.7
(each CH2), 14.1 (CH3). IR (ATR): 3472, 3340, 2956,
2923, 2852, 1743, 1702, 1639, 1596, 1508, 1482, 1468,
1439, 1416, 1389, 1310, 1237, 1191, 1132, 1120, 1098,
4.1.5. PAP dimer 3c. A Schlenk tube equipped with a stirbar
was charged with 10c (32.0 mg, 39.5 mmol), 9c (35.1 mg,
44.4 mmol), Pd(OAc)2 (0.44 mg, 1.2 mmol), XPhos (1.9 mg,
4.0 mmol), and K3PO4 (13.0 mg, 61.2 mmol). The system
was evacuated and backfilled with argon gas (this process
was repeated three times), and then anhydrous toluene
(1.6 mL) was added. The mixture was stirred at 100 ꢀC for
24 h. The resulting orange suspension was cooled to room
temperature and then the solvent was removed by pumping
to give an orange oil, which was purified by flash column
chromatography on silica gel, eluted with CH2Cl2/hexane
1026, 984, 939, 878, 820, 773, 741, 723, 704, 679 cmꢂ1
.
Anal. Calcd for C50H82N2O5: C, 75.90; H, 10.45; N, 3.54.
Found: C, 75.93; H, 10.50; N, 3.33.
4.1.3. 3-Chloro-N-(3,4,5-tridodecyloxyphenyl)phthal-
imide (10c). A mixture of 3-chlorophthalic anhydride

H. Katayama et al. / Tetrahedron 63 (2007) 6642–6653
6651
(2/1) to give 3c as a yellow sticky solid (56 mg, 91% yield).
1H NMR (CDCl3): d 10.00 (s, 1H, NH), 7.83 (d, J¼8.4 Hz,
2H, H4 of C6H3), 7.69 (apparent t, J¼7.9 Hz, 2H, H5 of
C6H3), 7.51 (d, J¼7.0 Hz, 2H, H6 of C6H3), 6.60 (s, 4H,
C6H2), 3.99–3.94 (m, 12H, OCH2), 1.82–1.72 (m, 12H,
OCH2CH2), 1.52–1.42, 1.38–1.19 (each m, 108H, CH2),
0.90–0.86 (m, 18H, CH3). 13C{1H} NMR (CDCl3): d
168.2, 167.0 (each C]O), 153.2 (C3,5 of C6H2), 139.5 (C3
of C6H3), 138.0 (C1 of C6H2), 135.6 (C5 of C6H3), 133.1
(C1 of C6H3), 126.3 (C4 of C6H2), 120.9 (C4 of C6H3),
116.5 (C6 of C6H3), 115.9 (C2 of C6H3), 105.5 (C2,6 of C6H2),
73.5 (4-OCH2), 69.2 (3,5-OCH2), 31.9, 31.9, 30.4, 29.8, 29.7,
29.7, 29.7, 29.6, 29.4, 29.4, 29.4, 29.3, 26.1, 26.1, 22.7 (each
CH2), 14.1 (CH3). IR (ATR): 3293, 2922, 2853, 1763, 1712,
1701, 1616, 1597, 1537, 1508, 1475, 1443, 1409, 1390, 1332,
5 mm 1H/X Inverse Detection probe equipped with gradient
capabilities at 298 K. Deuterated chloroform was de-
acidified and dried by passing it through a column of
activated basic alumina (type I). Solutions used for NOE
measurements were degassed by a repetitive freeze–pump–
thaw procedure. For all measurements the 90ꢀ 1H pulse
width was calibrated (4.8 ms at a transmitter power of
59 dB). The compression factor of the amplifier, needed
for ZQ suppression, was calculated from the 90ꢀ pulse width
at a transmitter power of 53 dB and was determined to be
0.9. Volume integrals were determined in VNMR using the
ll2d routine.
2D NOESY experiments were performed with a relaxation
delay time of 3 s and a mixing time of 100 ms. Zero quantum
artifacts were removed by swept-pulse/gradient pairs.55 All
2D-data were collected in the phase-sensitive mode using
the States–Haberkorn method. A total of 400 FIDs of 2K
complex data points were collected in t2 with 16 scans per
increment and zero-filling was applied in both dimensions
before Fourier transformation. These data was then pro-
cessed with a cosine squared window function in both di-
mensions.
1296, 1243, 1171, 1123, 1039, 876, 827, 810, 736 cmꢂ1
.
MALDI-TOF-MS calcd for [M]+: 1564.22. Found: 1565.26
([M+H]+). Anal. Calcd for C100H161N3O10: C, 76.73; H,
10.37; N, 2.68. Found: C, 76.98; H, 10.38; N, 2.52.
4.1.6. PAP trimer 4c. A Schlenk tube equipped with a stirbar
was charged with 12c (68.0 mg, 80.5 mmol), 9c (140 mg,
177 mmol), Pd(OAc)2 (0.18 mg, 0.80 mmol), XPhos
(0.80 mg, 1.7 mmol), and K3PO4 (51.0 mg, 240 mmol). The
system was evacuated and backfilled with argon gas (this pro-
cess was repeated three times), and then anhydrous toluene
(3.2 mL) was added. The mixture was stirred at 100 ꢀC for
24 h. The resulting orange suspension was cooled to room
temperature and then the solvent was removed by pumping
to give an orange oil, which was purified by flash column
chromatography on silica gel eluted with CH2Cl2/hexane
(3/2) to give4c as an orange stickysolid (182 mg, 97% yield).
1H NMR (CDCl3): d 9.85 (s, 2H, NH), 7.83 (s, 2H, C6H2 (in-
ner phthalimide)), 7.75 (d, J¼8.4 Hz, 2H, H4 of C6H3 (outer
phthalimide)), 7.67 (apparent t, J¼7.9 Hz, 2H, H5 of C6H3
(outer phthalimide)), 7.49 (d, J¼7.3 Hz, 2H, H6 of C6H3
(outer phthalimide)), 6.60 (s, 4H, outer C6H2(OR)3), 6.58
(s, 2H, inner C6H2(OR)3), 3.98–3.92 (m, 18H, OCH2),
1.82–1.70, 1.52–1.10 (each m, 180H, CH2), 0.92–0.82 (m,
27H, CH3). 13C{1H} NMR (CDCl3): d 168.4, 167.4, 167.1
(each C]O), 153.3 (C3,5 of C6H2(OR)3), 140.1 (C3 of
C6H3 (outer phthalimide)), 138.1 (C1 of inner C6H2(OR)3),
138.1 (C1 of outer C6H2(OR)3), 135.7 (C5 of C6H3 (outer
phthalimide)), 133.5 (C3,6 of C6H2 (inner phthalimide)),
133.2 (C1 of C6H3 (outer phthalimide)), 126.3 (C4 of outer
C6H2(OR)3), 126.0 (C4 of inner C6H2(OR)3), 124.0 (C4,5 of
C6H2 (inner phthalimide)), 120.0 (C4 of C6H3 (outer phthal-
imide)), 116.8 (C6 of C6H3 (outer phthalimide)), 116.0 (C2 of
C6H3 (outer phthalimide)), 115.2 (C1,2 of C6H2 (inner phthal-
imide)), 105.6 (C2,6 of inner C6H2(OR)3), 105.5 (C2,6 of outer
C6H2(OR)3), 73.5 (4-OCH2), 69.2 (3,5-OCH2), 32.0, 31.9,
30.4, 29.8, 29.7, 29.7, 29.4, 29.4, 29.4, 29.3, 26.2, 26.1,
22.7 (each CH2), 14.1 (CH3). IR (ATR): 2922, 2853, 1768,
1747, 1706, 1619, 1597, 1506, 1471, 1442, 1409, 1390,
1298, 1233, 1173, 1120, 875, 739 cmꢂ1. MALDI-TOF-MS
calcd for [M]+: 2352.82. Found: 2353.72 ([M+H]+). Anal.
Calcd for C150H241N5O15: C, 76.52; H, 10.32; N, 2.97.
Found: 76.71; H, 10.42; N, 2.97.
4.3. Computational procedure
The hybrid of Becke’s non-local three parameter exchange
functional with the Lee–Yang–Parr gradient-corrected cor-
relation functional (B3LYP) was used with the 6-311G(d,p)
basis set for calculating gas phase optimized geometries
and relative energies. The optimized geometry at the
B3LYP/6-311G(d,p) level was used as initial geometry
for a calculation at the B3LYP/6-311+G(d,p) level of
theory. Analytical frequency computation on the optimized
geometries revealed only real frequencies, indicating that
the optimized geometries are true local minima. Relative
stabilities include the zero-point energy (ZPE), calculated
with the same method from the unscaled harmonic
B3LYP frequencies. Energies reported are differences in
Gibbs free energy at 298.15 K and a pressure of 1 atm.
All computations were performed using the GAUSSIAN
0356 package. Geometry optimization was performed using
the Berny algorithm and normal convergence criteria were
used (rms force criterion 3ꢁ10ꢂ4). All geometries were op-
timized without symmetry constraints. An analytical Hes-
sian was computed at the initial point of the optimization
using the opt¼calcfc keyword. The size of the integration
grid was set to default (pruned (75,302) grid). The stability
of the final wave function was tested by using the stable
keyword, available in the GAUSSIAN 03 package. In all
cases the restricted wave function did not contain any sin-
glet instabilities.
Acknowledgements
We are grateful to Mr. Joost van Dongen, Mr. Ralf Bovee,
and Dr. Xianwen Lou for technical assistance. Dr. Christian
ꢀ
Nielsen and Prof. Dr. Rene Jansen are acknowledged for
4.2. Two dimensional NMR
helpful discussions on the DFT calculations and critical
reading of the document. This work is supported by the
Council for Chemical Sciences of The Netherlands Organi-
zation for Scientific Research (CW-NWO).
All two dimensional NMR spectra were recorded on
a 500 MHz NMR (Varian Unity Inova) by means of a

6652
H. Katayama et al. / Tetrahedron 63 (2007) 6642–6653
Kovalevsky, A. Y.; Mills, J. L.; Skrzypczak-Jankun, E.;
Supplementary data
Martinovic, S.; Smith, R. D.; Zheng, C.; Szyperski, T.; Zeng,
X. C. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 11583; (f)
Zhang, A.; Han, Y.; Yamato, K.; Zeng, X. C.; Gong, B. Org.
Lett. 2006, 8, 803.
Detailed experimental procedures and the characterization of
each compound. 2D COSY, TOCSY, HMQC, and NOESY
spectra for compound 4c. B3LYP/6-311G(d,p) optimized
geometries, B3LYP/6-311G+(d,p) optimized geometries,
frequency calculations, the energies of the corresponding
conformers of syn and anti PUP and PAP dimers, and com-
parison of calculated geometries with the crystal structures.
Crystal structures of 3a, 3b, and 20a as cif files. Supple-
mentary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2007.04.002.
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