Dipyrrinone imines: Controlling self-association

Article abstract of DOI:10.1080/10610278.2013.771777

We report the synthesis of three new dipyrrinone imine analogues and the characterisation of their self-association properties. Based on vapour pressure osmometry and nuclear magnetic resonance studies, placing the imine functional group at C(9) of the di

Full text of DOI:10.1080/10610278.2013.771777

Supramolecular Chemistry, 2013
Vol. 25, No. 5, 286–291, http://dx.doi.org/10.1080/10610278.2013.771777
Dipyrrinone imines: controlling self-association
Patrick Ward, Rebecca R. Chandler and Michael T. Huggins*
Department of Chemistry, University of West Florida, Pensacola, FL 32514, USA
(Received 28 November 2012; final version received 28 January 2013)
We report the synthesis of three new dipyrrinone imine analogues and the characterisation of their self-association
properties. Based on vapour pressure osmometry and nuclear magnetic resonance studies, placing the imine functional
group at C(9) of the dipyrrinone disrupts the native self-association of the dipyrrinone core in a manner that correlates with
the conformational A-value of the imine N-substituent.
Keywords: dipyrrinones; self-association; vapour pressure osmometry; hydrogen bonding
1. Introduction
actual self-association constant has been determined
(10,12,13). These few examples show a wide variation in
the strength of the self-association constants which deviate
depending on the substituents on the dipyrrinone back-
bone. In addition, extensive studies via VPO have shown
that the self-association of dipyrrinones is strongly
affected by the substituents at the C(9) position (3,8–
10,13). Specifically, the placement of an appropriate C(9)
substituent introduces steric repulsions between the C(2)
moiety on one molecule of the dimer and the C(9) group of
the second dipyrrinone which could substantially weaken
the dipyrrinone–dipyrrinone interactions, see Figure 1(C)
(10). This has been shown with 9-acyl dipyrrinone
derivatives; these analogues were found to be essentially
monomeric in non-polar solvents, i.e. chloroform.
Dipyrrinones, also known as pyrromethenones, have been
well studied due to their connection to linear tetrapyrroles
and bile pigments, such as bilirubin (1–7). Structurally,
dipyrrinones comprise lactam and pyrrole rings conjoined
via a central methine group to form a conjugated
chromophorewith a bright yellow colour, which is typically
planar or nearly planar in shape. In addition, the C(4)–C(5)
double bond is generally in the Z-configuration. The C(5)–
C(6) bond is syn which leads to the creation of a hydrogen
bonding pocket containing the lactam and pyrrole NHs
along with the lactam C ¼ O. This has been found to
predominate in both solid state and solution, as shown in
Figure 1. As these are essential building blocks in linear
oligopyrrole chemistry, dipyrrinones have an extensive
array of synthetic techniques available for their preparation,
as documented in a recent review (1).
Recently, we have initiated a programme to develop
dipyrrinone-based molecular receptors for external guests,
both anionic and neutral. Our initial efforts used
dipyrrinone 2 as a potential receptor (13). Dipyrrinone 2
was found to have a moderately strong self-association
constant, 3850 M21 in CDCl3 at 208C, which created a
competitive binding environment for external guests.
Dipyrrinone showed the strongest binding affinity for
hydrogen sulphate, Ka ¼ 1680 M21, with three hydrogen
bonds between dipyrrinone and hydrogen sulphate, see
Figure 2. Unfortunately, this specific dipyrrinone has little
practical use as a receptor for external guests due to the
competitive binding environment created by the self-
association process. As such, efforts were started for
developing analogues that completely disrupt the self-
association of the dipyrrinone receptor. Previous self-
association studies showed that the introduction of an
appropriate substituent at C(9) should provide the needed
disruption. Herein, we report the synthesis and character-
isation of a new class of dipyrrinone analogues possessing
a C(9) imine moiety, see Figure 3.
Dipyrrinones are well known to be avid participants in
hydrogen bonding and have been shown to form
dipyrrinone–dipyrrinone dimers via a network of four
intermolecular hydrogen bonds incorporating amide–
amide hydrogen bonds between the lactam moieties as
well as H bonds between the pyrrole N–H and the lactam
carbonyl, see Figure 1. In the solid state, the dipyrrinone-
to-dipyrrinone motif generally positions the two dipyrri-
none units in a coplanar arrangement. This dimerisation,
arising from intermolecular hydrogen bonding, is thus
apparently strongly preferred in non-polar solvents and has
been extensively studied using vapour pressure osmometry
1
(VPO) (3,8–10), H nuclear magnetic resonance (NMR)
spectroscopy (4,5,8) and X-ray crystallography (2,11). The
self-association constant of kryptopyrromethenone, 1, is
rather large (Ka ¼ 23,000 M21 at 238C in CDCl3) (12).
Although dipyrrinone self-association has been studied
extensively, relatively few examples exist in which the
*Corresponding author. Email: mhuggins@uwf.edu
q 2013 Taylor & Francis

Supramolecular Chemistry
287
Figure 3. Synthetic targets.
conditions afforded the dipyrrinone carboxylic acid in
good yield, and the reaction was easily scalable to produce
multi-gram quantities of the product (1). Decarboxylation
of dipyrrinone acid 8 via treatment with neat trifluoroacetic
acid followed by formylation under Clezy conditions (17)
produced the key dipyrrinone aldehyde 9 in a 70–85%
yield, in two steps. It should be noted that the addition of
cold triethyl orthoformate to the reaction mixture greatly
reduces the formation of biliverdin by-products. These blue
to blue-green by-products were easily removed by
trituration with cold acetone. Reaction of 9 with various
primary amines under acidic conditions afforded dipyrri-
none imines 3–5 in 70–95% yields after neutralisation by
addition of excess triethylamine.
The structure of all products was confirmed by 1H and
13C NMR spectroscopies. Complete NMR spectroscopic
assignments were made by a combination of [1H,1H]-
nuclear Overhauser enhancement spectroscopy (NOESY),
HSQC and HMBC techniques. The Z-configuration of the
C(4)–C(5) exocyclic double bond was confirmed by the
observation of a moderate nuclear Overhauser effect
(NOE) between the C(5)–H and the C(3) methyl in
CDCl3, which was observed for all dipyrrinone analogues
(Figure 4).
Figure 1. (A) Monomer–dimer equilibrium with generic
dipyrrinone showing four intermolecular hydrogen bonds
between the dipyrrinones, (B) kryptopyrromethenone 1 and (C)
intermolecular hydrogen bonded dimer showing steric
interactions between C(9) and C(2) positions with open arrows.
2. Synthesis and molecular structure
Using readily available starting materials, we envisioned a
relatively concise synthetic route to the desired target
molecules starting from pyrrole 6 (14), see Synthetic
Scheme 1. Ceric ammonium nitrate oxidation of the
a-methyl group on pyrrole 6 provided aldehyde 7 in
70–90% yield (15,16). Condensation of 3-ethyl-4-methyl-
pyrrolin-2-one with pyrrole aldehyde 7 under basic
3. Molecular conformation and aggregation
Literature reports on pyrroles and dipyrrinones indicate
that steric interactions with C(8) alkyl groups are typically
the controlling factor surrounding the conformation of
acyl groups at this position on a pyrrole ring (a-position on
a pyrrole or 9-position on a dipyrrinone) (10). Molecular
mechanics calculations on the 9-imine dipyrrinone
analogues suggest that the syn–trans conformer is the
most stable conformation by ,3 kcal/mol; Figure 5 shows
the lowest energy conformation of imine 4. In CDCl3, the
NOESY data found strong NOE interactions between the
imine C–H and the C(8)–CH3 of the dipyrrinone
backbone as well as between the imine C–H and the
N-substituents (butyl, phenyl and 4-nitrophenyl). Taken
together, these data suggest that the syn–trans conformer
is the predominate conformer present in the non-polar
Figure 2. X-ray crystal structure of dipyrrinone 2: HSO4–
complex, hydrogen sulphate as the tetra-n-butylammonium salt,
showing three intermolecular hydrogen bonds.

288
P. Ward et al.
Scheme 1. Synthetic scheme for the preparation of dipyrrinone imines 3–5.
solvent for all three analogues. The syn–trans confor-
mation places the sterically smallest group closest to the
C(8)–CH3, thus reducing any potential steric repulsion.
In addition, this conformation propels the imine N-sub-
stituent into the binding pocket of the dipyrrinone. For
dipyrrinone aldehyde 9, the NOESY spectrum showed
NOE interaction between the aldehydic C–H and the
pyrrole NH as well as the C(8) methyl which indicates
rotational mobility of the CHO moiety.
one can estimate the relative monomer–dimer ratio for
each molecule. Both the phenyl and 4-nitrophenyl
derivatives showed ratios of 1:9, whereas that of the
butyl analogue was 1:2.3. These ratios correlate well with
the larger observed conformational A-value for the phenyl
group than with that for the butyl group, 2.8 and 1.8 kcal/
mol, respectively (19). Thus, the sterically larger groups
influence the self-association to a greater extent. As seen in
Figure 6, the imine substituents project into the hydrogen
bonding pocket of the dipyrrinone and create a steric
repulsion with the C(2)-ethyl group, indicated with green
double headed arrows. The syn–trans conformation of the
imine also creates an electronic repulsion between the
imine-N and the lactam C ¼ O, indicated with red double
headed arrows in Figure 6. In this instance, the repulsive
It has been shown that dipyrrinones with relatively
strong self-association constants, Ka, provide molecular
weights consistent with the dimer structure when
characterised by VPO in non-polar solvents, e.g. chloro-
form (3,8,10,13,18). To determine the aggregation state of
the dipyrrinone imines in CHCl3 solution, we determined
their molecular weights by VPO. The calibration standard
was benzil (molecular weight (MW) calc ¼ 210, MW
obs ¼ 220), and molecular weights determined for 3–5
and 9 are summarised in Table 1. These data indicate that
dipyrrinone imines 3–5 gave molecular weights approach-
ing the value of their monomeric structures, whereas
dipyrrinone aldehyde 9 was dimeric in CHCl3 solution.
From the experimentally determined molecular weights,
Figure 5. Ball and stick structure of lowest energy
conformation for dipyrrinone imine 4 based on molecular
mechanics calculations.
Figure 4. NOE data for dipyrrinone imines 3–5. Arrows shown
indicate selected [1H,1H]-NOEs observed in CDCl3.

Supramolecular Chemistry
289
Table 1. Vapour pressure osmometry dataa.
Monomer formula weight
Estimated monomer–dimer
composition
Imine substituent
(FW) (g/mol)
Dimer FW (g/mol) Measured MW (g/mol)
n-Butyl 3
Phenyl 4
4-NO2 phenyl 5
CHO 9
327
347
392
272
654
694
784
544
426 ^ 15
373 ^ 10
429 ^ 20
528 ^ 25
70/30
90/10
90/10
5/95
a Measurements made in CHCl3 at 458C over a concentration range of 5–36 mM and calibrated with benzil.
interactions are magnified because each occurs in two
locations in the structure.
4. Tautomeric equilibria
Interestingly, there is a plausible explanation for the
unusual behaviour. Dipyrrinone imines have multiple
tautomeric and resonance forms available and the imine
N-substituent influences the stability of the various forms.
As shown in Figure 7, the various forms of the dipyrrinones
involve shifting the two NH hydrogens between the three
nitrogens, as well as resonance forms involving an
intramolecular charge transfer. This phenomenon can also
be seen by comparing in the infrared (IR) spectra for the
imine analogues. Butyl imine 3 was found to possess the
expected NH, C ¼ N and C ¼ O at ,3300, 1680 and
1705 cm21, respectively, see online supporting information
for actual IR spectra. However, phenyl imine 4 displayed
these peaks plus an additional new set of vibrational bands
at 2500 cm21. In 4-nitrophenyl imine 5, the NH peak was
missing whereas the bands at ,2500 cm21 were substan-
tially stronger in intensity. The new bands can be assigned
to structural forms involving an NHþ moiety (20). Thus, the
4-nitrophenyl group must provideadditional stabilisation to
the structural forms involving the intramolecular charge
separated states.
Typically, the self-association of dipyrrinones can be
tracked via 1H NMR by following the lactam and pyrrole
NH signals in non-polar solvents (7). For the dimeric
aggregation state in CDCl3, the pyrrole and lactam NH
resonances are generally located at 10.0–10.4 and 10.5–
11.2 ppm, respectively. Whereas the free, ‘non-hydrogen
bonded’ monomer has pyrrole and lactam NH resonances
typically located at 7.0–7.5 and 8.0–8.9 ppm in CDCl3,
respectively (7). Thus, each NH signal experiences a
2.5 þ ppm downfield shift due to the formation of the four
intermolecular hydrogen bonds in the dimeric form. For
the butyl analogue, a broad NH signal integrating to two
hydrogens was observed at ,8 ppm in CDCl3. Supported
by the VPO data, the location of the NH resonances would
support a monomer–dimer equilibrium that has the
monomer as its major constituent. The phenyl imine
derivative had a similar broad NH signal integrating to two
hydrogens; however, it was observed at ,9.7 ppm in
CDCl3. An NH signal with a chemical shift in this area
should be indicative of a monomer–dimer equilibrium
with a higher proportion of dimer than the butyl analogue,
which is not in agreement with the VPO data. Even more
unusual, there were no observed pyrrole and lactam NH
resonances for the 4-nitrophenyl analogue 5 in CDCl3.
In DMSO-d6, all three analogues 3–5 were found to have
pyrrole and lactam NH signals at 9.5–9.8 and 10.4–
11.0 ppm, respectively. The chemical shifts observed in
DMSO-d6 are as expected, and indicative of hydrogen
bonding between the dipyrrinone NHs and the solvent.
Molecular mechanics calculations indicated that
tautomeric forms Ia, IIa and IIIa of 3 were nearly equivalent
in energy, see Table 2. Interestingly, the calculations found
that tautomer IIa was the most stable for phenyl imine 3 and
4-nitrophenyl imine 4 by more than 2 kcals/mol over
tautomer IIIa and almost 6 kcal/mol over tautomer Ia.
Tautomer IIa was stabilised by two intramolecular
hydrogen bonds between azafulvene nitrogen and the
amide and amine NH moieties. This tautomer of pyrrole
imines was previously observed as the predominate form in
the naturally occurring tambjamines, a group of bipyrrolic
alkaloids (21–23).
Table 2. Calculated energies for dipyrrinone imine tautomers in
kcal/mola.
Dipyrrinone imine
I
II
III
Butyl (3)
C6H5 (4)
p-C6H4NO2 (5)
59.45
66.08
72.09
59.78
60.61
66.26
58.76
62.70
68.27
Figure 6. Structure of the traditional dipyrrinone–dipyrrinone
dimer with arrow indicating steric (open arrows) and electronic
repulsions (double headed arrows) responsible for inhibited
dimer formation.
a Relative energies (kcal/mol) based on parameters indicated in
Experimental section.

290
P. Ward et al.
Figure 7. Tautomeric and resonance forms of dipyrrinone imines which results in disappearance of NH signals in the 1H NMR spectra
for 5 and the appearance of absorbances in the IR spectra in the 2400–2600 cm21
.
5. Conclusions
6.2. Molecular mechanics calculations
The results have shown that dipyrrinone self-association
can be regulated by the substituents located at the C(9)
position. In this instance, imine functionality with varying
N-substituents was able to limit the amount of self-
associated dimers that are formed in non-polar organic
solvent. In addition, the dipyrrinone imines were found to
be present as a mixture of tautomers and resonance forms
which clouded interpretation of NMR data for binding
energy determination. Molecular mechanics calculations
indicated that the enamine tautomer IIa was the most
stable form for 4 and 5, whereas all three tautomers were
of comparable energy for 3.
All molecular mechanics calculations were carried out
using Materials Studio, c4.1.0.0; Accelerys Software, Inc.:
2006; force field, Dreiding; charges, Gasteiger; Electro-
statics & van der Waals, atom based.
6.3. Synthesis of dipyrrinone carboxylic acid (8)
Pyrrole aldehyde 7 (14,15) (1.83 g, 8.8 mmol) and 3-ethyl-
4-methylpyrrolin-2-one (1.2 g, 10 mmol) were dissolved in
60 ml of 4 M KOH and 40 ml of methanol. The reaction
mixture was heated at reflux for 14 h and then cooled in an
ice bath. The solution was acidified with cold concentrated
HCl after which a yellow product was formed. The product
was collected via vacuum filtration, washed with cold
acetone and dried under vacuum to give the desired product
8 (2.19 g, 87%). Mp 219–2248C; IR (ATR) 985, 1262,
6. Experimental
6.1. General methods
1
1655, 2939, 2976, 3184 (broad), 3386 cm21; H NMR
NMR spectra were measured in CDCl3 with tetramethylsilane
(TMS) as internal reference standard at 300 MHz on a Varian
MercuryPlus Spectrometer. VPO measurements were carried
out using an Osmomat 070 (Gonotec, Berlin, Germany) in
CHCl3 (from Allied, with amylene stabiliser) at 458C using a
concentration range of 5–36 mM; benzil was used for
calibration. Chemical shifts are reported in d(ppm) referenced
to TMS. CDCl3 was obtained from Cambridge Isotope Labs,
and stored over CaH2 to remove water and HCl. The solvent
was filtered immediately before use. The reported melting
points are uncorrected. Ethyl 4-ethyl-3,5-dimethylpyrrole-2-
carboxylate was prepared via standard methods (24). 3-Ethyl-
4-methylpyrrolin-2-one was purchased from AK Scientific
Inc. (Union City, CA). All other solvents and materials were
purchased from common sources (Fisher, Acros, Pittsburgh,
PA or Sigma-Aldrich, St. Louis, MO) and used as received.
Radial chromatography was carried out on Merck Silica Gel
PF254 with gypsum preparative layer grade, using a
Chromatotron (Harrison Research, Inc., Palo Alto, CA, USA).
(300 MHz, DMSO-d6): 1.1 (3 H, t), 2.05 (3 H, s), 2.2 (3 H,
s), 2.25 (2 H, q), 2.5 (2 H, q), 5.9 (1 H, s), 10.6 (1 H, bs), 11.0
(1 H, bs) ppm; 13C NMR (75.4 MHz, DMSO-d6): 9.31,
10.08, 13.37, 15.85, 16.38, 16.88, 96.02, 122.34, 124.93,
126.44, 129.55, 131.73, 133.75, 141.45, 162.59,
172.36 ppm; HR-MS (ESI þ ) C16H20N2O3 Calcd
288.1474 amu; found 288.1471 amu.
6.4. Synthesis of dipyrrinone aldehyde (9)
Dipyrrinone carboxylic acid 8 (11.9 g, 41.3 mmol) was
dissolved in 75 ml of trifluoroacetic acid and stirred at
room temperature (rt) for 35 min. The reaction mixture
was then cooled in an ice bath, and added dropwise to a
cooled solution of trifluoroacetic acid (10 ml) and triethyl
orthoformate (20 ml). This solution was stirred for an hour
in an ice bath, and then poured into 400 ml of crushed ice
and water and allowed to stir for an additional hour.

Supramolecular Chemistry
291
The resulting precipitate was collected via vacuum 6.8. Synthesis of p-nitrophenyl dipyrrinone imine 5
filtration and washed with cold acetone (35 ml) to yield
the desired pure product 9 (8.0 g, 71%). Mp 227–2288C;
This compound was prepared with p-nitroaniline and
acetonitrile as the solvent using the general imine
synthesis procedure (0.51 g, 70%) Mp 248–2508C; IR
(thin film) 667, 1111, 1298, 1593, 1662, 2498, 2605,
2944 cm21; 1H NMR (300 MHz, CDCl3): 8.283 (s), 8.209
(doublet of doublets), 7.214 (doublet of doublets), 5.981
(s), 2.557 (q), 2.295 (q), 2.276 (s), 2.092 (s), 1.145 (t),
0.998 (s) and HR-MS (ESI þ ) C22H24N4O3 Calcd for
M þ H 393.1926 amu; found 393.1933 amu.
IR (ATR) 1152, 1267, 1606, 1668, 1698, 2964, 3317 cm21
;
1H NMR (300 MHz, CDCl3): 1.13 (6 H, m), 2.14 (3 H, s),
2.35(3 H, s), 2.46 (2 H, q, 7.5 Hz), 2.55 (2 H, q, 7.5 Hz),
5.95 (1H, s), 9.73 (1 H, s), 10.66 (1 H, bs), 10.91 (1 H, s)
ppm; 13C NMR (75.4 MHz, CDCl3): 9.02, 9.93, 13.70,
15.79, 17.13, 17.45, 95.62, 130.96, 131.50, 132.80,
132.83, 134.15, 137.10, 141.65, 173.86, 177.60 ppm and
HR-MS (ESI þ ) C16H20N2O2 Calcd 272.1525 amu; found
272.1530 amu.
6.5. General procedure for imine synthesis
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Dipyrrinone aldehyde 9 (0.505 g, 1.90 mmol) was dissolved
in 175 ml of methanol. To this solution was added
concentrated HCl (2 ml) followed by the corresponding
primary amine (5.7 mmol). This solution was stirred for
24 h at rt, and then basified with 5.0 ml of triethylamine. The
solution was concentrated to approximately one-fourth of
the original volume and cooled in an ice bath. The resulting
precipitate was collected via vacuum filtration and dried
under vacuum to give the desired product.
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6.6. Synthesis of butyl dipyrrinone imine 3
This compound was prepared with butylamine using the
general imine synthesis procedure (0.50 g, 82%). Mp 185–
1878C; IR (thin film) 692, 1035, 1167, 1301, 1588, 1657,
1706, 2967, 3347 cm21; 1H NMR (300 MHz, CDCl3): 0.94
(3 H, t, 7.5 Hz), 1.09 (3 H, t, 7.5 Hz), 1.10 (3 H, t, 7.5 Hz),
1.39 (2 H, sextet, 7.5 Hz), 1.66 (2 H, pentet, 7.5 Hz), 2.09
(3 H, s), 2.14 (3 H, s), 2.37 (2 H, q, 7.5 Hz), 2.49 (2 H, q,
7.5 Hz), 3.48 (2 H, t, 7.5 Hz), 5.93 (1 H, s), 7.64 (1 H, s),
8.3 (2 H, bs, NHs) ppm; 13C NMR (75.4 MHz, CDCl3):
9.24, 9.77, 13.76, 14.01, 15.95, 17.11, 17.76, 20.32, 33.35,
55.05, 98.25, 130.02, 131.75, 132.43, 133.31, 137.50,
140.65, 141.73, 146.58, 172.80 ppm; HR-MS (ESI þ )
C20H29N3O1 Calcd 327.2311 amu; found 327.2316 amu.
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6.7. Synthesis of phenyl dipyrrinone imine 4
This compound was prepared with aniline using the general
imine synthesis procedure (0.57 g, 87%. Mp 193–1978C
(dec.); IR (thin film) 692, 1034, 1169, 1300, 1589, 1655,
1698, 2498, 2604, 2965, 3337 cm21; 1H NMR (300 MHz,
CDCl3): 0.93 (3 H, t), 1.17 (3 H, t), 2.10 (3 H, s), 2.26 (3 H,
s), 2.36 (2 H, q), 2.55 (2 H, q), 5.94 (1 H, s), 7.20 (1 H, m),
7.27 (2 H, m), 7.37 (2 H, m), 8.22 (1 H, s), 9.7 (2 H, bs) ppm;
13C NMR (75.4 MHz, CDCl3): 9.28, 9.88, 13.62, 15.95,
17.10, 17.17, 97.43, 120.91, 125.43, 127.36, 129.37,
130.73, 130.95, 131.18, 133.20, 135.62, 141.41, 147.12,
151.48, 173.51 ppm and HR-MS (ESI þ ) C22H25N3O1
Calcd for M þ H 348.2076 amu; found 348.2077 amu.
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