Diamine acylation with amino acid derivatives: An example of proximity effect in organic reactivity induced by supramolecular aggregation

Article abstract of DOI:10.1016/j.tetlet.2015.01.094

Unexpected high yields of diamide 3 are obtained in the reaction of 1,3-propanediamine with an activated ester of l-valine (1) under adverse proportions of the reactants, namely in the presence of an excess of 1,3-propanediamine. It is observed using different conditions that the yield of difunctionalized compound is considerably higher than that expected from a statistical distribution of products. Proximity effects associated to supramolecular interactions explain the described reactivity.

Full text of DOI:10.1016/j.tetlet.2015.01.094

Tetrahedron Letters 56 (2015) 1132–1134
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diamine acylation with amino acid derivatives: an example
of proximity effect in organic reactivity induced
by supramolecular aggregation
⇑
⇑
Carles Felip-León, María D. Segarra-Maset, Beatriu Escuder , Juan F. Miravet
Departament de Química Inorgànica I Orgànica, Universitat Jaume I, Avda. Sos Baynat s/n, 12071 Castelló de la Plana, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Unexpected high yields of diamide 3 are obtained in the reaction of 1,3-propanediamine with an
activated ester of -valine (1) under adverse proportions of the reactants, namely in the presence of an
excess of 1,3-propanediamine. It is observed using different conditions that the yield of difunctionalized
compound is considerably higher than that expected from a statistical distribution of products. Proximity
effects associated to supramolecular interactions explain the described reactivity.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 2 December 2014
Revised 8 January 2015
Accepted 13 January 2015
Available online 17 January 2015
L
Keywords:
Proximity effects
Supramolecular catalysis
Chemoselectivity
Introduction
corresponds to the acylation of 1,3-diaminopropane with an acti-
vated ester of N-protected valine (1) using THF as solvent. In order
Proximity effects are extensively described in the literature as a
way to rationalize the enzymatic processes and biological mecha-
to optimize the preparation of compound 2 different assays were
carried out using an excess of diamine. Unexpectedly, the yield
of monofunctionalized product was not improved using a large
excess of diamine. It was found that the yield of isolated difunc-
tionalized compound 3 was significantly higher than that expected
for a statistical product distribution (see Table 1, notice that yields
are calculated based on the conversion of the limiting reagent,
namely activated ester).
For example, when a large excess of diamine was used in a gram
scale reaction with a 1:4 ratio of activated ester/diamine (8-fold
excess considering the stoichiometric ratio of difunctionalized
compound), a 54% yield of compound 3 was obtained after isola-
tion. This yield is higher than that predicted from a statistical prod-
uct distribution, 13%. As shown in Table 1, this effect was similar
when 1:2 and 1:3 ratios of activated ester/diamine were employed,
being the yield of difunctionalized product insensitive to the use of
an increasing excess of diamine.
1
–3
nisms.
In a simplified way, it can be said that molecules that
are disposed in spatially close positions tend to react faster than
those without this feature. Examples of organic reactions that
4
,5
show proximity effects include intramolecular reactions
and
more rarely intermolecular reactions in supramolecular complexes
which are held together by interactions such as hydrogen bond-
ing or hydrophobic forces.8 The natural extension of proximity
6
,7
9
effects is related, among other topics, with auto-replicative, self-
1
0
11
assembling systems, and with systems chemistry in general.
Here we report an example of unusual substrate selectivity associ-
ated with a supramolecularly induced proximity effect. Activated
1
2
ester 1 reacts preferentially with the amine group of compound
in the presence of competing reagent 1,3-propanediamine.
2
Results and discussion
In order to gain further evidence of this effect, small scale assays
were performed with variation of the reactant ratio in THF and
MeOH at room temperature (Table 2). The ratio between mono
and difunctionalized products was determined from the reaction
As a result of our work in supramolecular gels, we were inter-
12
ested in the synthesis of compound 3 which is a low molecular
1
3,14
15
weight gelator
and related molecule 2. These compounds
1
crude by means of H NMR. In this way, the possible effects of
can be prepared, respectively, by difunctionalization and mono-
functionalization of 1,3-propanediamine (Scheme 1). The reaction
the isolation process in the final yield were avoided. The results
fully agree with those described in Table 1 for gram scale reactions
with isolation of difunctionalized compound 3. As seen in Table 2,
the yield of difunctional compound for a 1 to 1 ratio of reagents,
⇑
Corresponding authors.
E-mail addresses: escuder@uji.es (B. Escuder), miravet@uji.es (J.F. Miravet).
http://dx.doi.org/10.1016/j.tetlet.2015.01.094
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

C. Felip-León et al. / Tetrahedron Letters 56 (2015) 1132–1134
1133
H
N
O
O
N
H
NH
2
O
O
H
2
N
NH
2
H
N
O
O
N
2
3
excess
O
O
O
O
O
H
N
H
N
O
O
1
N
N
H
H
O
O
Scheme 1. Reaction under study.
Table 1
H
N
O
Yields of isolated difunctionalized product 3 calculated taking as limiting reagent
O
compound 116
N
H
NH
2
O
H
2
N
NH
2
Ratio activated
ester/diamine
Experimental
yield (%)
Statistically
predicted yield (%)
2
O
1
1
1
:2
:3
:4
45
52
54
25
17
13
H
N
O
O
N
k1
O
O
O
1
H
N
O
H
N
O
Table 2
O
N
H
NH
2
O
Yields of difunctionalized product calculated taking as limiting reagent compound 1
N
H
NH
2
and determined by 1H NMR from reaction crudes
17
O
O
O
H
N
O
Ratio activated
ester/diamine
Solvent
Experimental
yield (%)
Statistically
predicted yield (%)
2
O
N
O
O
O
1
1
1
1
1
:1
:2
:3
:3
:4
THF
THF
THF
Methanol
THF
85
54
55
8
50
25
17
17
13
k1 << k
2
k2
51
O
O
H
N
H
N
O
O
N
H
N
calculated taking as limiting reagent compound 1, is 85%, well
above that calculated for a statistical product distribution. Notice-
ably, the yield of compound 3 is almost invariant, being around
H
O
O
3
5
1
0% in all cases, upon increasing the ratio of diamine from 1:2 to
:4. Clearly, these results point to an ‘activation’ of the amine func-
Scheme 2. Proposed mechanism for the observed substrate selectivity.
tionality after the first functionalization takes place. In other
words, the amine groups from compound 2 seem to be more reac-
tive that those from the starting compound 1,3-propanediamine.
We have found that this effect is associated to the supramolecular
interaction of compounds 2 and 1. A schematic representation of
the supramolecular complex is shown in Scheme 2. In this way
the reactivity of the system is increased as a result of a proximity
effect, being the reaction faster in the supramolecular complex
and therefore favoring the formation of difunctionalized com-
pound 3.
Further evidences of the formation of the mentioned complex
come from NMR studies carried out in THF-d
see Supporting information). The interaction of 4 (an analogue
of compound 2 without the reactive amine unit) with the activated
8 3
(Fig. 1) and CDCl
14
(
1
18
ester 1 was followed by H NMR. As can be seen in Figure 1, NH
carbamate signal from 1, as well as carbamate and amide NH sig-
nals of compound 4, experience shifts revealing their involvement
in intermolecular H-bonding. Control experiments reveal that the
observed shifts are not due to self-association.
Figure 1. Partial 1H NMR spectra obtained in the study of the interaction of
compound 4 with compound 1 in THF-d at 30 °C.
8
Another strong evidence of the involvement of supramolecular
species in the observed reactivity comes from the reaction carried
out using methanol as solvent (Table 2). This highly polar protic
solvent minimizes intermolecular H-bonding interactions preclud-
ing aggregation of this type of molecules.14 This fact is reflected in
the poor yield, 8%, of compound 3 obtained for a 1:3 activated
ester/diamine ratio (6-fold diamine excess). The major product in
this case was the monofunctionalized one. In THF the reaction pro-
vides a much higher 55% yield of difunctionalized compound 3. It is
also noticeable that the yield of 3 in methanol is lower than that
statistically calculated, revealing that in this solvent the amine
function at 2 is less reactive than at 1,3-propanediamine.

1
134
C. Felip-León et al. / Tetrahedron Letters 56 (2015) 1132–1134
Supplementary data
Supplementary data ( H and 13C NMR spectra. Determination of
statistical yields.) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2015.01.094.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
1
References and notes
1
2
3
.
.
.
Pauling, L. Nature 1948, 161, 707–709.
Storm, D. R.; Koshland, D. E. Proc. Natl. Acad. Sci. U.S.A. 1970, 66, 445–452.
Di Stefano, S. D.; Cacciapaglia, R.; Mandolini, L. Eur. J. Org. Chem. 2014, 7304–
7
315
⁄
Figure 2. Energy minimized structure (AMBER force field) of the supramolecular
complex between 1 and 2.
4.
Bruice, T. C.; Pandit, U. K. Proc. Natl. Acad. Sci. U.S.A. 1960, 46, 402–404.
5. Kirby, A. J. Angew. Chem., Int. Ed. Engl. 1994, 33, 551–553.
6
7
8
9
.
.
.
.
Ercolani, G.; Scripilliti, A. Tetrahedron Lett. 1996, 37, 101–104.
Tomura, K.; Schimmel, P. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 1393–1397.
Knowles, J. R.; Parsons, C. A. Nature 1969, 221, 53–54.
Molecular models obtained with molecular mechanics calcula-
tions agree with the association proposed for the supramolecular
complex in Scheme 1. As shown in Figure 2, an energy minimized
model is obtained which presents two intermolecular H-bonds
between carbonyl units and carbamate and amide NHs. The aro-
Dadon, Z.; Wagner, N.; Ashkenasy, G. Angew. Chem., Int. Ed. 2008, 47, 6128–
6136.
10. Leininger, S.; Olenyuk, B.; Stang, P. J. Chem. Rev. 2000, 100, 853–908.
1
1
1. Frederick, R.; Otto, S. Chem. Soc. Rev. 2008, 37, 101–108.
2. Becerril, J.; Bolte, M.; Burguete, M. I.; Galindo, F.; García-España, E.; Luis, S. V.;
Miravet, J. F. J. Am. Chem. Soc. 2003, 125, 6686–668212.
matic units are stacked in the model, hinting a possible
ing favorable interaction.
p
–
p
stack-
13. Steed, J. W. Chem. Commun. 2011, 1379–1383
1
1
4. Escuder, B.; Miravet, J. F. Langmuir 2005, 22, 7793–7797.
5. For characterization purposes, compound 2 can be prepared univocally using
protecting groups. 2.68 g of tert-butyl-(3-(2-(((benzyloxy)carbonyl)amino)-3-
methylbutanamido)propyl)carbamate (6.26 mmol) was dissolved in 103 mL of
Summarizing, the first acylation of 1,3-propanediamine pro-
vokes an activation of the remaining amine group which becomes
more reactive. In this way the reaction is driven toward the
formation of difunctionalized products under unfavorable relative
concentration values of the reagents. The capability of monofunc-
tionalized compound 2 to form a supramolecular complex with acti-
vated ester 1 explains the observed substrate selectivity by means of
proximity effects. The supramolecular interaction is demonstrated
to take place via at least two H-bond interactions involving carba-
mate and amide NHs as H-donors and oxygen atoms of carbonyl
groups as H-bond acceptors. The reported example represents a case
of supramolecular control of reactivity which is related to the chem-
istry of life, whose efficiency and selectivity are based very often on
proximity effects associated to supramolecular interactions.
2 2 2
CH Cl and 13.2 mL of TFA was added under N atmosphere. The mixture was
left under stirring for 3 h at room temperature. Finally the solvent was
eliminated under vacuum and a white solid appeared corresponding to the
trifluoroacetate salt of 2. (0.624 g, 2.03 mmol 33%). 1H NMR (500 MHz, DMSO-
d
4
6
6
): d = 7.90 (s, 1H), 7.42–7.15 (m, 5H), 5.02 (s, 2H), 3.77 (t, 1H), 3.26–2.87 (m,
H), 2.50 (t, 1H), 2.02–1.87 (m, 1H), 1.54–1.37 (m, 2H), 0.83 (dd, J = 6.7, 3.9 Hz,
13
H). C NMR (125 MHz, DMSO-d
6
): d = 171.42 (C@O), 156.53 (C@O), 137.57
), 60.87
). HRMS
308.1969; found 308.1974
(
CH), 128.76 (Â2) (CH), 128.18 (Â2) (CH), 128.05 (CH), 65.80 (CH
2
(CH
2
), 36.63 (CH), 33.27 (CH
2
), 30.67 (CH), 19.55 (CH
3
), 18.68 (CH
3
+
(
[
ESI-TOF, positive mode): m/z calcd for C16
M+H]
H
25
N
3
O
3
+
(D = 0.5 ppm).
1
1
6. In a representative example, 1.16 g of 3.4 mmol activated ester was dissolved
in 50 mL of THF. Then 2 mL of a 1.66 M solution of 1,3-diaminopropane in THF,
3.4 mmol were added at once at 25 °C under vigorous stirring. After 4 h the
solvent was evaporated. To isolate compound 3 the solid residue was washed
thrice with aqueous KOH 1 M, then with distilled water and then dried
overnight at 60 °C.
7. In
a
representative example, 57.7 mg of 0.17 mmol activated ester was
1.66 M solution of 1,3-
Acknowledgments
dissolved in 0.9 mL of THF. Then 0.1 mL of
a
diaminopropane in THF, 0.17 mmol were added at once at 25 °C under
vigorous stirring. After 5 minutes 1 mL of a solution of 20% acetic acid in THF
was added in order to protonate the excess of diamine. Then the solvent was
evaporated and the solid residue dried and homogenized with an agate mortar.
Ministry of Science and Innovation of Spain (grant CTQ2012-
7735) and Universitat Jaume I (grants P1.1B2012-25 and
P1.1B2013-57) are thanked for financial support. Carles Felip-
León thanks Ministry of Science and Innovation of Spain for a
PhD fellowship (FPI program). Vicente Martí-Centelles is acknowl-
edged for helpful discussion.
3
6
The solid was dissolved in DMSO-d to analyze the proportion of compounds
present in the crude by 1H NMR.
18. Solutions of compounds 4 and 1 in THF-d
8 3
or CDCl (0.1 M) were mixed in
varying amounts and NMR spectra recorded at 30 °C.