Dynamic Constitutional Chemistry

Constitutional Dynamic Chemistry (CDC) defined as the chemistry under

thermodynamic control
CDC studiestheconstitutionaldynamiclibraries(CDLs)generatedfromoneorseveral
monomericbuildingblocksthatcaninteractbothbynoncovalentinteractions
(DynamicNonCovalentLibraries,DNCL)andbyreversiblecovalentbonds(Dynamic
C bi
CombinatorialLibrariesorDynamicCovalentLibraries,DCL).
i l Lib i
D
i C l
Lib i DCL)

Dynamic Constitutional Chemistry (DCC)

Covalent bonds

Non covalent bonds

Non-covalent

Supramolecular Chemistry
Self-assembly and self-organisation
Molecular recognition
Dynamic character

Combinatorial Chemistry
Large libraries of compounds
Screening of the biological activity

Dynamic Constitutional Chemistry

Complex combinatorial libraries under thermodynamic control, template
directed synthesis and screening in one step

Non-covalent
Non
covalent bonds
(Dynamic Non-Covalent Chemistry)

Reversible covalent bonds

(Dynamic Covalent Chemistry or
Dynamic Combinatorial Chemistry)

DynamicCovalentChemistry(DCC) wasintroducedinthemid90sbythegroupsof
Lehn[1] andSanders.[2]
The main characteristic of a CDL is its dynamic nature. In a CDL all components are in
equilibrium. The composition of a given CDL is determined by the thermodynamic
stabilityy of its components
p
and can be modified ((through
g reorganization
g
or component
p
exchange) under the influence of internal or external factors which can be either physical
(e.g. temperature, pressure, UV irradiation, electric or magnetic field) or chemical (e.g.
pH, solvent, molecular targets).

For instance, addition of a molecular target to a CDL induces a change in the

thermodynamic equilibrium and, according to the Le Chatelier principle, the system
adapts to the new condition and the equilibrium shifts toward the formation of the new
most thermodynamically stable member(s) of the library (e.g
(e g amplification of the
member(s) with high affinity for the molecular target).
Such behavior of the constitutional dynamic systems to adapt to internal or external
perturbations was defined as Dynamic Adaptive Chemistry

I.Huc,J.M.Lehn,Proc.Natl.Acad.Sci.U.S.A.1997,94,21062110.
P.A.Brady,R.P.BonarLaw,S.J.Rowan,C.J.Suckling,J.K.M.Sanders,Chem.Commun.1996,319320

TypesofbondsusedinDCC
non
noncovalent
covalent(e.g.hydrogenbonds),
(e g hydrogen bonds)
coordinative,
covalentbonds

P.T.Corbett,J.Leclaire,L.Vial,K.R.West,J.L.Wietor,J.K.M.Sanders,S.Otto,Chem.Rev. 2006,106,36523711

ReversibleReactionsUsedforDynamicCombinatorialChemistry

P.T.Corbett,J.Leclaire,L.Vial,K.R.West,J.L.Wietor,J.K.M.Sanders,S.Otto,Chem.Rev. 2006,106,36523711

ReversibleReactions
This reaction needs to meet a number of requirements:
( ) it needs to be reversible on a reasonable time scale;;
(i)
(ii) because equilibration and selection ideally occur simultaneously, the
reversible reaction needs to be compatible with the experimental
conditions of the selection process, including the functional groups on the
b ildi blocks
building
bl k and
d template,
t
l t the
th solvent,
l t and
d the
th pH
H (physiological
( h i l i l for
f the
th
use of biomolecules);
(iii) reaction conditions need to be mild (e.g., temperature, pressure,
concentration), so as not to interfere with the delicate noncovalent
interactions involved in molecular recognition;
(iv) it needs to guarantee the solubility of all the library members at
equilibrium because any not sufficiently soluble material could act as a
thermodynamic or,
or at slow dissolution rates,
rates kinetic trap;
(v) it should be possible to turn off the reaction so as to kinetically freeze
the selected library member(s) enabling their isolation and handling;

P.T.Corbett,J.Leclaire,L.Vial,K.R.West,J.L.Wietor,J.K.M.Sanders,S.Otto,Chem.Rev. 2006,106,36523711

Imine,hydrazoneanddisulfideexchangereactions

Imines equilibrates fast at neutral to acidic pH, but the resulted imines are often
unstable in the presence of water and make difficult the analysis of the libraries.

Hydrazones
y
are stable in water even at acidic p
pH but have the ggreat disadvantage
g
of a slow exchange or even to become kinetically inert near the neutral pH. Low
solubility.

Disulfide exchange reaction has the great advantage to occur in aqueous

environment nearly neutral pH and is tolerant to a wide range of functional groups.
environment,
groups
However, long equilibration times, especially when diluted solutions are used
constitutes a drawback of this reaction.

ApplicationsofDCC
i)

Biochemistry identificationofinhibitorsfordifferentenzymefamilies
(i e lectins,glycosidases,acetylcholineesterase,kinases/phosphatases
(i.e.
lectins glycosidases acetylcholine esterase kinases/phosphatases
etc.)aswellasnucleicacidligands;

ii) Supramolecularchemistry identificationofhighaffinityreceptorsfor

cations,anionsandneutralmolecules.
iii) material
materialsciences
sciences throughthedevelopmentofdynamicmaterials
through the development of dynamic materials
suchasdynamicconstitutionalpolymers(alsocalleddynamers),
dynamicconstitutionalframeworksanddynamicmembranes;
iv) catalysis

ApplicationsofDCC
Castingofasubstrate

Figure 1.

The schematic representation of the general principle used in dynamic constitutional chemistry for
identification of a biologically active compound in presence of a protein that acts as an external factor,
exemplified on the particular case of the imine formation reversible reaction. The reversible reaction between
three different aldehydes and three different amines generates a dynamic library composed of nine imines. The
protein which is the external factor,
protein,
factor favors formation of the compound having the highest affinity,
affinity thus leading
to its amplification.

Castingthesubstrate ExampleI

O.Ramstrm,J.M.Lehn, NatRevDrugDisc 2002,1,26

Castingthesubstrate ExampleII

O.Ramstrm,J.M.Lehn, NatRevDrugDisc 2002,1,26

Castingthesubstrate ExampleIII

ApplicationsofDCC
Moldingthereceptor

Figure 3. The general principle used in DCC for identification of a receptor having the
highest affinity for a certain organic molecule (guest molecule),
molecule) exemplified on the
particular case of the hydrazone formation reversible reaction. Various subunits
reversibly react yielding a DCL containing linear or macrocyclic receptors. Presence of
the guest molecule that acts as an external factor favours (amplifies) formation of the
receptor with the highest affinity. The reversible nature of the subunits connections
allows errors corrections thus yielding the best receptor

Moldingthereceptor Imine exchangereaction receptorsformetalions

AmplificationofdifferenthostsbydifferentmetalionguestsfromiminesDCLs.

Moldingthereceptor Imine exchangereaction receptorsforanions

R

R
O

NH2

NH2

NH2

12

R
N

NH2

NH
NH2

NH HN

NH

NH

NH

O
NH2

NH

NH

R
O

13a

13b

R= ii-Pr,
R
Pr, Bn

NH HN
O

N
O

NH

14
O
HN

HN
HN

NH
O

NH

H
H

N
R
16

H
H

O
N

N
N
O

R
15

15formedinthepresenceofterephthalate
15
formed in the presence of terephthalate dianion
16 formedinthepresenceofbenzene1,3,5tricarboxylateanion

Moldingthereceptor Metalcoordination receptorsforanions

ShapePersistentOrganicCagesobtainedbyDCC

Angew.Chem.Int.Ed. 2010,49,5042 5053

ShapePersistentOrganicCagesobtainedbyDCC

Angew.Chem.Int.Ed. 2010,49,5042 5053

ShapePersistentOrganicCagesobtainedbyDCC

Angew.Chem.Int.Ed. 2010,49,5042 5053

DynamicCovalentSynthesisofaChiral Nanocube

J.AM.CHEM.SOC.2008,130,75207521

ShapePersistentOrganicCagesobtainedbyDCC

Hydride reduction of 27 yielded the

corresponding amines which display
a high selectivity for absorption of
CO2 over N2 (i.e. 73:1,[50a] 100:1[50b]
and 138:1[50b] v/v for the cages
obtained
bt i d from
f
aldehyde
ld h d 24,
24 25 and
d
26, respectively), under standard
ambient conditions (298 K, 1 bar).

Figure7.Structureoftheporous3Dprismaticcages27 obtainedfromaldehydes
24,25 and26.

ShapePersistentOrganicCagesobtainedbyDCC

Angew.Chem.Int.Ed. 2010,49,5042 5053

MolecularFlasksobtainedbyDCC

Chem.Eur.J.2012,18,12864 12872

Moldingthereceptor Disulphideexchangereaction receptorsfororganiccations

Chem SocRev2013,DOI:10.1039/c3cs60326a

Interlockedstructures [n]Catenanes

theguestislocatedinthecentertocreateafullyalternatingDADADsequence

Angew.Chem.Int.Ed.2010,49,53315334

Fig. 2. HPLC traces (absorption at 290 nm) of the pPFm libraries. (A) In the
presence of ACh, a series of cyclic and linear intermediatesare observed 2
min after initiation of library formation. (B) [2]Catenane (7) is first
observed within 25 min. (C) Cyclic dimer 2 is substantially amplified in the
first 3 days. (D) The yield of ACh receptor 7 is optimized after 44 days of
equilibration. (E) In the absence of ACh, the pPFm library reaches
equilibrium in 3 days.

Science308,667(2005)

Interlockedstructures [n]Catenanes

OrganicTrefoilKnotobtainedbyDCC

Science338,783(2012)

ExamplesofinterlockedstructuresobtainedbyiminebasedDCC

Chem. Eur. J. 2013 DOI: 10.1002/chem.201303504

DoubleDynamicsProcesses
MolecularBorromean RingsandSolomonKnots

Chem.Eur.J.2010,16,12570 12581

DoubleDynamicsProcesses

Angew.Chem.Int.Ed.2012,51,66816685

DynamicPolymers Dynamers

DynamicPolymers Dynamers

Disulphidebasedmechanosensitive selfreplicationsystems

Chem SocRev2013,DOI:10.1039/c3cs60326a