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The development of artificial "intelligent" electrodes, capable to discriminate and quantify the enantiomers of chiralanalytes, particularly of biological and pharmaceutical interest,
is a quite attractive issue in electroanalysis.
Obviously, selectivity towards specular molecules can only be achieved in an enantiopure environment.
For this aim, many approaches have been proposed in the last years.
Towards artificial enantioselective electrodes
Aramata et al.,Chem. Commun. 1997
Nakanishi, Osaka et et al.,JACS Comm. 2006
Electrodes modified with chiral SAMs
Some examples of the proposed approaches I
Chiral monolayer of self-assembled ∆-[Os(bpy)2L(Cl)]+ [bpy = 2,2’-bipyridyl,
L = 1,2-bis(4-pyridyl)ethane] on a platinum electrode
Fu et al.,Electroanal. 2012
Enantioselective Recognition of Dopa Enantiomers
in the Presence of Ascorbic Acid or Tyrosine
Enantioselectivity of Redox Reaction of DOPA at the Gold Electrodes Modified
with a Self-Assembled Monolayer of Homocysteine
Marx et al., Langmuir, 2005
Advincula et al., Small, 2012
Electrodes modified with molecularly imprinted molecular layers
Some examples of the proposed approaches II
Chiral Electrochemical Recognition by Very Thin Molecularly
Imprinted Sol-Gel Films Nanostructured, Molecularly Imprinted, and Template-Patterned
Polythiophenes for Chiral Sensing and Differentiation
Molecularly imprintedchiral mesoporous Pt
Kuhn et al., Nature Comm. 2014Mogi & Watanabe, Sci. Tecn.
Attard, Feliu et al., Langmuir1999 & other papers in the
following years
Some examples of the proposed approaches III
Chiral organic thin-film transistor (OTFT)
A sensitivity-enhanced field-
effect chiral sensor
Torsi et al. Nature Materials, 2008
However, • even the most successful attempts at chiral discrimination almost invariably resulted in the detection of a difference in current intensity between the signals of the two antipodes of a chiral probe• the chiral enantioselective layer is in many instances not of general use, but tailored for a given probe;• many preparation procedures are very sophisticated/expensive…• … and/or the active films fragile.
Desirable features: • both peak potential separation and current linear dynamic range• easy, fast and low-cost preparation• equal availability in both enantiomer configurations• general applicability to many probes• reproducibility and stability• possibility of recycling the active surface• should work on different supports and in different operating media
Fast and regular film electrodeposition in a widerange of conditions, even at low monomer
concentration
-0.10
-0.05
0.00
0.05
0.10
0.15
0.20
0.25
-1 -0.75 -0.5 -0.25 0 0.25 0.5 0.75 1 1.25
E /V (Fc+/Fc)
I / m
A
-1100
-1000
-900
-800
-700
-600
-500
-400
-300
-200
-100
0
ηf / H
z
0
0.0000005
0.000001
0.0000015
0.000002
0.0000025
0.000003
0.0000035
0.000004
0 25 50 75 100 125 150 175 200 225
t /s
ηm/g
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
monomer u
nits n
m-2
Au electrode (EQCM), CH2Cl2 + 0.1 M TBAPF6, 0.2 V s-1
0.001 M BT2T4
Regular increa
se of the
polymer film
Counteranioningress/egress
SS
SS
S
S SSS
SSS
S S S
S S S
n-1BT2-T4
(BT2-T4)n n = 2-5
oxidation
S S S
S S S
SSS
SSS
Electrooligomerization yields cyclic oligomers!
Dimer
Recently, we found byhigh resolution MALDI that the electrodepositedfilms mostly consist of cyclic oligothiophenes, constituted by 12, 18, 24 … conjugated thiopheneunits!
Electrochemical or chemical oxidation
(by FeCl3)
The same cycles alsoconstitute a large fraction of the electrodepositedoligomer films.
The cyclic vs linearelectrodeposited oligomerratio appears to depend on the electrode surfacematerial (GC>>ITO)
F. Sannicolò, S. Arnaboldi et al., Chemistry 2014F. Sannicolò, S. Arnaboldi et al., Pat. Appl., MI2014A000948
Trimer
SSS S
S
S
S
S
S S
S
S
S
S
S
S
S
S
The new molecular materials possess an outstanding pool of attractive properties.
Even as racemates:
Oligomer properties as racemates
SSS
SSS
S S S
S S S
n-1
(BT2-T4)n n = 2-5
they provide cavitiesfunctionalized withheteroatoms, which, like e.g cyclodextrins, can act as hosts for a variety of guests
they idealize conducting polymerswithout end, with no defectivityconnected with active terminals
they exhibit very facile, reversible charge
transfer and very fast charge transport, as
revealed by CV and EIS
their redox potentials are convenient for energy
applications, and modulable by structure
design
they are electrochromic,photoactive, and display charge-
trapping effects
an appropriate protocolaffords the oligomer films tobe obtained as self-standing membranes
Enantiorecognition Capability using chiral probes with different bulkiness and chemical nature
N
F
N
N O
O
OH
O
HMeMe
N
F
N
NO
O
OH
O
HMe Me
(S)-ofloxacin (R)-ofloxacin
Enantiorecognition tests towards DOPA probe
D-DOPA and L-DOPA signals
on bare GC electrode
-0.0002
0.0000
0.0002
0.0004
0.0006
0.0008
0.0010
-0.2 0.0 0.2 0.4 0.6 0.8 1.0
j / (Acm-2)
E vs Fc+|Fc / (V)
L-DOPA
D-DOPA
(R)-(BT2 -T4 )n
-0.0002
0.0000
0.0002
0.0004
0.0006
0.0008
0.0010
-0.2 0.0 0.2 0.4 0.6 0.8 1.0
j / (A cm-2)
E vs Fc+|Fc (V)
L-DOPA
D-DOPA
(S)-(BT2 -T4)n
(R)-BT2T4
(S)-BT2T4
Tests alternating D- and L-
DOPA on both
enantiopurefilms
Tests on GC support
in H2O+HCl 0.05M
-0.0010
-0.0005
0.0000
0.0005
0.0010
0.0015
0.0020
-0.2 0.0 0.2 0.4 0.6 0.8 1.0
j / (A cm -2)
E vs Fc+|Fc/ (V)
L-DOPA
D-DOPA
OH
OH
OH
O
NH2
OH
OH
OH
O
NH2
(R)-BT2T4(S)-BT2T4
OH
OH
OH
O
NH2
M.C. EscherBond of Union
Enantiorecognition tests towards Naproxen, Catechin, Norepinephrine, Ascorbic Acid
0.0E+00
2.0E-05
4.0E-05
6.0E-05
8.0E-05
1.0E-04
1.2E-04
1.4E-04
-0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
E vs Fc+|Fc (V)
j / (A cm-2)
(S)-BT2T4
(R)-BT2T4
Naproxen
Buffer Solution pH7
0.0E+00
2.0E-05
4.0E-05
6.0E-05
8.0E-05
1.0E-04
1.2E-04
1.4E-04
1.6E-04
-0.2 0.0 0.2 0.4 0.6 0.8 1.0 1.2
E vs Fc+|Fc (V)
j/ (A cm-2)
(S)-BT2T4
(R)-BT2T4
(−−−− )-CatechinBuffer solution pH 7
-0.0004
-0.0002
0.0000
0.0002
0.0004
0.0006
0.0008
-0.2 0.0 0.2 0.4 0.6 0.8 1.0
E vs Fc+|Fc (V)
j / (A cm-2)
(S)-BT2T4
(R)-BT2T4
L-(−)-Norepinephrine (+)-bitartrate
salt monohydrate
HCl Aqueous Solution (0.05 M)
0.0E+00
2.0E-05
4.0E-05
6.0E-05
8.0E-05
1.0E-04
1.2E-04
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6
E vs Fc+|Fc (V)
j / (A cm-2)
(S)-BT2T4
(R)-BT2T4
L-Ascorbic Acid
ACN+TBAPF6
5. Confirming the conceptwith chemically different starting monomers
NMe N
Me
S
SS
SS S
SS
S
S
S
S
Enantiorecognition tests using pyrrole-based atropisomeric scaffold
Enantiorecognitiontests on GC electrode in a 0.05 M HClaqueous solution
-1.0E-03
0.0E+00
1.0E-03
2.0E-03
3.0E-03
4.0E-03
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 0.8 1.0
j / (A cm-2)
E vs Fc+|Fc / (V)
L DOPA
D DOPA
2,2’-Ind2T4(N-Me)-1Electrooligomerizationon GC electrode in
DCM+TBAPF6 0.1M
•100o node angle between moieties
•Possibility to locate the heteroatom in ortho position
•Two homotopic positions available forelectrooligomerization
NMe N
Me
S
SS
S
OH
OH
OH
O
NH2
OH
OH
OH
O
NH2
OH
OH
OH
O
NH2
OH
OH
OH
O
NH2
SS
S S
S S
SS
T84
The same concept in all-thiophene materials: inherently chiral spider-like oligothiophenes
α, α-link: a node/distortionarises, but the energy
barrier for rotation is low
S
SS
S
S
S
S
S
S
SS
S
S
S
S
S
β, β-link: a node/distortion withhigh energy barrier fo rotation
→→→→ the molecule is chiral
α, α-link: a node/distortionarises, but the energy
barrier for rotation is low
β, β-link: a node/distortion withhigh energy barrier fo rotation
→→→→ the molecule is chiral
α, α-link: a node/distortionarises, but the energy
barrier for rotation is low
β, β-link: a node/distortion withhigh energy barrier fo rotation
→→→→ the molecule is chiral
M. C. Escher
-1500
-1000
-500
0
500
1000
1500
2000
-0.2 -0.1 0.0 0.1 0.2 0.3 0.4 0.5
j/ (µA cm
-2)
E vsAg/AgCl /V
oligo-T83-1electrode
(R)(S)
-1500
-1000
-500
0
500
1000
1500
2000
-0.2 -0.1 0.0 0.1 0.2 0.3 0.4 0.5
j/ (µA cm
-2)
E vsAg/AgCl /V
oligo-T83-2 electrode
(R) (S)
-2000
-1000
0
1000
2000
3000
4000
5000
-0.3 -0.2 -0.1 0.0 0.1 0.2 0.3 0.4 0.5 0.6
j/ (µA cm
-2)
E vsAg/AgCl /V
oligo-T83-1 electrode
((((±±±±))))
Similar tests on inherently chiral spider-like oligothiophenes(ββββ,ββββ’-bithiophene core)
R
FeFe
S
H
Me
NMe2H
Me
Me2N
-1300
-800
-300
200
700
1200
0.2 0.3 0.4 0.5 0.6 0.7
j/ (µA cm
-2)
E vsAg/AgCl /V
oligo-T83-1electrode
D-DOPA
L-DOPA
L/D-DOPA on bare Au electrode
OH
OH
OH
O
NH2
OH
OH
OH
O
NH2
Enantiorecognition tests on SPEs both in BMIMPF6 and in
aqueous HCl
highly 3D,
four homotopic
αααα positions foroligomerization,
but does not give
cyclic oligomers
• both peak potential separation and current linear dynamic range
Coming back to the checklist of desiderable features…
Conclusions 1
• reproducibility and stability
• general applicability to many probes
• equal availability in both enantiomer configurations
• easy, fast and low-cost preparation
• efficiency on different supports and operating media
• possibility of recycling the active surface
COMPLIES
COMPLIES
COMPLIES
COMPLIES
COMPLIES
COMPLIES
COMPLIES
Moreover, •The concept works as well in chemically different oligomers•The enantiopure film can be also obtained and processed as self-standing membranes
Inherently chiral electroactive films are indeed attractive tools for chiral voltammetry
6. An alternative approach:Working on an achiral surface
but in an inherently chiral medium
An alternative approach to chiral electroanalysis: chiral working media
As an alternative approach to using a chiral electrode surface, differentchiral media for electrochemical processes have been proposed
Chiral organic solvents
Chiral supportingelectrolytes
Increasingly more orderedat the electrode/solutioninterphase, resulting in increasing enantioselectiveeffects
Chiral ionic liquids(CILs)
Already adopted in organic chemistry, still to be explored in electrochemistry
Possibly the best:
Inherently chiral ionic liquids(ICILs)
The cationic bibenzimidazolium or bipyridinium moiety responsible for the CILs physical properties is also part of the stereogenic element responsible for
molecular chirality.
Inherently Chiral Ionic Liquids
N
N
N
R
N
R
N N
NNR
R
N
R
RR
N
RR
R
+N
N
N
N
R'
R' +X
X
R
R
+NN
NN
R
R
+
X
X
R'
R'
N
R
N
R
R'
R'
RR
+
+
X-
X-
3,3’-Bi(collidinium) cation
220 240 260 280 300 320 340
-40
-30
-20
-10
0
10
20
30
40
Ellipticity (mdeg)
Wavelength (nm)
Firs t Eluted
Se cond Eluted
Mono- and di-alkylation
Easy synthesis Scalable procedures
N Me
MeN
Me
Me
Me
Me
MeMeSO3
N Me
MeN
Me
Me
Me
Me
MeMeSO3
MeMeSO3
N Me
MeN
Me
Me
Me
Me
CH2PhMeSO3
N Me
MeN
Me
Me
Me
Me
Ch2PhMeSO3
CH2PhMeSO3
6 8 10
0
200
400
600
6 8 10
0
20
40
6 8 10
0
50
100
150
200
CSP: Chiralpak IA-3 250 mm x 4.6 mm i.d.
Mobile phase: n-hexane-ethanol-DEA 100:2:0.3Flow rate: 1 mL/min
Detector: UV (black) and CD (red) at 254 nm
Temperature: 15 °C
DFT calculation demostrated that the racemisation
barrier of the
3,3’-bicollidine is 42.5 kcal mol-1.
The most promising family: bicollidinium scaffolds and salts
∼ 3.6 V potential window
220 240 260 280 300 320 340
-40
-30
-20
-10
0
10
20
30
40
Ellipticity (mdeg)
Wavelength (nm)
First Eluted
Second Eluted
First inherently
chiral ionic liquids at
room temperature!!
∼ 3.6 V potential window
-0.6 -0.4 -0.2 0 0.2 0.4 0.6
E vs Ag|Ag+ / V
j/c / Acm
-2mol-1dm
3
(R)-Fc
(S)-Fc
(R)-Fc and (S)-Fc on bare Electrode
(1)-3mE2BF4 0.01 mol dm-3 in BMIMPF6
(2)-3mE2BF4 0.01 mol dm-3 in BMIMPF6
(R )-Fc e (S )-Fc 0.002 mol dm-3
N
Me
Me Me
N
Me Me
Me
Et
Et
BF-4
BF-4
Ratio 1 : 500Ratio 1 : 500
Recently we have confirmed that also these materials hold an impressive enantiorecognition ability like a