Joana Campainhas Bas os
Licenciada em Biologia Humana
Ionic Liquids in he De elopmen
o No el Bioma e ials
Disse ação pa a Ob enção do G au de Mes e em
Bioquímica pa a a Saúde
O ien ado : Ana Belén Pe ei o, In es igado a Auxilia do REQUIMTE,
Faculdade de Ciências e Tecnologia da Uni e sidade No a de Lisboa
Co-o ien ado : João Miguel Mendes de A aújo, In es igado Auxilia do
REQUIMTE, Faculdade de Ciências e Tecnologia da Uni e sidade No a de
Lisboa
No emb o 2016
Joana Campainhas Bas os
Licenciada em Biologia Humana
Ionic Liquids in he De elopmen o No el Bioma e ials
Disse ação pa a ob enção do G au de Mes e em
Bioquímica pa a a Saúde
O ien ado : Ana Belén Pe ei o, In es igado a Auxilia do REQUIMTE,
Faculdade de Ciências e Tecnologia da Uni e sidade No a de Lisboa
Co-o ien ado : João Miguel Mendes de A aújo, In es igado Auxilia do
REQUIMTE, Faculdade de Ciências e Tecnologia da Uni e sidade No a de
Lisboa
Cons i uição do Jú i:
P esiden e:
Dou o Ped o Ma ias, In es igado P incipal do Ins i u o de
Tecnologia Química e Biológica An ónio Xa ie da Uni e sidade
No a de Lisboa
A guen e:
Dou o a Ka ina Shimizu, In es igado a do Ins i u o Supe io Técnico
da Uni e sidade de Lisboa
Vogais:
Dou o a Ana Es e éz, In es igado a Auxilia do REQUIMTE,
Faculdade de Ciências e Tecnologia da Uni e sidade No a de
Lisboa
Dou o a Ma ga ida A che , In es igado a P incipal do Ins i u o de
Tecnologia Química e Biológica An ónio Xa ie da Uni e sidade
No a de Lisboa
Ins i u o Tecnológico de Química e Biológica An ónio Xa ie da
Uni e sidade No a de Lisboa (ITQB), Oei as, Po ugal
No emb o 2016
I
Ionic Liquids in he De elopmen o No el Bioma e ials
COPYRIGHT
Joana Campainhas Bas os
Ins i u o de Tecnologia Química e Biológica An ónio Xa ie
Uni e sidade No a de Lisboa
O Ins i u o de Tecnologia Química e Biológica An ónio Xa ie e a
Uni e sidade No a de Lisboa êm o di ei o, pe pé uo e sem limi es
geog á icos, de a qui a e publica es a disse ação a a és de
exempla es imp essos ep oduzidos em papel ou de o ma digi al,
ou po qualque ou o meio conhecido ou que enha a se
in en ado, e de a di ulga a a és de eposi ó ios cien í icos e de
admi i a sua cópia e dis ibuição com obje i os educacionais ou de
in es igação, não come ciais, desde que seja dado c edi o ao au o
e edi o .

II
III
Aos meus pais, po me pe mi i em alcança
odos os meus sonhos
IV
V
Ag adecimen os
Es e espaço é dedicado a odos os que, de alguma o ma con ibuí am pa a que es a disse ação
osse ealizada. Não pudendo nomeá-los a odos, há alguns a quem não posso deixa de mani es a o
meu ap eço e ag adecimen o since os.
Em p imei o luga que o ag adece á minha o ien ado a, Dou o a Ana Belén Pe ei o e co-o ien ado
Dou o João Miguel Mendes de A aújo, po me e em p opo cionado es a opo unidade. Exp esso ainda
o meu p o undo ag adecimen o pelo apoio e disponibilidade mani es ada, con iança deposi ada e
pa ilha de conhecimen o que con ibuí am decisi amen e pa a que es e abalho enha chegado a um
bom e mo.
Aos meus colegas do labo a ó io Fluídos Al e na i os pa a a Química Ve de po me e em acolhido e
animado nos dias mais á duos de abalho. À Sa a Ca alho e à Fá ima Moscoso pelo companhei ismo
e pala as amigas. Um ag adecimen o especial à Ma ga ida Fe ei a e à Nicole Viei a po pode semp e
con a com o osso en usiasmo, aleg ia e paciência nos meus dias menos bons du an e es e ano.
Gos a ia de ag adece ambém à P o esso a Dou o a Isabel Fonseca e Dou o a Isabel Pacheco pela
disponibilidade dos seus labo a ó ios pa a ealização de algumas medidas espo ádicas expe imen ais.
Ainda, um especial ob igada à Dou o a Manuela Dias pela ajuda imp escindí el nes a úl ima ase do
meu abalho.
Aos meus amigos, especialmen e à Ve a Mo ei a e à Inês Cab i a, ou in es e a en os aos meus desânimos
e sucessos, que mesmo longe semp e me ajuda am mui o. Um mui o ob igada pelo apoio e pela
alo ização semp e ão en usias a do meu abalho.
À minha amília, uma pala a de econhecimen o mui o especial pelo amo incondicional e pela o ma
como ao longo de odos es es anos, ão bem, me soube am ajuda . Aos meus pais o meu e e no ob igada
po me p opo ciona em es a opo unidade de p og edi na ida p o issional.
XII
2.4.1.1. The mal P ope ies ……………………………………………………………………. 24
2.4.1.2. The mophysical Cha ac e iza ion ……………………………………………………... 26
2.4.1.3. Walden-Plo …………………………………………………………………………… 30
2.4.2. Mix u es o Fluo ina ed Ionic Liquids and Wa e …………………………………………... 31
2.4.2.1. Liquid-liquid Equilib ia ……………………………………………………………….. 31
2.4.2.2. Sel -agg ega ion Beha iou …………………………………….……………………... 34
2.5. Conclusions ……………………………………………………………………………………. 38
2.6. Re e ences ……………………………………………………………………………………... 39
3. Pa i ion P ope ies o Fluo ina ed Ionic Liquids……………………………………………….. 43
3.1. In oduc ion ……………………………………………………………………........................ 45
3.2. Ma e ials ………………………………………………………………………………………. 47
3.3. Expe imen al P ocedu es …………………………………………………………………….. 48
3.3.1. Slow S i ing Me hod ……………………………………………………………………….. 48
3.4. Resul s and Discussion ………………………………………………………………………... 49
3.5. Conclusion …………………………………………………………………………………….. 52
3.6. Re e ences ……………………………………………………………………………………... 53
4. Kamle -Ta Sol a och omic Pa ame e s o Fluo ina ed Ionic Liquids ………………………. 55
4.1. In oduc ion …………………………………………………………….................................... 57
4.2. Ma e ials ………………………………………………………………………………………. 59
4.3. Expe imen al P ocedu es …………………………….............................................................. 61
4.3.1. Dye Solu ions and Samples P epa a ion ……………………………………………………. 61
4.3.2. UV-Vis Measu emen s ………………………………………………................................... 62
4.4. Resul s and Discussion ………………………………………………………………………... 62
4.4.1. Kamle -Ta Pa ame e s o Nea Fluo ina ed Ionic Liquids ……………............................... 62
4.4.1.1 In luence o he Imidazolium, Py idinium and Te abu ylammonium Ca ions…….….. 63
4.4.1.2. In luence o he Hyd ogena ed Alkyl Chain Leng h o he Ca ion ……………………. 64
4.4.1.3. In luence o he Fluo ina ed Chain Leng h o he Anion …………………………….. 66

XIII
4.4.2. Kamle -Ta Sol a och omic Pa ame e s o Aqueous Solu ions o Fluo ina ed Ionic
Liquids…………………………………………………………………………………………….. 68
4.4.2.1. In luence o he Imidazolium, Py idinium and Te abu ylammonium Ca ion ………… 70
4.4.2.2. In luence o he Hyd ogena ed Alkyl Chain Leng h on he Imidazolium Ca ion …….. 71
4.4.2.3. In luence o he Fluo ina ed Chain Leng h on he Anion ……………………………... 72
4.5. Conclusion………………..……………………………………………………………………. 74
4.6. Re e ences ……………………………………………………………………………………... 75
5. Conclusions and Pe spec i es……….……………………………………………………………. 79
5.1. Conclusions …………………………………………………………………...……………….. 81
5.2. Pe spec i es …………………………………………………………………..……………….. 82
6. Scien i ic Communica ions…………….……………..................................................................... 83
6.1 Pape s………………………………………………………………….………………………... 85
6.2. Pos e s in Scien i ic Mee ings…………………….....……….................................................... 85
XIV
XV
Lis o Abb e ia u es
R&D
Resea ch and De elopmen
IL
Ionic Liquids
FILs
Fluo ina ed Ionic Liquids
PFC
Pe luo oca bons
C
Ca bon
F
Fluo
C-F bonds
Ca bon and Fluo Bonds
F-Chains
Fluo ina ed Chains
O2
Oxygen
CO2
Ca bon Dioxide
CMC
C i ical Micella Concen a ions
ACV
Acyclo i
ETO
E odolac
pH
Po encial o Hyd ogen
MMT
Mon mo illoni e
MAA
Me hhac ylic Acid
PDA
Polydopamine
DOX
Doxo ubicin
MWTT
Mic owa e The mal The apy
ECD
Elec ochemical de ec o
CE
Capilla y elec opho esis
UV-Vis
Ul a iole isible
Abs
Abso bance
AFMC
Analy e Focusing by Micelle Collapse
DNA
Deoxy ibonucleic Acid
LLE
Liquid-Liquid Equilib ium
CTAB
Ce yl ime hylammonium B omide
-AuNPs
Fluo ina ed Gold Nanopa icles
siRNA
In e e ing Ribonucleic Acid
TEM
T ansmission Elec on Mic oscopy
NMR
Nuclea Magne ic Resonance
XVI
KF
Ka l Fishe
TGA
The mog a ime ic Analysis
TA
The mal Analysis
DSC
Di e en ial Scanning Calo ime e
D
Demal (1 g equi alen o solu e dissol ed in 1dm3
sol en )
KCl
Po assium Chlo ide
API
Ac i e Pha maceu ical Ing edien s
ADME
Abso p ion, Dis ibu ion, Me abolism and Exc e ion
HPLC
High-Pe o mance Liquid Ch oma og aphy
HBD
Hyd ogen Bond Dona ion
HBA
Hyd ogen Bond Accep ance
KT
Kamle -Ta
DCM
Diclo ome hane
RSD
Rela i e S anda d De ia ion
dsDNA
Double-s and DNA
ssDNA
Single-s anded
H-bonding
Hyd ogen bonding
N-H
Ni ogen hyd ogen bond
C-H
Ca bon hyd ogen bond
XVII
Lis o Symbols
[CnC1Im]+
Imidazolium-based Ils (n, numbe o me hylene g oups)
[C2C1py]+
Py idinium-based ILs
[C1CO2]-
Ace a e anion
[(CH3O)2PO2]-
Dime hylphospha e anion
[C1C1Im][(CH3O)2PO2]
Dime hylimidazole dime hylphospha e
[C4C1Im][PF6]
1-Bu yl-3-me hylimidazolium hexa luo ophospha e
[C16C1Im]B
1-Hexadecyl-3-me hyllimidazolium b omide
[C4C1Im]B
1-Bu yl-3-me hylimidazolium b omide
[C8C1Im][PF6]
1-Oc yl-3-me hylimidazolium hexa luo ophospha e
Cº
Celsius
[C8C1Im] B
1-Oc yl-3-me hylimidazolium b omide
[C4C1Im][PF6]
1-Bu yl-3-me hylimidazolium hexa luo ophospha e
[C2C1Im] [(CH3)2PO4)]
1-E hyl-3-me hylimidazolium dime hylphospha e
[C10POHIM] B
1-(1,2-Dihyd oxyp opyl)-3-decylimidazolium b omide
[C16POHIM] B
1-(1,2-Dihyd oxyp opyl)-3-hexadecylimidazolium b omide
[C2C1Im] Cl
1-E hyl-3-me hylimidazolium chlo ide
[C2C1Im][BF4]
1-E hyl-3-me hylimidazolium e a luo obo a e
[C2C1Im] [NT 2]
1-E hyl-3-me hylimidazolium
bis( i luo ome hylsul onyl)imide
[NT 2]-
Bis( i luo ome hylsul onyl)imide anion
[BF4]-
e a luo obo a e anion
[PF6]-
hexa luo ophospha e anion
Cl-
Chlo ide anion
[C6C1Im] Cl
1-Hexyl-3-me hylimidazolium chlo ide
[C4C1Im][BF4]
1-Bu yl-3me hylimidazolium e a luo obo a e
[C1C2py][C4F9SO3]
1-E hyl-3-me hylpy idinium pe luo obu anesul ona e
[C4C1Im][C4F9SO3]
1-bu yl-3me hylimidazolium pe luo obu anesul ona e
[C10C1Im][C4F9SO3]
1-decyl-3-me hylimidazolium pe luo obu anesul ona e
[C4F9SO3]-
Pe luo obu anesul ona e anion
[C8F17SO3]-
Pe luo ooc anesul ona e anion

XVIII
[N4444]+
Te abu ylammonium based-ILs
K
Kel in
ppm
Pa s pe million
Tonse
onse empe a u e
Ts a
s a ing empe a u e
Tdec
decomposi ion empe a u e
Tm
Mel ing empe a u e
[C2C1Im][C4F9SO3]
1-e hyl-3-me hylimidazolium pe luo obu anesul ona e
[C8C1Im][C4F9SO3]
1-bu yl-3-me hylimidazolium pe luo obu anesul ona e
[C6C1Im][C4F9SO3]
1-hexyl-3-me hylimidazolium pe luo obu anesul ona e
[C12C1Im][C4F9SO3]
1-dodecyl-3-me hylimidazolium pe luo obu anesul ona e
ρ
Densi y
η
Viscosi y

Fluidi y
nD
Re ac i e Index
k
Ionic Conduc i i y
T
Tempe a u e
αe
Elec onic pola izabili y
Rm
Mola pola izabili y
NA
A ogad o’s numbe
ε0
Vacuum pe mi i i y
Vm
Mola ee olume
Mw
Molecula weigh
a
Sphe ical molecula adius
m
F ee olume
𝛬
Mola conduc i i y
𝐶
Cons an
𝑤𝑤𝑎𝑡𝑒𝑟
1
Wa e mass ac ion on FIL ich-phase
𝑤𝐹𝐼𝐿
1
FIL mass ac ion on FIL ich-phase
𝑤wa e
2
Wa e mass ac ion on wa e ich-phase
XIX
𝑤FIL
2
FIL mass ac ion on wa e ich-phase
αCMC
Deg ee o ioniza ion o he agg ega es
βCMC
Deg ee o coun e ion binding o coun e ions condensed on he
micella in e ace
ΔG0agg
S anda d ee ene gy o he agg ega ion p ocess
RT
Uni e sal gas cons an and absolu e empe a u e
𝑙𝑛 𝑥𝐶𝑀𝐶
Nepe ian loga i hm o c i ical micella concen a ion
exp essed in mole ac ion
π
Pi
ʎmax
Maximum abso p ion wa eleng h

Hyd ogen bond acidi y / hyd ogen bond dona ion


Hyd ogen bond basici y / hyd ogen bond accep ance


Dipola i y/pola izabili y


Maximum abso p ion wa eleng h o he sol a och omic dyes
𝐸𝑇
30,
Pola i y scale based only on Reicha d ’s dye
w %
Weigh pe cen age
[C2C1Im][CF3SO3]
1-E hyl-3-me hylimidazolium i luo ome hanesul ona e
[C4C1Im][CF3SO3]
1-Bu yl-3-me hylimidazolium i luo ome hanesul ona e
[C2C1py][C4F9SO3]
1-E hyl-3-me hylpy idinium pe luo obu anesul ona e
[C2C1Im][C4F9SO3]
1-E hyl-3-me hylimidazolium pe luo obu anesul ona e
[C6C1Im][C4F9SO3]
1-Hexyl-3-me hylimidazolium pe luo obu anesul ona e
[C8C1Im][C4F9SO3]
1-Oc yl-3-me hylimidazolium pe luo obu anesul ona e
[N1112OH][C4F9SO3]
Choline pe luo obu anesul ona e
[N4444][C4F9SO3]
Te abu ylammonium pe luo obu anesul ona e
[N4444][C8F17SO3]
Te abu ylammonium pe luo oc anesul ona e
[C2C1Im][C1CO2]
1-E hyl-3-me hylimidazolium ace a e
[C2C1py] B
1-E hyl-3-me hylpy idinium b omide
[C2C1Im] Cl
1-E hyl-3-me hylimidazolium chlo ide
[N1112OH] Cl
Choline chlo ide
[N1112OH]+
Choline-based ILs
XX
XXI
Lis o Figu es
1.In oduc ion
Page
Figu e 1.1. Mos common ca ions s uc u es o ILs: a) py olidinium; b) imidazolium; c)
pipe idinium; d) py idinium; e) ammonium and ) choline whe e R could be a hyd ogena ed
chain, a luo ina ed chain o a unc ional g oup………………………………………………
4
Figu e 1.2. Mos common anion s uc u es o ILs: a) chlo ide; b) b omide; c)
e a luo obo a e; d) hexa luo ophospha e; e) ni a e; ) ace a e; g) dicyanamide; h)
dime hylphosphona e i) me hylphosphona e j) e hylphosphona e; k)
i luo ome hanesul ona e and l) bis( i luo ome hylsul onyl)imide…………………………
4
Figu e 1.3. Rele an applica ions o ionic liquids as bioma e ials in chemis y, chemical
enginee ing, bio echnology and pha maceu ics indus ies……………………………………
5
Figu e 1.4. Applica ion a eas o imidazolium-based su ac an s……………………………..
7
Figu e 1.5. Schema ic illus a ion o he use o IL-PDA-DOX nanopa icles o combined
chemo he apy wi h MWTT……………………………………………………………………
8
Figu e 1.6. T anspo , elease, and accumula ion o analy es by micelle collapse……………
9
Figu e 1.7. Ad an ages o using ILs o biomolecula p ocesses……………………………..
9
Figu e 1.8. Schema ic illus a ion o sel -assembly o phy ase enzyme (Aspe gillus nige
phy ase) in [C4C1Im][BF4], leading o phy ase nanosphe es and pla inum–phy ase nanosphe e.
Cu cumin was loaded on bo h samples and was en apped in inne hyd ophobic domains o
p o ein empla e…………………………………………………………………...
11
2. Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase
Equilib ia and Agg ega ion Beha iou
Figu e 2.1. a) TA ins umen Model TGA Q50 used o he measu emen s and b) TA
Ins umen Model DSC Q200 used o he measu emen s……………………………………..
21
Figu e 2.2. a) SVM 300 An on Paa used o iscosi y measu emen s and b) DMA 5000
An on Paa densime e used o densi y measu emen s………………………………………
22
Figu e 2.3. a) ABBEMAT 500 An on Paa au oma ed e ac ome e and b) CDM210
Radiome e Analy ical………………………………………………………………………...
23
Figu e 2.4. Cells used o liquid-liquid equilib ium measu emen s whe e a u bidi y ansi ion
can be obse ed, om a) an immiscible sample o b) a miscible one, as well as he c)
expe imen al se up. conduc ime e …………………………………………………………….
24
Figu e 2.5. Decomposi ion empe a u es e sus mel ing empe a u es o he luo ina ed ionic
liquids in his s udy, [C4C1Im][C4F9SO3] and [C10C1Im][C4F9SO3], and hose ound on
li e a u e o he same amily…………………………………………………………………..
25
2

Ionic Liquids in he De elopmen o No el Bioma e ials
In oduc ion
3
1.1 Gene al con ex
The pha maceu ical indus y is acing a g owing p essu e due o en i onmen al issues, pa en
expi a ions, leng hening o d ug-de elopmen cycles and mo e demanding egula o y equi emen s (1).
Thus, pha maceu ical R&D is mo e han e e ocusing on a ew new molecula compounds o enhance
clinical e icacy a low cos (2). The possibili y o p oducing inno a i e medicinal ma e ials “by design”
b ough an inc easing numbe o compounds possessing low aqueous solubili y and limi ed
bioa ailabili y (1). To o e come hese es ain s pha maceu ical indus ies a e pu suing new s a egies,
such as, de elopmen o p od ugs (3), emulsions using su ac an componen s (4), micella sys ems
(5,6), solid dispe sions (7) and c ys al enginee ing (8).
Ionic liquids (ILs) ha e eme ged as a new class o ma e ials ha ha e conside able po en ial o p o ide
ad ances in pha maceu ical applica ions (9–11). Thei negligible apo p essu e a ambien condi ions,
low su ace ension, high he mal, chemical and elec ochemical s abili y, and widely unable p ope ies
such as iscosi y, densi y, pola i y, hyd ophobici y and sol en miscibili y a e some in e es ing
p ope ies o hese compounds (8). These ema kable cha ac e is ics a e a esul o he innume ous
possible combina ions be ween ILs cons i u i e ions (10). Due o hei su ac an beha iou , ILs can
o m micelles which can be used as d ug-deli e y de ices o spa ingly wa e -soluble d ugs (12). In he
pas decades, a emp s o use ILs o enhance bioa ailabili y o d ug molecules ha e been made
(5,11,13,14).
Fluo ina ed anions such as bis( i luo ome hylsul onyl)imide, hexa luo ophospha e, o e a luo obo a e
ha e been equen ly cha ac e ized and explo ed o se e al biomedical applica ions (15). Howe e , ew
wo ks ha e ocused on he luo ina ed ionic liquids (FILs) he e cha ac e ized, wi h a anionic luo ina ed
alkyl chain o a leas ou ca bons (16). One o he majo in e es in FILs is ha hey combine he bes
p ope ies o pe luo oca bon compounds (PFCs) wi h hose ones o ionic liquids (15). Then, FILs can
be use ul in a eas we e PFCs a e applied such as o oxygen he apeu ics o enhance oxygen anspo ,
pulmona y d ug deli e y de ices wi h dispe sions o d ug mic opa icles and mic oemulsions, gel
mic oemulsions o de mal d ug deli e y, and also luo ina ed mic ocon aine s o gene al d ug deli e y
(17,18).
The main ocus o his wo k is he de elopmen o luo ina ed ionic liquids o biomedical applica ions
in o de o esol e some o he abo emen ioned d awbacks o he pha maceu ical indus y. To design
he mos sui able FILs as no el and imp o ed ma e ials o pha maceu ical applica ions, such as d ug
deli e y sys ems, he he mophysical and pa i ion p ope ies, solu ion and sel -agg ega ion beha iou
we e e alua ed. Fu he mo e, he hyd ogen-bonding abili y and pola izabili y we e also s udied o
add ess he ele ance o designing unc ionalized (so-called ask-speci ic) ILs ha ha e been
syn hesized wi h a pa icula applica ion in mind, e.g. dissolu ion o he apeu ic molecules.
Ionic Liquids in he De elopmen o No el Bioma e ials
In oduc ion
4
1.2 Ionic Liquids
Ionic liquids a e sal s, en i ely cons i u ed o ions whe e ca ions a e o ganic while anions can
be o ganic o ino ganic (8). The mos common amilies o ca ions and anions used o biomedical
applica ions a e shown in Figu e 1.1. and Figu e 1.2., espec i ely (19,20).
Figu e 1.1. Mos common ca ions s uc u es o ILs: a) py olidinium; b) imidazolium; c) pipe idinium;
d) py idinium; e) ammonium and ) choline whe e R could be a hyd ogena ed chain, a luo ina ed chain
o a unc ional g oup.
Figu e 1.2. Mos common anion s uc u es o ILs: a) chlo ide; b) b omide; c) e a luo obo a e; d)
hexa luo ophospha e; e) ni a e; ) ace a e; g) dicyanamide; h) dime hylphosphona e i)
me hylphosphona e j) e hylphosphona e; k) i luo ome hanesul ona e and l)
bis( i luo ome hylsul onyl)imide.
Ionic Liquids in he De elopmen o No el Bioma e ials
In oduc ion
5
The possibili y o manage he inal cha ac e is ics h ough he di e se combina ion o ca ions and anions
make his compounds sui able o nume ous applica ions (21). Nowadays, ILs a e used as eac ion media
o o ganic ans o ma ions, sepa a ions and ex ac ions (10) in nano echnology, bio echnology (20) and
enginee ing p ocesses (22). In he biomedical ield, ILs ha e p o en o be use ul as sol en s o enhance
solubili y o poo wa e soluble d ugs, and hus o be used as d ug deli e y de ice (8,23,24). In Figu e
1.3. a e ep esen ed some o he ele an applica ions whe e ILs ha e been ex ensi ely s udied.
Figu e 1.3. Rele an applica ions o ionic liquids as bioma e ials in chemis y, chemical enginee ing,
bio echnology and pha maceu ics indus ies.
1.2.1 Fluo ina ed Ionic Liquids
Fluo ina ed ionic liquids a e de ined as ionic liquids wi h luo ine ags equal o longe han ou
ca bon a oms (15). The in e es in hese compounds is ha hey can combine he bes p ope ies o ILs
wi h hose ones o pe luo oca bons compounds, such as, excep ional chemical and biological ine ness,
low su ace ension and e ac i e index, ex eme su ace ac i i y, high densi y and excellen sp eading
cha ac e is ics (17,25).
In oducing luo ine a oms o he IL’s composi ion can gene a e no el beha iou and an unma ched
pe o mance in se e al p ocesses in ol ing biomolecules (16,26–28). The high ioniza ion po en ial,
high elec onega i i y and low pola izabili y a e some o he a ibu es ha poin ed ou he elemen
luo ine (29). The he mal and chemical s abili y o F-chains a e due o he s eng h o he C-F bonds,
he s onges single bond in o ganic chemis y (30). Addi ionally, esis ance o F-chains o me abolism
could be use ul in enzyma ic ma e ials (27).
IONIC
LIQUIDS
Chemis y
O ganic syn hesis
and nanoma e ial
syn hesis
Chemical
enginee ing
Sepa a ion, ex a ion
and ca aly ic
eac ions
Pha maceu ics
D ug o mula ion,
d ug deli e y and
o mula ion o APIs
Bio echnology
Bioca alysis and
bio uel p oduc ion
Ionic Liquids in he De elopmen o No el Bioma e ials
In oduc ion
6
One o he mos ema kable cha ac e is ics o FILs is hei amphiphilic beha iou which enhance hei
sel -agg ega ion (31). Due o he luo ina ed componen s he e is a mo e o ganized space (a molecula ,
nanome e and mic ome e scales) inc easing he hyd ophobic seg ega ion e ec and making hem
sui able su ac an s (32). P e ious wo ks shown ha he c i ical micella concen a ion (CMC) alues
o sho chain luo ina ed su ac an s a e analogous o hose o hyd ogena ed su ac an s wi h longe
chain leng hs as will be u he discussed (31).
Al hough luo ina ed compounds ha e been ex ensi ely in es iga ed (18), no signi ican s udies using
FILs o biomedical applica ions ha e been ca ied ou . Mo eo e , a comp ehensi e in es iga ion o
FILs p ope ies is needed o e alua e he applica ion o hese ema kable ILs.
1.2.2. Applica ions o Ionic Liquids as Bioma e ials
One o he mos challenging p oblems aced by he pha maceu ical indus y is he limi ed
aqueous solubili y p esen in 20-30% o he pha maceu ical compounds which en ails a e y poo
bioa ailabili y (33). The e o e, o inc ease d ugs solubili y se e al app oaches ha e been desc ibed such
as he use o liquid and gel mic oemulsions , sal o ma ion and coa ing sys ems (8). Ionic liquids we e
ound o play a special ole in he pha maceu ical indus y (10). As unable chemicals hey a e ideal
candida es o inco po a ing a ious unc ional g oups, including biologically ac i e subs ances (8,15).
An impo an se ies o ionic liquids based on he 1-alkyl-3-me hylimidazole [CnC1Im]+ ca ion, whe e n
is he ca bon numbe in he alkyl g oup, we e ex ensi ely in es iga ed (34). These imidazolium-based
ILs can ha e amphiphilic beha iou depending on he alkyl side chain, such as ca ionic su ac an s (34).
Due o hei hyd ophobic chains and pola imidazolium g oups hey ha e been called “su ac an -like”
ionic liquids (35). In he pas decades, imidazolium-based ILs we e explo ed o se e al pha maceu ical
and indus ial applica ions as illus a ed in Figu e 1.4..
The i s wo k ha uses IL-based mic oemulsions as d ug deli e y de ices was epo ed in 2010 by
Moni uzzanan e al. (36). In his s udy, he solubili y o acyclo i (ACV), a poo wa e and o ganic
soluble an i i al, was es ed in [C1-4C1Im]+ imidazolium-based ILs combined wi h se e al anions. I was
obse ed ha ACV was only soluble on IL wi h ace a e ([C1CO2]-) and dime hylphospha e
([(CH3O)2PO2]) anions. Despi e he enhanced solubili y, u he es s o ep esen anspo o ACV
h ough skin we e pe o med and no signi ican esul s we e ound. The e o e, dime hylimidazole
dime hylphospha e ([C1C1Im][(CH3O)2PO2])) was es ed as a co-sol en o AVC mic oemulsion
oge he wi h Tween-80 and Span-20 comme cial su ac an s. The esul s show ha he skin
pe meabili y was inc eased by se e al o de s o magni ude compa ed o esul s ob ained o he c eam
cu en ly a ailable on ma ke (37). Since hen, ionic liquids ha e been s udied as addi i es in se e al
o mula ions as well as enhance s o d ug solubili y.
Ionic Liquids in he De elopmen o No el Bioma e ials
In oduc ion
7
Goindi e al. used 1-bu yl-3-me hylimidazolium hexa luo ophospha e ([C4C1Im][PF6]) oge he wi h
Tween 80 and e hanol o c ea e a ype gel mic oemulsion o a opical deli e y o e odolac (ETO) (38).
ETO
1
demons a e poo o al bioa ailabili y in which gas oin es inal and ca dio ascula side e ec s a e
no iced (39). To o e come hese side e ec s and ob ain high d ug concen a ion a he a ge si e, opical
applica ion o d ug seems o be an ideal ou e o adminis a ion (38). Thus, he au ho s compa ed he
esul s ob ained om he gel- ype mic oemulsion wi h he a ailable comme cial o mula ion (P oxym
gel®) (38). The esul s showed a d op in g anuloma issue weigh in mice up o 20 %w wi h he IL-
o mula ions. In addi ion, a dec ease in he numbe o leukocy es on he a ec ed a ea whe e obse ed
(7800 o IL o mula ions and 8333.33 o P oxym gel®) demons a ing he an i-in lamma o y e ec
(38). The au ho s jus i ied he esul s on he basis o an enhanced pe mea ion o ETO h ough he IL
(38). In addi ion, Wang e al. epo ed ha 1-hexadecyl-3-me hyllimidazolium b omide ([C16C1Im] B )
p esen ed mo e sui able esul s o p epa ing d ug-loading nanopa icle mic oemulsions in compa ison
wi h con en ional su ac an s molecules (40). In his pape , nanopa icles we e loaded wi h me hylene
blue (d ug model) and he IL enhanced encapsula ion and mic oemulsion s abiliza ion up o 2h.
Mo eo e , a d ug elease p o ile was conduc ed and me hylene blue showed a elease p ocess almos up
o 8 hou s wi h an 99.9% e iciency (40).
Figu e 1.4. Applica ion a eas o imidazolium-based su ac an s. Adap ed om li e a u e (35).
Taking in o accoun he use o ILs as nanoca ie s o d ug deli e y de ices, Mahkam e al. p epa ed a
no el pH-sensi i e nanoca ie o colon speci ic d ug deli e y
2
(41). An imidazolium chlo ide based
1
E odolac (ETO) is a poo ly wa e soluble nons e oidal an i-in lamma o y (NSAID) used o elie e in lamma ion, swelling,
s i ness, and pain associa ed wi h heuma oid a h i is and os eoa h i is (39)
2
Colon-speci ic d ug deli e y sys em is a so o pH sensi i e sys em ha p o ec s he d ugs om deg ada ion in he acidic
medium o s omach and a e passing he acidic medium, hey elease con aining d ugs a he alkaline media o colon (pH 7.4)
(41)

Ionic Liquids in he De elopmen o No el Bioma e ials
In oduc ion
8
IL was placed be ween mon mo illoni e (MMT) laye s and copolyme ized wi h me hac ylic acid (MAA)
o encapsula e nap oxen (used o ea pain o in lamma ion). The inco po a ion o posi i e cha ges in o
he amewo k o he nanocomposi es (IL++MMT+MAA) p omo ed a con olled d ug ealise by changes
o he pH media. By inc easing he pH alue (pH 7.4), di usion o he hyd olysing agen s in o he ca ie
is inc eased, he e o e he a e o hyd olysis inc eased (41).
Tang and co-wo ke s ha e epo ed o he i s ime an amazing use o ILs as mic owa e sensi iza ion
agen (42). By loading polydopamine (PDA) nanopa icles wi h 1-bu yl-3-me hylimidazolium
hexa luo ophospha e ([C4C1Im] [PF6]) i was possible o enhance encapsula ion o doxo ubicin (DOX).
Since [C4C1Im][PF6] is conside ed highly suscep ible o mic owa e i adia ion, a combined
chemo he apy and mic owa e he mal he apy (MWTT) was p oposed o imp o e he deli e y e ec o
he d ug o umou si es. The esul s showed ha IL-PDA-DOX nanopa icles can abla e DOX unde
mic owa e adia ion inhibi ing e icien ly he umou size wi hou inducing any app eciable issue
oxici y (42). In Figu e 1.5 is illus a ed he e ec o IL-PDA-DOX nanopa icles.
Figu e 1.5. Schema ic illus a ion o he use o IL-PDA-DOX nanopa icles o combined chemo he apy
wi h MWTT. Adap ed om li e a u e (42).
Ionic liquids a e powe ul sol en s and elec ically conduc ing luids (10). They can be used as
bioma e ials o enhance de ec ion o biomolecules h ough elec opho e ic echniques as desc ibed by
Abd El-Hady e al. (43). In his wo k, an elec ochemical de ec o (ECD) based on 1-oc yl-3-
me hylimidazolium hexa luo ophospha e ([C8C1Im][PF6]) was de eloped o imp o e de ec ion o
i amins B2, B6 and C. This de ice, coupled wi h capilla y elec opho esis (CE) based on micelle
collapse
3
(see Figu e 1.6), enhanced he micella encapsula ion o i amins and p e en ed i amin
deg ada ion on he elec opho esis bu e /solu ion media. Thus, he sensi i i y o he me hod was
subs an ially imp o ed up o 5000- old compa ed o con en ional CE coupled wi h UV- isible
echniques (43).
3
Analy e ocusing echnique achie ed by micelle collapse. The CE/AFMC me hod is based on he p esence o a sample zone
con ained he micelles- o ming agen wi h highe conduc i i y a he beginning o he un. Due o concen a ion di e ence a
micelle dilu ion zone is o med. Subsequen ly, micelles we e collapsed and he analy e is accumula ed (43).
Ionic Liquids in he De elopmen o No el Bioma e ials
In oduc ion
9
In addi ion, Abd El-Hady and co-wo ke s also es ed he use o ILs o s abilize i amins in biological
samples in which 1-oc yl-3-me hylimidazolium b omide ([C8C1Im] B ) showed he bes esul . The
samples we e iable up o 5 days unde lab s o age condi ions (25ºC, ligh and ai oxygen) wi hou he
need o leng hy and ex ensi e p e ea men (43).
Figu e 1.6. T anspo , elease, and accumula ion o analy es by micelle collapse. Adap ed om
li e a u e (44).
The echnological u ili y o biomolecules can also be signi ican ly enhanced by using ILs a he han
o he o ganic sol en s o aqueous eac ion media due o he IL’s unique sol en cha ac e is ics (10). In
Figu e 1.7. a e ep esen ed some o he ad an ages o using ILs o biomolecula p ocesses in con as
wi h o he o ganic sol en s.
Figu e 1.7. Ad an ages o using ILs o biomolecula p ocesses (20).
ADVANTAGES OF USING ILS FOR BIOMOLECULAR PROCESSES
 Oppo uni y o design pa icula biop ocesses due o ailo -made and inimi able physical,
chemical and biological p ope ies o ILs.
 In se e al cases, biomolecules ha e become mo e soluble and s able (bo h ope a ionally and
he mally) in p esence o ILs.
 Easy eco e ies o sub ac , p oduc s and ILs a e bioca alys s and bio ans o ma ion
 P e en sel -agg ega ion o biomolecules du ing solubilisa ion p ocess
 Enhance solubili y in o insoluble/spa ingly soluble sub ac s in ILs p omo ing biomolecula
eac ions
 Enhance immobiliza ion o biomolecules in highly iscous ILs o biochemical p ocesses
Ionic Liquids in he De elopmen o No el Bioma e ials
In oduc ion
10
Fo ins ance, DNA can be ex ac ed om biological samples using he phenol/chlo o o m me hod whe e
he p o eins a e dissol ed in he o ganic medium (phenol/chlo o o m) while DNA emains in he
aqueous solu ion (45). Howe e , his ype o p ocesses can in ol e oxic o ganic compounds and ha e
se e al ime-consuming s eps (45). Recen ly, a numbe o s udies epo ed he use o ILs o sepa a ion
and ex ac ion o nuclei acids, especially DNA (46,47). A p e ious s udy employed he 1-bu yl-3-
me hylimidazolium hexa luo ophospha e ([C4C1Im][PF6]) IL o di ec ex ac ion o DNA om aqueous
solu ion using he liquid-liquid ex ac ion echnique (LLE) (48). The in e ac ions be ween he
imidazolium ca ion alkyl chain and he phospha e g oups o he DNA we e deemed esponsible o he
DNA/IL binding and he e icien ex ac ion and pu i ica ion (48). Ga cía e al. also es ed se e al ILs
o p oduce a as and e icien s a egy o he ex ac ion o DNA di ec ly om maize (49). The esul s
sugges ed ha 1-e hyl-3-me hylimidazolium dime hylphospha e ([C2C1Im] [(CH3)2PO4)]) was he mos
e icien ex ac ion sys em wi h a yield anging om 696.7-721.2 μg DNA / g sample (49). These esul s
imp o e he common a ailable me hod based on he su ac an ce yl ime hylammonium b omide
(CTAB) wi h a yield be ween 252.3 and 256.2 μg DNA / g sample. Mo eo e , his echnique
demons a ed imesa ings o app oxima ely 3h and he DNA ex ac ed was s able when s o ed a oom
empe a u e o 10 days (49). The hyd ogen bonding in e ac ions be ween ILs and DNA we e conside ed
an impo an pa ame e when ILs a e used as sol en in ex ac ion p ocess (49,50).
Addi ionally, Li e al. s udied wo speci ically designed ILs, namely 1-(1,2-dihyd oxyp opyl)-3-
decylimidazolium b omide ([C10POHIM] B ) and 1-(1,2-dihyd oxyp opyl)-3-hexadecylimidazolium
b omide ([C16POHIM] B ) which con ain wo hyd oxyl g oups capable o o ming hyd ogen bonds (45).
Conside ing he ex ac ion e iciency, [C10POHIM] B and [C16POHIM] B show he mos sui able
yields (52.4% and 95.2%, espec i ely) when compa ed wi h o he ILs con aining simila s uc u es bu
lacking hyd oxyl unc ional g oups (45). Thus, he impo ance o he alkyl chain o he IL o DNA
biding was also p o ed in his wo k (45).
Fo success ully design o IL i is c ucial o mee he equi emen s o he pa icula ask. Fo ins ance,
in IL-based ex ac ion p ocesses, he numbe o ca bons p esen in he alkyl chain is aken in o
conside a ion since i in luences he abili y o o m biphasic sys ems (51).
The ac i i y and s abili y o enzymes, such as lipases, p o eases, alcohol dehyd ogenases and
oxido educ ases, ha e been e alua ed using ILs as media (20). The pola i y, ca ion/anion na u e, alkyl
chain leng h, hyd ophobici y and iscosi y a e some o he main ac o s ha can a ec he enzyme
pe o mance (52). Rega ding he anion, hey can ha e a p o ound e ec on he s abili y and ac i i y o
enzymes due o hei high hyd ogen bond o ming capabili ies which s ongly in e ac wi h p o eins and
can cause con o ma ional changes (20). No i omi e al. compa ed he e ec o a ious anions on he
ac i i y o lysozyme and ound ha i had lowe ac i i y in [C2C1Im] Cl a he han [C2C1Im][BF4] and
[C2C1Im] [NT 2] (53). In his case, i was sugges ed ha luo ina ed anions can p omo e s abili y o his
Ionic Liquids in he De elopmen o No el Bioma e ials
In oduc ion
11
enzyme (53). In ac , some wo ks ha e epo ed ha enzymes a e mos ac i e in a p esence o a
hyd ophobic anion, such as [BF4]- and [PF6]-. On he o he hand, he mos deac i a ing enzyma ic
eac ions a e ound when a e used ILs con aining anions capable o b eaking hyd ogen bonds, such as
Cl- (20). Machado and Sa ai a in es iga ed he e ec o he ca ion chain leng h o alkyl-imidazolium
based ILs (e hyl-, bu yl-, and hexyl-imidazolium based ILs) on he enzyme ac i i y o ho se adish
pe oxidase(54) and ound ha 1-hexyl-3-me hylimidazolium chlo ide ([C6C1Im] Cl) lowe ed he
pe oxidase enzyme ac i i y.
Co ela ing he enzyme s abili y and nanoca ie s, Soni e al. epo ed he inhe en an i umo e iciency
o sel -assembled phy ase enzyme nanosphe es (55). This e iciency can be enhanced wi h he use o
pla inum nanopa icles loaded wi h he an icance d ug cu cumin. In his s udy, he 1-bu yl-3-
me hylimidazolium e a luo obo a e IL ([C4C1Im][BF4]) was used o o m he apeu ically ac i e
phy ase nanosphe es (55). Figu e 1.8. illus a es he sel -assembled phy ase nanosphe es p omo ed by
he IL.
Figu e 1.8. Schema ic illus a ion o sel -assembly o phy ase enzyme (Aspe gillus nige phy ase) in
[C4C1Im][BF4], leading o phy ase nanosphe es and pla inum–phy ase nanosphe e. Cu cumin was
loaded on bo h samples and was en apped in inne hyd ophobic domains o p o ein empla e. Adap ed
om li e a u e (55).
Al hough he numbe o publica ions ega ding ILs has g own exponen ially, he e a e s ill nume ous
unexplo ed applica ions o FILs amily. Fluo oca bons o luo ina ed amphiphiles ha e been widely
s udied o hei applica ion in oxygen he apeu ics, pulmona y d ug deli e y sys ems, gel emulsions
and micelle ype con aine s o d ug deli e y de ices (17,18). Recen ly, i was pa en ed (56) he use o
luo opolyme -based emulsions o he in a enous deli e y o luo ina ed ola ile anaes he ics. This
ype o emulsion enhanced he capabili y o deli e ing and eleasing con olled amoun s o luo ina ed
18

Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
19
2.1 In oduc ion
One o he mos ou s anding ad an age o ionic liquids, and hus o luo ina ed ionic liquids, is
he possibili y o uning he inal cha ac e is ics h ough in ini e combina ions be ween ca ions and
anions. This manipula ion allows o con ol se e al cha ac e is ics such as he mal and he mophysical
p ope ies, solubili y, hyd ophobici y and oxici y (1). As he in e es in ionic liquids inc ease
exponen ially, he demand o a comp ehensi e in es iga ion o hei physicochemical p ope ies is
clea . In o de o e alua e he ad an ages o luo ina ed ionic liquids, he modynamic, he mophysical
and he mal cha ac e iza ion, liquid-liquid equilib ia, as well as he sel -agg ega ion beha iou in
aqueous solu ion we e ob ained o imidazolium-based ionic liquids wi h he pe luo obu anesul ona e
anion.
De e mina ion o densi y and iscosi y could headligh FILs anspo p ope ies (2). On he o he hand,
iscosi y can es ima e he FIL ease o mo emen h ough di e en sol en s, also called luidi y (3).
Addi ionally, ionic conduc i i y ela ed wi h FIL concen a ion may p edic he o ma ion o agg ega es
(4). The ela ionship be ween conduc i i ies and iscosi y, known as ionici y, is also impo an o
cha ac e ize pu e FILs (5). Fo ins ance, pe luo ina ed compounds (PFC) p o ed o be use ul in se e al
biomedical applica ions such as a i icial blood subs i u es and in i o gas ca ie s (6). Since luo ina ed
ionic liquids sha e some common cha ac e is ics wi h PFC (1), a compa ison be ween hese wo
compounds is done when possible.
The sel -agg ega ion beha iou o some FILs in aqueous solu ions induces he o ma ion o sel -
assembled s uc u es ha can be used ad an ageously in he deli e y o di e en he apeu ic compounds
(4). Fo example, d ug molecules exhibi ing poo solubili y due o hei high molecula weigh s and
s uc u e complexi y ha lead o low bioa ailabili y (7). Acco dingly, designing no el excipien s wi h
uneable physicochemical p ope ies and capable o o ming micelles o mic oemulsions is p omising.
Wi h his aim in mind, a solubili y and sel -agg ega ion beha iou analysis o imidazolium-based
luo ina ed ILs was conduc ed.
In conclusion, he da a ob ained in his chap e will allow he c i ical e alua ion o FILs he mophysical
p ope ies, and solu ion beha iou , acknowledging hei use as bioma e ials such as gas ca ie
compounds, su ac an o mic oemulsions o nanos uc u ed d ug deli e y componen s (8).
2.2 Ma e ials
1-Bu yl-3-me hylimidazolium pe luo obu anesul ona e, ≥98% mass ac ion pu i y; and 1-
decyl-3-me hylimidazolium pe luo obu anesul ona e, ≥98% mass ac ion pu i y; we e syn he ized in
ou lab acco ding o he ion exchange esin me hod (9). 1-Hexyl-3-me hylimidazolium
pe luo obu anesul ona e, >99% mass ac ion pu i y; 1-oc yl-3-me hylimidazolium
Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
20
pe luo obu anesul ona e, >99% mass ac ion pu i y and 1-dodecyl-3-me hylimidazolium
pe luo obu anesul ona e, >98% mass ac ion pu i y we e acqui ed om IoLiTec. S uc u es and
ac onyms a e lis ed in Table 2.1
In o de o con i m he pu i y o he compounds 1H and 19F NMR we e pe o med. The compounds we e
i s d ied unde a 3·10-2 To acuum wi h a con inuous s i ing a 323.15 K o a leas 48h o educe
ola ile impu i ies. The wa e con en o FILs used in his wo k was de e mined using Ka l Fishe
Table 2.1. Designa ion and chemical s uc u e o each ionic liquid used along his s udy.
IL designa ion
Chemical s uc u e
1-Bu hyl-3-me hylimidazolium
pe luo obu anesul ona e
[C4C1Im][C4F9SO3]
1-Hexyl-3-me hylimidazolium
pe luo obu anesul ona e
[C6C1Im][C4F9SO3]
1-Oc yl-3-me hylimidazolium
pe luo obu anesul ona e
[C8C1Im][C4F9SO3]
1-Decyl-3-me hylimidazolium
pe luo obu anesul ona e
[C10C1Im][C4F9SO3]
1-Dodecyl-3-me hylimidazolium
pe luo obu anesul ona e
[C12C1Im][C4F9SO3]
Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
21
coulome ic i a ion me hod (Me ohm 831 KF Coulome e ) and i was less han 100 ppm. Milli-Q
ul apu e wa e (Milli-Q In eg al Wa e Pu i ica ion Sys em) was used when necessa y h oughou he
wo k.
2.3 Expe imen al P ocedu es
2.3.1 Nea Fluo ina ed Ionic Liquids
2.3.1.1. The mal P ope ies
The he mal s abili ies o he FILs we e de e mined using a he mog a ime ic analysis (TGA),
using he TA Ins umen model Q50 ep esen ed in Figu e 2.1. a). Samples o FILs we e loaded in an
aluminium pan and hea ed wi h a ni ogen low a e o 60 ml·min–1 un il comple e he mal deg ada ion
using a scan a e o 1 K·min–1. TA Uni e sal Analysis (so wa e e sion 4.4) was used o de e mina e
he onse empe a u e (Tonse ), s a ing empe a u e (Ts a ) and decomposi ion empe a u e (Tdec) which
co espond o he empe a u es a which he baseline slope changed du ing hea ing, he weigh loss was
less han 1%, and he weigh loss was 50%, espec i ely. Duplica es we e measu ed and he unce ain y
o hese empe a u es is ± 3 K.
Mel ing poin s we e de e mined using a Di e en ial Scanning Calo ime e (DSC), TA Ins umen model
Q200 (see Figu e 2.1. b)), calib a ed wi h an Indium s anda d. In hese expe imen s, samples o FILs
we e loaded in an aluminum pan and con inuously pu ged wi h 50 ml∙min-1 o ine ni ogen gas. Nex ,
he samples we e cooled o 183.15 K, empe ed du ing 30 min, and hea ed o 313.15 K. This p ocess
was epea ed h ee imes a di e en a es (10 K·min-1, 5 K·min-1 and 1 K·min-1). The ob ained alues
om he second and subsequen cycles we e ep oducible a he same a e. Duplica es we e measu ed
and he unce ain y o he mel ing empe a u e is ±2K
Figu e 2.1. a) TA ins umen Model TGA Q50 used o he measu emen s and b) TA Ins umen Model
DSC Q200 used o he measu emen s.
a)
b)
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22
2.3.1.2. Viscosi y and Densi y Measu emen s
Measu emen s o dynamic iscosi y we e ca ied ou using an au oma ed SVM 3000 An on Paa
o a ional S abinge iscome e (see Figu e 2.2. a)) ope a ing a a mosphe ic p essu e in he empe a u e
ange 288.15 o 358.15 K. The equipmen uses Pel ie elemen s o as and e icien he mos abili y
wi h a empe a u e unce ain y o ± 0.02 K. Duplica es we e measu ed and he epo ed da a a e a e age
alues wi h a maximum ela i e s anda d de ia ion o 1%. The unce ain y o he expe imen al alues,
aking in o accoun he pu i y and handling o he samples is es ima ed o be 2%.
Densi y was measu ed wi h an An on Paa ib a ing ube densime e , model DMA 5000 (see Figu e
2.2. b)) ope a ing a a mosphe ic p essu e and in he empe a u e ange 288.15 K o 358.15 K. The e ec
o iscosi y was conside ed in all expe imen s using he in e nal calib a ion. The empe a u e was
con olled by se e al Pel ie uni s and he cell was embedded in a ca i y inside a me allic block. This
equipmen allowed a empe a u e s abili y o 0.002 K. Duplica es we e measu ed and he epea abili y
and expanded unce ain y o he densi y is be e han 5·10-5 and ± 3·10-4 g·cm-3, espec i ely.
Figu e 2.2. a) An on Paa SVM 300 used o iscosi y measu emen s and b) An on Paa DMA 5000
densime e used o densi y measu emen s.
2.3.1.3. Re ac i e Index Measu emen s
An An on Paa ABBEMAT 500 au oma ic e ac ome e wi h a esolu ion o ± 10-6 was used o
measu e he e ac i e index. The equipmen was calib a ed using Millipo e quali y wa e and
e achlo oe hylene p o ided by he supplie . Duplica es we e measu ed and he epo ed esul s ha e
an unce ain y o ± 4·10-5. The appa a us is ep esen ed in Figu e 2.3. a).
2.3.1.4. Ionic Conduc i i y Measu emen s
Ionic conduc i i y measu emen s we e de e mined using a Radiome e Analy ical CDM210
conduc ime e in a jacke ed glass cell wi h a magne ic s i e as ep esen ed in Figu e 2.3. b).
a)
b)
Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
23
Figu e 2.3. a) An on Paa ABBEMAT 500 au oma ed e ac ome e and b) Radiome e Analy ical
CDM210 conduc ime e .
A wa e ba h was used o he mos a ize he cell and he empe a u e was measu ed by a pla inum
esis ance he mome e coupled o a Kei hley 199 Sys em DMM/Scanne wi h an unce ain y o ± 0.01
K. To ensu e a secu e seal and o p e en humidi y, he sample was closed wi h d y ni ogen and sc ew
caps. The calib a ion was pe o med a each empe a u e wi h 0.01 D KCl s anda d solu ions supplied
by Radiome e Analy ical. The ionic conduc i i y alues we e alida ed as desc ibed p e iously (10).
Duplica es we e measu ed and he epo ed da a a e he a e age alues wi h an unce ain y o ± 1%
2.3.2. Mix u es o Fluo ina ed Ionic Liquids and Wa e
2.3.2.1. Liquid-liquid Equilib ia
In o de o de e mine he empe a u e-composi ion phase diag ams, he u bidi y o he bina y
sys em FIL + wa e was analyzed using a isual me hod a a mosphe ic p essu e. Ini ial immiscible
samples we e p epa ed di ec ly in Py ex glass cells wi h inco po a ed magne ic s i e s using an
analy ical high-p ecision balance (unce ain y o ± 0.00002 g). Then, he cell was imme sed in a
he mos a ic ba h (a mix u e o wa e and e hylene glycol was used as he mos a ic luid) and bo h
mix u e and he mos a ic luid we e con inuously s i ed. The liquid-liquid phase ansi ion was
accomplished by aking he empe a u e when he u bidi y o he sys em disappea ed. The empe a u e
was measu ed using a ou -wi e pla inum esis ance P 100 he mome e coupled o a Kei hley 199
Sys em DMM/Scanne mul ime e (unce ain y o 0.01 K). The o e all unce ain y o he empe a u e
ansi ions in his isual me hod was es ima ed o be ± 0.5 K and he unce ain y o he mix u e
composi ion was ± 0.0001 in mass ac ion. Figu e 2.4. depic s (a) cell wi h isible u bidi y
co esponding o immiscibili y, a (b) cell wi h o al miscibili y and (c) he expe imen al se up o
pe o ming liquid-liquid equilib ia measu emen s
a)
b)

Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
24
Figu e 2.4. Cells used o liquid-liquid equilib ium measu emen s whe e a u bidi y ansi ion can be
obse ed, om a) an immiscible sample o b) a miscible one, as well as he c) expe imen al se up.
2.3.2.2. C i ical Micella Concen a ion
To de e mine he c i ical micella concen a ion (CMC), he Philips de ini ion was used (11).
Acco ding o Philips e al., he concen a ion a which he e is a maximum change in g adien in he
conduc i i y-concen a ion cu e co esponds o a CMC. The ionic conduc i i ies we e measu ed a
298.15 K and pe o med wi h a Radiome e Analy ical CDM210 conduc ime e using a CDC749
elec ode in a glass cell wi h a magne ic s i e (see Figu e 2.3. b)). The equipmen was calib a ed o
each empe a u e by using a ce i ied 0.01 D KCl s anda d solu ion p o ided by Radiome e Analy ical.
The cell was he mos a ized wi h a wa e ba h and he empe a u e was measu ed using a pla inum
esis ance he mome e coupled o a Kei hley 199 sys em DMM/scanne (unce ain y o ±0.01 K). Each
aqueous solu ion was added o he cell and s i ed o he expe imen al measu emen s. Conduc i i y was
measu ed a leas h ee imes and he unce ain y o each sample was es ima ed o be 1%.
2.3.2.3. T ansmission Elec on Mic oscopy (TEM)
The samples analyzed wi h mic oscopy we e placed on a 200 nesh coppe g id wi h 3 mm
diame e using a o m a ilm. A il e pape was used o emo e he excess o aqueous solu ion.
Solu ions we e d ied and measu ed using a Philips CM20 model wi h LaB6 ilamen , a a wo king
ol age o 200 kV. These measu emen s we e ca ied ou by an ex e nal se ice (Uni e si y o Vigo).
2.4. Resul s and Discussion
2.4.1. Nea Fluo ina ed Ionic Liquids
2.4.1.1. The mal P ope ies
Mel ing and decomposi ion empe a u es a e one o he mos ema kable p ope ies o ionic
liquids which de e mine he liquid ange, and, consequen ly, hei ange o applica ions (1). Fo his
a)
b)
c
)
Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
25
pu pose, [C4C1Im][C4F9SO3] and [C10C1Im][C4F9SO3] we e analyzed and in Table 2.2. a e epo ed he
he mal p ope ies (onse empe a u e, Tonse , s a empe a u e, Ts a , decomposi ion empe a u e, Tdec,
and mel ing empe a u e, Tm) o he luo ina ed ionic liquids s udied in his wo k.
Table 2.2. The mal p ope ies o luo ina ed ionic liquids: s a ing empe a u e, Ts a , onse
empe a u e, Tonse , decomposi ion empe a u e, Tdec, and mel ing empe a u e, Tm a 1 K·min-1.
FIL
Tm / K
Ts a / K
Tonse / K
Tdec / K
[C4C1Im][C4F9SO3]
286
554
638
670
[C10C1Im][C4F9SO3]
307
545
627
655
Expe imen al da a a e plo ed in Figu e 2.5. whe e he mel ing empe a u es speci y he empe a u e a
which he compound becomes liquid and he decomposi ion empe a u es de e mine he uppe ope a ing
empe a u e a which he luid can be used (3). Also, he ob ained esul s o he s udied FILs we e
compa ed wi h he luo ina ed ionic liquids [C2C1Im][C4F9SO3], [C6C1Im][C4F9SO3],
[C8C1Im][C4F9SO3] and [C12C1Im][C4F9SO3] om p e ious wo ks (1,3).
Figu e 2.5. Decomposi ion empe a u es e sus mel ing empe a u es o he luo ina ed ionic liquids
in his s udy, [C4C1Im][C4F9SO3] and [C10C1Im][C4F9SO3], and hose ound on li e a u e o he same
amily (1,3).
In o de o e alua e he use o hese luo ina ed ionic liquids o biomedical pu poses he mos ele an
empe a u e is 310.15K, which is accep ed o be he a e age body empe a u e in humans (1). Wi h he
a ailable da a, i is possible o analyse he e ec o he inc emen o he hyd ogena ed alkyl side chain
leng h on he imidazolium-based luo ina ed ionic liquids wi h he pe luo obu anesul ona e anion,
[C4F9SO3]-.
Taking in o accoun he onse empe a u e alues, Tonse , no subs an ial di e ences we e ound. These
high he mal s abili ies a e cha ac e is ic o hese compounds and an ad an age o se e al applica ions
in he elec ochemical ield, o example as ba e y elec oly es (12). Compa ing he decomposi ion
Mel ing Tempe a u e / K
280 290 300 310 320
Decomposi ion Tempe a u e / K
630
642
654
666
678
[C2C1Im][C4F9SO3]
[C4C1Im][C4F9SO3]
[C6C1Im][C4F9SO3]
[C8C1Im][C4F9SO3]
[C10C1Im][C4F9SO3]
[C12C1Im][C4F9SO3]
Tempe a u e = 310.15 K (37ºC)
Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
26
empe a u es (Tdec), co esponding o 50% o weigh loss o he compound, i is possible o obse e ha
he inc emen o he hyd ogena ed side chain dec eases his empe a u e. When analyzed wi h o he FILs
i leads o he ollowing end: [C4C1Im]+ ≈ [C2C1Im]+ ≈ [C6C1Im]+ > [C8C1Im]+ ≈ [C10C1Im]+ >
[C12C1Im]+. The same end is obse ed o he mel ing empe a u es: [C4C1Im]+ ≈ [C2C1Im]+ ≈
[C6C1Im]+ > [C10C1Im]+ ≈ [C8C1Im]+ > [C12C1Im]+. These ends a e in ag eemen wi h he li e a u e,
whe e he inc emen o he hyd ogena ed alkyl chain leng h is ela ed o an inc ease on he mel ing and
dec ease on he decomposi ion empe a u es (1,3,5).
2.4.1.2. The mophysical Cha ac e iza ion
The he mophysical p ope ies measu ed in his wo k, namely densi y, dynamic iscosi y,
e ac i e index and ionic conduc i i y o he wo luo ina ed ionic liquids s udied in his hesis a e lis ed
in Table 2.3. as unc ion o empe a u e. The densi ies, luidi ies (1 / dynamic iscosi y) and ionic
conduc i i ies a e ep esen ed in Figu e 2.6., Figu e 2.7. and Figu e 2.8., espec i ely, oge he wi h
da a o [C2C1Im][C4F9SO3], [C6C1Im][C4F9SO3], [C8C1Im][C4F9SO3] and [C12C1Im][C4F9SO3] aken
om he li e a u e (1,3).
Densi y and luidi y a e impo an pa ame e s o be analyzed when one wan o apply his no el
compounds o biomedical applica ions, such as anspo and deli e y o espi a o y gases (13),
o mula ion o d ug deli e y sys ems (14),among o he s (1). The ob ained densi y alues we e compa ed
wi h [C2C1Im][C4F9SO3], [C6C1Im][C4F9SO3], [C8C1Im][C4F9SO3] and [C12C1Im][C4F9SO3] (1,3) in
o de o obse e he e ec o he hyd ogena ed alkyl chain leng h o he imidazolium ca ion.
In o de o e alua e he densi y o luo ina ed ionic liquids, he densi y o blood (1.05 g∙cm-3) was aken
in o accoun (15). Addi ionally, since PFCs p o ed o be use ul in a ple ho a o biomedical uses as
su ac an s o mic oemulsions and o d ug deli e y encapsula ions, he densi y o hese compounds
(≈1.7 g∙cm-3) is also conside ed as e e ence alue (16). The bes candida es will be he luo ina ed ionic
liquids wi h densi ies close o he alues men ioned abo e.
Analysing he esul s o [C4C1Im][C4F9SO3] and [C10C1Im][C4F9SO3] i can be concluded ha in he
ange o empe a u es s udied he inc ease in he hyd ogena ed alkyl side chain leng h leads o a dec ease
o he densi ies: [C4C1Im][C4F9SO3] > [C10C1Im][C4F9SO3]. Compa ing he esul s wi h blood densi y
a app oxima ely 310.15 K (a e age body empe a u e, 37ºC) he [C10C1Im][C4F9SO3] (≈1.29 g∙cm-3) is
closes o 1.05 g∙cm-3. Howe e , while inc easing he hyd ogena ed chain leng h could be ad an ageous
conce ning he blood low, i leads o an inc ease in lipophilici y (highe oxici y) as will be discussed
in Chap e 3. Taking in o accoun he densi y o PFCs (≈1.7 g∙cm-3) (16), [C2C1Im][C4F9SO3] and
[C4C1Im][C4F9SO3] p esen ed he closes alues ≈ 1.55 g∙cm-3 and ≈ 1.44 g∙cm-3 a 310.15 K,
espec i ely. Consequen ly, hese luo ina ed ionic liquids could be p omising bioma e ials o eplace
Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
27
(ei he pa ially o o ally) PFCs, in hei dis inc use ul applica ions (e.g. d ug deli e y, con as
ul asound imaging agen ) (6).
Compa ing he ob ained esul s wi h hose ound in he li e a u e o he same amily o imidazolium-
based ionic liquids (see Figu e 2.6), i is e i ied ha densi y dec eases wi h he inc ease o empe a u e
and wi h he inc emen o he hyd ogena ed alkyl side chain o he imidazolium ca ion. These esul s a e
in ag eemen wi h he li e a u e (1,3,5)
Figu e 2.6. Densi y o he luo ina ed ionic liquids measu ed in his wo k and compa ison wi h
[C2C1Im][C4F9SO3], [C6C1Im][C4F9SO3], [C8C1Im][C4F9SO3] and [C12C1Im][C4F9SO3] ound on
li e a u e (1,3).
The a e age blood iscosi y s ands be ween 1.1 o 1.35 mPa∙s, and so blood luidi y is in a ange o
0.74-0.91 mPa-1s-1 (17). The PFCs iscosi y a ied om 0.6 o 5.4 mPa∙s wi h a luidi y ange o 0.19-
1.67 mPa-1s-1 depending on he composi ion (18). In Figu e 2.7., i is possible o obse e luidi y
dependence on empe a u e o [CnC1Im][C4F9SO3] (n=2; 4; 6; 8; 10; 12) FILs. A 310.15 K, conside ed
o be he a e age human body empe a u e, luidi ies o all he FILs s and be ween 0.003-0.013 mPa-
1s-1. Howe e , wi h he inc ease in empe a u e he di e ences a e mo e p onounced. Compa ing he
measu emen s o [C4C1Im][C4F9SO3] and [C10C1Im][C4F9SO3] i can be concluded ha he inc emen
o he hyd ogena ed alkyl chain leng h leads o a dec ease in luidi y (3,5). Rela ing hese esul s wi h
hose ound on he li e a u e o [C2C1Im][C4F9SO3], [C6C1Im][C4F9SO3], [C8C1Im][C4F9SO3] and
[C12C1Im][C4F9SO3] he end become mo e ob ious (1,3).
Despi e densi y and iscosi y alues (see Table 2.3.) being highe han ac ual blood physical p ope ies
and so c ea ing an obs acle, addi ion o wa e may lead o a dec ease on bo h p ope ies (19). Rod íguez
and B ennecke (19) s udied he densi y and iscosi y o aqueous solu ions o imidazolium-based ILs
wi h he anions e hylsul a e, i luo oace a e and i luo ome hanesul ona e. Bo h p ope ies we e ound
o dec ease wi h an inc ease in ei he empe a u e o in mola ac ion o wa e .
275 300 325 350 375
Densi y
/ g.cm-3
1.20
1.30
1.40
1.50
1.60
[C2C1Im][C4F9SO3]
[C4C1Im][C4F9SO3]
[C6C1Im][C4F9SO3]
[C8C1Im][C4F9SO3]
[C10C1Im][C4F9SO3]
[C12C1Im][C4F9SO3]
Tempe a u e
T / K
Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
34
could lead o he unexpec ed beha iou o he aqueous- ich phase o he LLE phase diag am epo ed in
his wo k. A close analysis ega ding he epo ed end is being conduc ed by ou esea ch g oup.
Figu e 2.10. a) Full composi ion o he liquid-liquid phase diag am o bina y mix u es (FILs (1) +
wa e (2)) in e ms o mass ac ion; ampli ied liquid-liquid phase diag am a he b) wa e ich-phase
and c) a ≈335 K and he d) FIL ich-phase.
2.4.2.2. Sel -agg ega ion Beha iou
Fluo ina ed ionic liquids a e amphiphilic molecules and a e cons i u ed by a pola head and a
hyd ophobic ail (34). In aqueous media, FILs can sel -assembly in di e en o agg ega e s uc u es o
hide hei hyd ophobic moie ies and expose he hyd ophilic ones. Some common o ms o agg ega es
a e ubules, esicles, ibbons and helices (4). Fo ins ance, his abili y o FILs o c ea e o ganized
nanos uc u es could be use ul in he de elopmen o no el d ug deli e y sys ems whe e a d ug wi h
low solubili y could be encapsula ed in one o hese s uc u es and di ec ed o he a ge (14).
Addi ionally, hei su ac an beha iou could be also use ul o acili a e he o ma ion and s abiliza ion
o mic oemulsions o enhanced biomolecule solubili y (29,36).
Measu emen s o ionic conduc i i y a e gene ally implemen ed in he s udy o ionic micella solu ions.
The p esence o micelles can dec ease he mobili y and as consequence a slope on conduc i i ies could
be no iced (11). Thus, ionic conduc i i y measu emen s o [C4C1Im][C4F9SO3] and
w FIL
0.0 0.2 0.4 0.6 0.8 1.0
T/ K
294
308
322
336
350
364
[C4C1Im] [C4F9SO3]
[C6C1Im] [C4F9SO ]
[C8C1Im] [C4F9SO3]
[C10C1Im] [C4F9SO3]
[C12C1Im] [C4F9SO3]
w FIL
0.00 0.02 0.04 0.06 0.08 0.10
T/ K
294
308
322
336
350
364
w FIL
0.75 0.80 0.85 0.90 0.95 1.00
T/ K
294
308
322
336
350
364
n in [CnC1Im][C4F9SO3]
4 6 8 10 12
wFIL
0.012
0.016
0.020
0.024
0.028
C4
C12
C10
C8
C6
C4
C6
C8
C10
C12
C12
C10
C8
C6
C4
a)
b)
d)
c)

Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
35
[C10C1Im][C4F9SO3] we e pe o med a 298.15 K, 308.15 K and 318.15 K. Figu e 2.11. illus a e hese
measu emen s a 298.15 K o [C10C1Im][C4F9SO3], whe e he expe imen al conduc i i ies a e depic ed
agains FIL concen a ion. This change in beha iou is explained by Philips de ini ion, whe e he c i ical
micella concen a ion (CMC) is he concen a ion co esponding o he maximum change in he
g adien o he solu ion p ope y, ionic conduc i i y, e sus concen a ion cu e (11). The CMC alues
can be de e mined using hese plo s.
Figu e 2.11. Concen a ion dependence o he ionic conduc i i y o [C10C1Im][C4F9SO3] in aqueous
solu ion a 298.15 K a he CMC. The dashed line shows a maximum change in he g adien o ionic
conduc i i y as a unc ion o FIL concen a ion, ob ained second de i a i e.
In his wo k, he ionic conduc i i y measu emen s we e ca ied ou a 298.15, 308.15 and 318.15 K and
he CMC alues calcula ed om hese plo s a e epo ed in Table 2.5 and compa ed wi h he CMC o
FILs om same amily measu ed a 298.15 K (4,30).
Figu e 2.12 illus a es he beha iou o he FILs s udied in his wo k as well as o [C2C1Im][C4F9SO3],
[C6C1Im][C4F9SO3], [C8C1Im][C4F9SO3] and [C12C1Im][C4F9SO3] (4,30). Taking in o accoun hese
expe imen al esul s, i can be concluded ha he inc emen o he hyd ogena ed alkyl side-chain o he
imidazolium ca ion is di ec ly ela ed o lowe CMC alues, as expec ed (30).
The CMC is in ima ely ela ed o he su ac an beha iou o a compound: a lowe CMC leads o an
inc ease o su ac an beha iou (1). The comme cial pe luo oca bon su ac an s such as sodium
pe luo ooc anoa e and ammonium pe luo ooc anoa e ha e CMC alues o ≈30 mmol∙Kg (37–39) ,
app oxima ely 30 imes highe han some FILs, such as [C10C1Im][C4F9SO3]. This ad an ageous
cha ac e is ic could be use ul o subs i u ing ( o ally o pa ially) he PFCs in mic oemulsion
o mula ions whe e he main pu pose is hei su ac an ac ion (40).
FIL Concen a ion / (mmol.Kg-1)
0.00 0.46 0.92 1.38 1.84 2.30
Conduc i i y/ (mS.cm-1)
0.00
0.02
0.04
0.06
0.08
0.10
Concen a ion dependence o he ionic conduc i i y be o e CMC
Concen a ion dependence o he ionic conduc i i y a e CMC
Second De i a i e
Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
36
Table 2.5. Values o c i ical micella concen a ion, CMC, a di e en empe a u es o FILs in his
wo k and compa ison wi h alues ound on li e a u e * a 298.15 K (4,30).
T/K
FILs
CMC (mmol/ Kg)
298.15
[C2C1Im][C4F9SO3]
14.55*
[C4C1Im][C4F9SO3]
12.17
[C6C1Im][C4F9SO3]
8.22*
[C8C1Im][C4F9SO3]
2.41*
[C10C1Im][C4F9SO3]
1.29
[C12C1Im][C4F9SO3]
0.01*
308.15
[C4C1Im][C4F9SO3]
11.36
[C10C1Im][C4F9SO3]
1.21
318.15
[C4C1Im][C4F9SO3]
11.31
[C10C1Im][C4F9SO3]
1.14
Figu e 2.12. Compa ison o he CMCs alues o he luo ina ed ionic liquids s udied in his wo k a
298.15 K and hose ound in he li e a u e (4,30) o he same empe a u e.
The deg ee o ioniza ion o he agg ega es, αCMC, is also a pa ame e o be e alua ed. I is ela ed wi h
he ac ion o cha ges o su ac an ions in he micelle neu alized by micelle-bound coun e ions. The
ions o hese su ac an s a e comple ely dissocia ed in aqueous solu ions. Howe e , hey a e pa ly
associa ed wi h coun e ions when o ming hei agg ega es (4). The deg ee o ioniza ion o he
agg ega es can be calcula ed om he a io o he slopes o he linea agmen s abo e and below he
CMC concen a ion (4). These alues a e p esen ed in Table 2.6. o he s udied [CnC1Im][C4F9SO3]
(n = 2, 4, 6, 8, 10, 12) FILs. A lowe alue o αCMC indica es a be e packed micelle (4). Fu he mo e,
he deg ee o ioniza ion o he agg ega es is mo e p onouced a lowe empe a u es. On he o he hand,
CMC (mmol/ Kg)
0
1
2
3
8
10
12
14
16
[C2C1Im][C4F9SO3]
[C4C1Im][C4F9SO3]
[C6C1Im][C4F9SO3]
[C8C1Im][C4F9SO3]
[C10C1Im][C4F9SO3]
[C12C1Im][C4F9SO3]
Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
37
he deg ee o coun e ion binding o coun e ions condensed on he micella in e ace, βCMC, can be
de e mined hough he ela ionship (4):
𝜷𝑪𝑴𝑪 = 𝟏−𝜶𝑪𝑴𝑪 Equa ion 2.5.
This pa ame e , βCMC, is ela ed o he size o he agg ega e, he cha ge densi y a he agg ega e su ace,
and he hyd ophobic na u e o he coun e ions (4). FILs wi h long chains can o m bulkie agg ega e
s uc u es, compa a i ely o smalle FILs ([C2C1Im][C4F9SO3]) (30). Then, he numbe o ions pe
agg ega e and he olume pe su ac an ion in he case o [C10C1Im][C4F9SO3] a e highe . Mo eo e ,
he pola headg oups o hese su ac an s a e packed mo e closely and hey a e neu alized by a la ge
ac ion o hei coun e ions (30). Fo he [CnC1Im][C4F9SO3] he αCMC dec eases and βCMC inc eases
wi h he inc ease o he hyd ogena ed alkyl chain up o a decyl (n=10). Howe e , [C12C1Im][C4F9SO3]
does no ollow his end. In o de o unde s and hese esul s, a comp ehensi e s udy needs o be done
o e alua e he αCMC and βCMC alues o he imidazolium-based FILs up o a dodecyl.
Table 2.6. Deg ee o ioniza ion o he agg ega es, αCMC, deg ee o coun e ion binding o ac ion o
coun e ions condensed on he micella in e ace, βCMC, and s anda d ee ene gy o he agg ega ion p ocess,
ΔG0agg, measu ed o FILs in his wo k a 298.15 K and compa ed wi h hose ound on li e a u e* o he
same amily (4,30).
FILs
αCMC

βCMC

ΔG0agg
[C2C1Im][C4F9SO3]*
0.79
0.21
-24.7
[C4C1Im][C4F9SO3]
0.89
0.11
-23.2
[C6C1Im][C4F9SO3]*
0.63
0.37
-29.9
[C8C1Im][C4F9SO3]*
0.38
0.62
-40.3
[C10C1Im][C4F9SO3]
0.35
0.65
-43.8
[C12C1Im][C4F9SO3]*
0.73
0.27
-41.7
The s anda d ee ene gy o he agg ega ion p ocess (ΔG0agg, mmol∙Kg-1) was also calcula ed aking in o
accoun he pseudophase model o micelliza ion (43):
∆𝑮𝒂𝒈𝒈
𝟎=𝑹𝑻(𝟏+𝜷𝑪𝑴𝑪)𝒍𝒏𝒙𝑪𝑴𝑪 Equa ion 2.6.
whe e he R and T a e he uni e sal gas cons an and absolu e empe a u e, espec i ely. The 𝒙𝑪𝑴𝑪 is
he c i ical micella concen a ion exp essed in mole ac ion. Table 2.6. lis s s anda d ee ene gies o
he agg ega ion p ocess o he FILs in his s udy and includes alues o o he FILs aken om he
li e a u e (4,30). The s anda d Gibbs ee ene gy o agg ega ion, ΔG0agg, quan i ies he ee ene gy
di e ence pe mole be ween FIL monome s in aqueous solu ions and in he agg ega es o med (30).
Nega i e alues o his pa ame e indica e spon aneous agg ega ion o hese su ac an s. Conside ing
he ΔG0agg alues he e epo ed, he agg ega ion p ocess is spon aneous as indica ed om he nega i e
Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
38
alues. Addi ionally, an inc ease on he hyd ogena ed alkyl side chain len gh leads o an inc ease o he
agg ega ion p ocess as he ΔG0agg alues become mo e nega i e (30).
In o de o be e unde s and he sel -agg ega ion beha iou o hese FILs based on he
pe luo obu anesul ona e anion, TEM images we e ob ained o he i s ime o [C6C1Im][C4F9SO3],
[C8C1Im][C4F9SO3] and [C12C1Im][C4F9SO3] (see Figu e 2.13). The sel -assembly o
[C2C1Im][C4F9SO3] (Figu e 2.13 a)) was p e iously published (4) and used o compa ison. To ensu e
he micelle o ma ion, he concen a ions used in he aqueous solu ions we e 2-4 imes highe han he
CMC alues p e iously calcula ed.
Figu e 2.13. TEM images o a) [C2C1Im][C4F9SO3] a a concen a ion 2.5 imes highe han CMC (4), b)
[C6C1Im] [C4F9SO3] a a concen a ion 2 imes highe han CMC, c) [C8C1Im] [C4F9SO3] a a concen a ion
4 imes highe han CMC and d) [C12C1Im] [C4F9SO3] a a concen a ion 4 imes highe han CMC. The
scales o images a e 200 nm, 0.5 m, 0.5 m and 1 m, espec i ely.
Analyzing he esul s, i is possible o see ha agg ega es size inc eases wi h he inc emen o he
hyd ogena ed alkyl chain leng h. The [C2C1Im][C4F9SO3] and [C6C1Im] [C4F9SO3] yield a mo e
sphe ical micelle shape whe eas [C8C1Im][C4F9SO3] and [C12C1Im] [C4F9SO3] seem o o m micelles
g owing om sphe ical o globula .
2.5. Conclusions
The main objec i e o his chap e was o cha ac e ize he [C4C1Im][C4F9SO3] and [C10C1Im]
[C4F9SO3] FILs in o de o expand he knowledge on he pe luo obu anesul ona e-based FILs, and o
a)
b)
c)
d)
Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
39
assess hei mos ema kable ea u es in he selec ion o he mos sui able FIL o biomedical
applica ions. The mal and he mophysical p ope ies, as well as hei beha iou on aqueous solu ions
we e s udied. The esul s we e compa ed wi h o he membe s o he [CnC1Im][C4F9SO3] amily o
unde s and how he inc emen o he hyd ogena ed side-chain o he imidazolium ca ion (n=2, 4, 6, 8,
10, and 12) could in luence he beha iou o hese FILs.
Taking in o accoun he he mal p ope ies, bo h [C4C1Im][C4F9SO3] and [C10C1Im] [C4F9SO3] showed
a good he mal s abili y and highe decomposi ion empe a u es. Then, hey can be liquid in a la ge
ange o empe a u es and ye no decompose. Mo eo e , he mel ing empe a u es inc eased wi h he
inc emen o he hyd ogena ed alkyl side-chain leng h and he opposi e beha iou was obse ed o he
decomposi ion empe a u es, as expec ed. The [C4C1Im][C4F9SO3] showed o be a be e op ion in
compa ison wi h [C10C1Im][C4F9SO3] when analysing he he mophysical and he mochemical
p ope ies he e epo ed. In he ange o empe a u es s udied, he inc ease in he hyd ogena ed alkyl
side-chain leng h lead o a dec ease on densi ies and luidi y, being he [C4C1Im][C4F9SO3] wi h a
densi y (≈1.44 g∙cm-3) and luidi y (0.01-0.05 mPa-1∙s-1) close o PFCs 1.7 g∙cm-3 and 0.19-1.67 mPa-
1∙s-1, espec i ely. Mo eo e , conduc i i ies p o en o be be e o luo ina ed ionic liquids wi h sho
hyd ogena ed alkyl side chain leng hs showing highe ionici y.
The agg ega ion beha iou was he e e alua ed by measu emen s o CMC and cha ac e ized by elec on
mic oscopy. The FILs wi h long hyd ogena ed chains ha e smalle CMC and o m mo e s able and
o ganized micelles. These sel -assemblies could in luence he solubili y o FILs in aqueous solu ion
since hey ha e dis inc ea angemen s depending on he hyd ogena ed chain leng h. These indings
co obo a e he esul s om LLE in which he FILs solubili y in he wa e phase appea s o be closely
linked o he hyd ogena ed chain leng h: up o [C6C1Im]+ / [C8C1Im]+ he solubili y inc eases and hen a
u he inc ease on he alkyl chain leads o a inc emen on he solubili y.
2.6. Re e ences
(1) Pe ei o A. B. e al. Fluo ina ed Ionic Liquids: P ope ies and Applica ions. ACS Sus ain. Chem. Eng.
2013, 1, 427–439.
(2) Ta iq, M.; Fo e, P. A. S.; Gomes, M. F. C.; Lopes, J. N. C; Rebelo, L. P. N. Densi ies and Re ac i e
Indices o Imidazolium- and Phosphonium-based Ionic Liquids: E ec o Tempe a u e, Alkyl Chain
Leng h, and Anion. J. Chem. The modyn. 2009, 41, 790–798.
(3) Viei a, N. S. M. e al. A The mophysical and S uc u al Cha ac e iza ion o Ionic Liquids wi h Alkyl
and Pe luo oalkyl Side Chains. RSC Ad . 2015, 5, 65337–65350.
(4) Pe ei o, A. B.; A aújo, J. M. M.; Teixei a, F. S.; Ma ucho, I. M.; Piñei o, M. M; Rebelo, L. P. N.
Agg ega ion Beha io and To al Miscibili y o Fluo ina ed Ionic Liquids in Wa e . Langmui . 2015, 31,
1283–1295.
(5) Viei a, N. S. M. e al. Fluo ina ion E ec s on he The modynamic, The mophysical and Su ace
P ope ies o Ionic Liquids J. Chem. The modyn. 2016, 97, 354–361.

Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
40
(6) K a , M. P.; Riess, J. G. Pe luo oca bons: Li e Sciences and Biomedical Uses. J. PJ Polym. Sci.
Pa B: Polym. Phys. 2007, 45, 1185–1198.
(7) Jin, W. e al. Sel -assembly Induced Solubiliza ion o D ug-like Molecules in Nanos uc u ed Ionic
Liquids. Chem. Commun. 2015; 51, 13170–13173.
(8) Ma ucho, I. M.; B anco, L. C.; Rebelo, L. P. N. Ionic Liquids in Pha maceu ical Applica ions. Annu.
Re . Chem. Biomol. Eng. 2014, 5, 527–546.
(9) Fukumo o, K.; Yoshizawa, M.; Ohno, H. Room Tempe a u e Ionic Liquids om 20 Na u al Amino
Acids. J. Ame . Chem. Soc. 2005, 127, 2398–2399.
(10) Łuczak, J; Paszkiewicz, M.; K ukowska, A.; Malankowska, A.; Zaleska-Medynska, A. Ionic liquids
o Nano- and Mic os uc u es P epa a ion. Pa 1: P ope ies and Mul i unc ional Role. Ad . Colloid
In e ace Sci. 2016, 230, 13–28.
(11) Phillips, J. N. The Ene ge ics o Micelle Fo ma ion. T ans. Fa aday Soc. 1955, 51 ,561-569.
(12) Plechko a, N. V.; Seddon, K. R. Applica ions o Ionic Liquids in he Chemical Indus y. Chem.
Soc. Re . 2008, 37, 123–150.
(13) Riess, J. G.; K a , M. P. Fluo ina ed Ma e ials o In i o Oxygen T anspo (Blood Subs i u es),
Diagnosis and D ug Deli e y. Bioma e ials. 1998, 19, 1529–1539.
(14) K a , M. P. Fluo oca bons and Fluo ina ed Amphiphiles in D ug Deli e y and Biomedical
Resea ch. Ad . D ug Deli . Re . 2001, 47, 209–228.
(15) Owens, C. D.; Rybicki, F. J.; Wake, N.; Schanze , A.; Ge ha d-he man, M. D.; Con e, M. S. Ea ly
Remodelling o Lowe Ex emi y Vein G a s: In lamma ion In luences Biomechanical Adap ion. J.
Vasc. Su g. 2008, 47, 1235–1242.
(16) Dias, A. M. A. e al. Densi ies and Vapo P essu es o Highly Fluo ina ed Compounds. J. Chem.
Eng. Da a. 2005, 50, 1328–1333.
(17) Melo ose, J.; Pe oy, R.; Ca eas, S.; Endo helium : molecula aspec s o me abolic diso de s. CRC
P ess. 2015.
(18) F ei e, M. G.; Fe ei a, A. G. M.; Fonseca, I. M. A.; Ma ucho, I. M.; Cou inho, J. A. P. Su ace
Tension o Liquid Fluo ocompounds. J. Chem. Eng. Da a. 2008, 53, 538–542.
(19) Rod íguez, H.; B ennecke, J. Tempe a u e and Composi ion Dependence o he Densi y and
Viscosi y o Bina y Mix u es o Wa e + Ionic Liquid. J. Chem. Eng. 2006, 2145–2155.
(20) Ge, M.; Ren, X.; Song, Y. Densi ies and Viscosi ies o 1-P opyl-2,3-dime hylimidazolium
Te a luo obo a e + H2O a T = (298.15 o 343.15) K. 1400 J. Chem. Eng. Da a 2009, 54, 1400–1402.
(21) Ca alho, P. J.; Reguei a, T.; San os, L. M.; Fe nandez, J; Cou inho J. A. P. E ec o Wa e on he
Viscosi ies and Densi ies o 1-Bu yl-3-me hylimidazolium Dicyanamide and 1-Bu yl-3-
me hylimidazolium T icyanome hane a A mosphe ic P essu e. J. Chem. Eng. Da a. 2010, 55, 645–652.
(22) Ne es, C. M. S. S.; Ca alho, P. J.; F ei e, M. G.; Cou inho, J. A. P. The mophysical P ope ies o
Pu e and Wa e -sa u a ed Te adecyl ihexylphosphonium-based Ionic Liquids. J. Chem. The modyn.
2011, 43, 948–957.
(23) Walden P. O ganic Solu ions - and Ionisa ion Mean III. Chap e : In e nal F ic ion and I
Connec ion wi h Conduc i i y. Plenum P ess, 1906.
Ionic Liquids in he De elopmen o No el Bioma e ials
Cha ac e iza ion o Fluo ina ed Ionic Liquids: The mophysical, Phase Equilib ia and Agg ega ion Beha iou
41
(24) MacFa lane, D. R.; Fo sy h, M.; Izgo odina, E. I; Abbo , A. P.; Anna , G.; F ase , K. On he
Concep o Ionici y in Ionic Liquids. Phys. Chem. Chem. Phys. 2009, 11, 4962–4967.
(25) Ueno, K.; Tokuda, H; Wa anabe, M. Ionici y in Ionic Liquids: Co ela ion wi h Ionic S uc u e and
Physicochemical P ope ies. Phys. Chem. Chem. Phys., 2010, 12, 1649–1658.
(26) Flo indo, C. e al. E alua ion o Solubili y and Pa i ion P ope ies o Ampicillin-based Ionic
Liquids. In . J. Pha m. 2013, 456, 553–559.
(27) Papaiconomou, N e al. The E ec o Posi ion and Leng h o Alkyl Subs i uen s in Py idinium
based Ionic Liquids on Tempe a u e Dependen T anspo P ope ies Elec ochim. Ac a. 2012, 70, 124–
130.
(28) Xu, W.; Coope , E. I.; Angell, C. A. Ionic Liquids:  Ion Mobili ies, Glass Tempe a u es, and
F agili ies. J. Phys. Chem. B. 2003, 107, 6170–6178.
(29) Ma inho, S.; A aújo, J. M. M.; Rebelo, L. P. N.; Pe ei o, A. B.; Ma ucho, I. M. (Liquid + liquid)
Equilib ia o Pe luo oca bons wi h Fluo ina ed Ionic Liquids. J. Chem. The modyn. 2013, 64, 71–79.
(30) Teixei a, F. S. e al. Phase Equilib ia and Su ac an Beha io o Fluo ina ed Ionic Liquids wi h
Wa e . J. Chem. The modyn. 2015, 82, 99–107.
(31) Najdano ic-Visak, V.; Lopes, J. N. C.; Visak, Z. P.; T indade, J.; Rebelo, L. P. N. Sal ing-ou in
Aqueous Solu ions o Ionic Liquids and K3PO4: Aqueous Biphasic Sys ems and Sal P ecipi a ion. In .
J. Mol. Sci. 2007, 8, 736–748.
(32) F ei e, M. G.; Ne es, C. M. S. S.; Lopes, J. N. C.; Ma ucho, I. M.; Cou inho, J. A. P.; Rebelo, L.
P. N. Impac o Sel -Agg ega ion on he Fo ma ion o Ionic-Liquid-Based Aqueous Biphasic Sys ems.
J. Phys. Chem. B. 2012, 116, 7660-7668.
(33) Luís, A. e al. In luence o Nanoseg ega ion on he Su ace Tension o Fluo ina ed Ionic Liquids.
Langmui . 2016, 32, 6130−6139.
(34) Pe ei o A. B. e al. On he Fo ma ion o a Thi d, Nanos uc u ed Domain in Ionic Liquids. J. Phys.
Chem. B. 2013, 117, 10826–10833.
(35) Shen, Y. e al. P o ic Ionic Liquids wi h Fluo ous Anions: Physicochemical P ope ies and Sel -
assembly Nanos uc u e. Phys. Chem. Chem. Phys. 2012, 14, 7981-7992.
(36) Si ap agasam, M.; Moni uzzaman, M.; Go o, M. Recen Ad ances in Exploi ing Ionic Liquids o
Biomolecules: Solubili y, S abili y and Applica ions. Bio echnol. J. 2016, 1–14.
(37) González-Pé ez, A.; Ruso, J. M.; P ie o, G.; Sa mien o. F. Appa en Mola Quan i ies o Sodium
Oc anoa e in Aqueous Solu ions. J. M. Colloid Polym. Sci. 2004, 282, 1133–1139.
(38) López-Fon án, J. L.; Sa mien o, F.; Schulz, P. The Agg ega ion o Sodium Pe luo ooc anoa e in
Wa e . Colloid Polym. Sci. 2005, 283, 862–871.
(39) Szajdzinska-Pie ek, E.; Wolszczak, M. Time-Resol ed Fluo escence Quenching S udy o Aqueous
Solu ions o Pe luo ina ed Su ac an s wi h he Use o P o ia ed Luminopho e and Quenche .
Langmui . 2000, 16, 1675-1680.
(40) K a , M. P.; Chi o a i, A.; Riess, J. G. Syn hesis o O de ed Mesopo ous Ma e ials using
Su ac an Liquid C ys als o Micella Solu ions. Colloid and In e ace Sci. 2003, 8, 145-155.
Ionic Liquids in he De elopmen o No el Bioma e ials
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43
3.Pa i ion P ope ies o Fluo ina ed
Ionic Liquids
Ionic Liquids in he De elopmen o No el Bioma e ials
Pa i ion P ope ies o Fluo ina ed Ionic Liquids
50
In Figu e 3.3. i is possible o obse e he ends o he Kow alues wi h he s udied ange o FILs
concen a ions. In all cases no subs an ial di e ences we e ound. Then i can be concluded ha o he
ange o concen a ions he ein s udied, Kow is concen a ion independen and can be de e mined.
Figu e 3.3. Va ia ion o Kow wi h concen a ion o he s udied FILs.
The in luence o he alkyl side chain leng h o he imidazolium ca ion on he Kow alue is also an
impo an pa ame e o ake in o conside a ion. Thus, he [CnC1Im] [C4F9SO3] amily (n=2, 4, 6 and 8)
was s udied. Taking he analysis o he esul s in o conside a ion (see Figu e 3.4.), i is possible o e i y
ha he inc emen o he alkyl side chain p o ides an inc ease on Kow alues. By de ini ion, i he Kow is
≥ 1 (Log Kow > 0) i is expec ed ha all he es compound emain in he oc anol-phase (see Equa ion
3.1) demons a ing a lipophilic beha iou (12). Thus, a end ega ding lipophilici y o he es
compounds could be made, since alkyl chains highe han an oc yl (n=8) could be conside ed lipophilic.
Figu e 3.4. In luence o he imidazolium hyd ogena ed side-chain leng h on Kow alues.
A change om [C2C1Im][C4F9SO3] o [C8C1Im][C4F9SO3] leads o an inc ease o lipophilici y wi h a
Kow app oxima ely 6 imes highe . This beha iou is explained since alkyl chain leng h o he ca ionic
Concen a ion (mol/L)
0.00 5.00e-4 1.00e-3 1.50e-3 2.00e-3
Log Kow
-1.8
-0.9
0.0
0.9
1.8
[C2C1Im][C4F9SO3]
[C4C1Im][C4F9SO3]
[C6C1Im][C4F9SO3]
[C8C1Im][C4F9SO3]
[C2C1py][C4F9SO3]
[C2C1Im][C8F17SO3]
Log Kow
-1.6
-1.0
-0.4
0.2
0.8 Lipophilic
Hyd ophilic
[C2C1Im][C4F9SO3]
[C4C1Im][C4F9SO3]
[C6C1Im][C4F9SO3]
[C8C1Im][C4F9SO3]

Ionic Liquids in he De elopmen o No el Bioma e ials
Pa i ion P ope ies o Fluo ina ed Ionic Liquids
51
ing c ea es s ong an de Waals in e ac ions be ween he alkyl g oup o he FIL and he hyd ophobic
pa o 1-oc anol (11,18). These esul s a e consis en wi h he indings o o he au ho s o con en ional
ILs wi h luo ina ed anions such as bis( i luo ome hylsul onyl)imide, [NT 2]-, (20)
hexa luo ophospha e, [PF6]-, and e a luo obo a e, [BF4]- (21) as well as o ionic liquids in gene al (12,
14). Mo eo e , Ropel e al. epo ed ha solubili y o imidazolium based ionic liquids in alcohols
inc eases wi h alkyl chain leng h (18).
The dis ibu ion and posi ion o he luo ine a oms, as well as he amoun o luo ina ion, a e known o
a ec he lipophilic beha iou (22). The e o e, he e ec o changing a pe luo obu anesul ona e,
[C4F9SO3]-, o a pe luo oc anesul ona e anion, [C8F17SO3]-, was analysed. The inc ease o he
luo ina ed chain leng h o he anion p omo es an ex eme dec ease o he hyd ophilici y. The Kow alue
o he [C8F17SO3]-based FIL is app oxima ely 16 imes highe han he [C4F9SO3]-based FIL, as shown
in Figu e 3.5..
Figu e 3.5. In luence o he luo ina ed chain leng h on Kow alues.
These ends a e consis en wi h he li e a u e and ollow an empi ical ule which dic a es ha a luo ine
con en ep esen ing ca. 60% o he o al molecula weigh can in luence he hyd ophilici y beha iou
o he compound (23). In his case, he [C2C1Im][C4F9SO3] exhibi ed 41.6 %w and [C2C1Im][C8F17SO3]
52.9 %w . Pu se e al. epo ed ha a oma ic luo ina ion, pe /poly luo ina ion and luo ina ion adjacen
o a oms wi h π-bonds (as p esen on he imidazolium ca ion) exponen ially inc eases lipophilici y (24).
This beha iou is due o he excellen o e lap be ween he luo ine 2s o 2p o bi als wi h he
co esponding o bi als on ca bon, making he C–F bond highly non-pola izable, he eby con ibu ing o
inc eased lipophilici y (24). In addi ion, he Kow o 1-bu yl-3-me hyilimidazolium
i luo ome hylsul ona e [C4C1Im][CF3SO3] was no measu ed in his wo k bu can be ound in he
li e a u e wi h a alue o 0.20 (20). Thus, compa ing ou measu emen s o [C4C1Im][C4F9SO3], wi h a
Kow o 0.43, he same end can be seen. The o e me hyla ion and luo ina ion o he ca ion enhances
FIL solubili y in lipophilic cons i uen s which will allow hei en y in cells (10,22).
Log Kow
-1.6
-1.0
-0.4
0.2
0.8
[C2C1Im][C4F9SO3]
[C2C1Im][C8F17SO3]
Lipophilic
Hyd ophilic
Ionic Liquids in he De elopmen o No el Bioma e ials
Pa i ion P ope ies o Fluo ina ed Ionic Liquids
52
The las s udy was ca ied ou in o de o unde s and how he ca ionic ing p esen in FILs can in luence
he hyd ophilici y. Conside ing [C4F9SO3]-based FILs, he imidazolium ([C2C1Im]+) and py idinium
([C2C1py]+) ca ions we e compa ed. Bo h ionic liquids p esen a highly hyd ophilic beha iou (see
Figu e 3.6.). In he li e a u e, he same end o imidazolium and py idinium-based ILs was obse ed
(20,21). Mon albán e al. mesu ed he Kow o [C4C1py][BF6] and [C4C1Im][BF6] (21) and Lee e al. o
[C6C1py][NT 2] and [C6C1Im][NT 2](20). Bo h au ho s demons a ed ha he Kow o imidazolium-based
ILs a e sligh ly highe when compa ed o py idinium.
Figu e 3.6. E alua ion o Kow alues o imidazolium and py idinium [C4F9SO3]-based FILs.
3.5 Conclusion
Compounds wi h low Kow can p e en bioaccumula ion on human cells and ensu e a sui able
ci cula ion o he compounds in he blood s eam (10). Thus, [C2C1Im][C4F9SO3] and
[C2C1py][C4F9SO3] wi h Kow ≤ 0.3 a e he mos sui able FILs o he de elopmen o a d ug coa ing
de ice. Fo ins ance, using hose FILs d ugs a e deli e ed in o he issues bu he compounds a e kep
in he blood s eam. On he o he hand, i an API is conjuga ed wi h a FIL a high Kow
([C2C1Im][C8F17SO3] o [C8C1Im][C4F9SO3]) is equi ed. In his way, he FIL enhance he pe mi i i y
o he d ug hough cellula memb anes (6).
Fo he [CnC1Im][C4F9SO3] amily, a u he inc ease o he alkyl chain leng h (up o an oc yl,
n=8), FILs concen a ions in oc anol a e highe sugges ing a lipophilic beha iou . Conce ning he
anionic luo ina ed chain, when compa ing [C4F9SO3]- and [C8F17SO3]- anions he Kow alues we e
app oxima ely 15 imes highe . Thus, by inc easing luo ina ion on he FIL anion lipophilici y is
enhanced. Finally, bo h sho alkyl chain leng h FILs based on imidazolium and py idinium wi h a
pe luo obu anesul ona e anion p esen ed a highly hyd ophilic beha iou .
Log Kow
-1.6
-1.0
-0.4
0.2
0.8 Lypophilic
Hyd ophilic
[C2C1Im][C4F9SO3]
[C2C1py][C4F9SO3]
Ionic Liquids in he De elopmen o No el Bioma e ials
Pa i ion P ope ies o Fluo ina ed Ionic Liquids
53
3.6 Re e ences
(1) Lipinski, C. A.; Lomba do, F.; Dominy, B. W.; Feeney, P. J. Expe imen al and Compu a ional
App oaches o Es ima e Solubili y and Pe meabili y in D ug Disco e y and De elopmen Se ings. Ad .
D ug. Deli . Re . 2012, 64, 4-17.
(2) Mizuuch, H.; Jai ely, S.; Mu dan, S.; Flo ence, A.T. Room Tempe a u e Ionic Liquids and Thei
Mix u es: Po en ial Pha maceu ical Sol en s. Pha m. Sci., 2008, 33, 326–331.
(3) Moni uzzaman, M.; Kamiya, N.; Go o, M. Ionic Liquid Based Mic oemulsion Wi h
Pha maceu ically Accep ed Componen s: Fo mula ion and Po en ial Applica ions J. Colloid In e ace
Sci., 2010, 352, 136–142.
(4) Moni uzzaman, M.; Tamu a, M.; Taha a, Y; Kamiya, N.; Go o, M. Ionic Liquid-in-Oil
Mic oemulsion as a Po en ial Ca ie o Spa ingly Soluble D ug: Cha ac e iza ion and Cy o oxici y
E alua ion. In . J. Pha m., 2010, 400, 243–250.
(5) Jai ely, V.; Ka a as, A.; Flo ence, A. T. Wa e -immiscible Room Tempe a u e Ionic Liquids (RTILs)
as D ug Rese oi s o Con olled Release. In . J. Pha m., 2008, 354, 168–173.
(6) A aújo J. M. M.; Flo indo, C.; Pe ei o, A. B.; Viei a, N. M. S.; Ma ias, A. A.; Dua e, C. M. M.;
Rebelo, L. N. R.; Ma ucho, I. M. Cholinium-based Ionic Liquids wi h Pha maceu ically Ac i e Anions
RSC Ad ., 2014, 4, 28126–28132.
(7) Flo indo, C. e al. E alua ion o Solubili y and Pa i ion P ope ies o Ampicillin-based Ionic
Liquids. In . J. Pha m. 2013, 456, 553–559.
(8) Fe az, R.; B anco, L. C. B.; Ma ucho, I. M. De elopmen o No el Ionic Liquids Based on
Ampicillin. Med. Chem. Commun., 2012, 3, 494-497.
(9) Boe hling, R. S.; Mackay, D.; Lyman, W. J. Handbook o p ope y es ima ion me hods o chemicals:
en i onmen al and heal h sciences; 2000, CRC p ess.
(10) Finizio, A.; Vighi, M.; Sand oni, D. De e mina ion o n-Oc anol/Wa e Pa i ionCoe icien (Kow)
o Pes icide: C i ical Re iew and Compa ison o Me hods. Chemosphe e. 1997; 34; 131–161.
(11) Jain, P.; Kuma , A. Concen a ion-Dependen Appa en Pa i ion Coe icien s o Ionic Liquids
Possessing E hyl- and Bi-sulpha e Anions. Phys. Chem. Chem. 2016, 18, 1105–13.
(12) Lee, S. H.; Lee. S. B. Oc anol/Wa e Pa i ion Coe icien s o Ionic Liquids. J. Chem. Technol.
Bio echnol. 2009, 84, 202–207.
(13) Kdd mann, T.; Rei h, D.; A nold, A. Why he Pa i ion Coe icien o Ionic Liquids Is
Concen a ion-Dependen . J. Phys. Chem. B. 2013, 117, 10711−10718.
(14) Kah, M.; B own, C. D. LogD: Lipophilici y o Ionisable Compounds. Chemosphe e. 2008, 72,
1401–1408.
(15) Poole, S. K.; Poole, C. F. Sepa a ion Me hods o Es ima ing Oc anol–Wa e Pa i ion Coe icien .
J. Ch oma og . B. 2003, 797, 3–19.
(16) Ing am, T.; Rich e , U.; Mehling, T.; Smi no a. I. Modelling o pH Dependen n-Oc anol/Wa e
Pa i ion Coe icien s o Ionizable Pha maceu icals. Fluid Phase Equilib. 2011, 305, 197–203.
(17) B uijn, J.; Busse , F.; Seinen, W.; He mens, J. De e mina ion o Oc anol/Wa e Pa i ion
Ionic Liquids in he De elopmen o No el Bioma e ials
Pa i ion P ope ies o Fluo ina ed Ionic Liquids
54
Coe icien s o Hyd ophobic O ganic Chemicals wi h he “Slow-s i ing” Me hod. En i on. Toxicol.
Chem. 1989, 8, 499–512.
(18) Ropel, L.; Bel èze, L. S.; Aki, S. N. V. K.; S ad he , M. A.; B ennecke, J. F. Oc anol–Wa e
Pa i ion Coe icien s o Imidazolium-based Ionic Liquids. G een Chem. 2005, 7, 83–90.
(19) Fukumo o, K.; Yoshizawa, M.; Ohno, H. Room Tempe a u e Ionic Liquids om 20 Na u al Amino
Acids. J. Ame . Chem. Soc. 2005, 127, 2398–9.
(20) Lee, B. S.; Lin, S. T. A p io i Pedic ion o he Oc anol-Wa e Pa i ion Coe icien (Kow) o Ionic
Liquids. Fluid. Phase. Equilib. 2014, 363, 233–8.
(21) Mon albán, M. G.; Collado-González M.; T igo, R.; Díaz, F. G. B.; Víllo a, G. Expe imen al
Measu emen s o Oc anol-Wa e Pa i ion Coe icien s o Ionic Liquids. J. Ad . Chem. Eng. 2015, 5.
(22) Jeschke, P. The Unique Role o Fluo ine in he Design o Ac i e Ing edien s o Mode n C op
P o ec ion. Chem. Bio. Chem. 2004, 5, 570–89.
(23) Ojogun, V.; Knu son, B. L.; Vyas, S.; Lehmle , H. J. Fluo ophilici y o Alkyl and Poly luo oalkyl
Nico inic Acid Es e P od ugs. J. Fluo . Chem. 2010, 131, 784–790.
(24) Pu se , S.; Moo e, P. R.; Swallow, S.; Gou e neu , V. Fluo ine in Medicinal Chemis y. Chem.
Soc. Re . 2008, 37, 320–330.
55
4.Kamle -Ta Sol a och omic
Pa ame e s o Fluo ina ed Ionic
Liquids

56
Ionic Liquids in he De elopmen o No el Bioma e ials
Kamle -Ta Sol a och omic Pa ame e s o Fluo ina ed Ionic Liquids
57
4.1 In oduc ion
Recen ly, ionic liquids a e becoming o pa icula in e es as new and highly e icien sol en s
o co-sol en s o biomolecule-based applica ions due o hei unique cha ac e is ics and
biocompa ibili y (1). Using ILs can d ama ically enhance solubili y and s abili y o p o eins (2), DNA
(3) and enzymes (4). The key cha ac e is ics o a sol en a e hose ha de e mine how i will in e ac
wi h po en ial solu es. Pola i y scales ha e been used o desc ibe he a ini y o solu es o molecula
sol en s as well as ionic liquids (5).
One o he mos used pola i y scales was de ised by Kamle and Ta in 1975 (6). The Kamle -Ta
me hod is based on he compa ison o he e ec s on he UV- is spec a o se s o dyes. Th ee pola i y
pa ame e s ha e been p oposed: he dipola i y/pola izabili y e ec s (

); he hyd ogen bond acidi y (

),
ha is, hyd ogen bond dona ion (HBD) abili y; and he hyd ogen bond basici y (

), ha is, hyd ogen
bond accep ance (HBA) o elec on pai dona ion abili y o o m a coo dina ion bond (6). I should be
highligh ed ha he hyd ogen bond accep o s eng h o an IL is domina ed by he anion while he
hyd ogen bond dono abili y is essen ially con olled by he ca ion (7). Howe e , ca ion-anion
in e ac ions could in luence he IL’s abili y o hyd ogen bonding (7). In addi ion, he Kamle -Ta
desc ip o s p o ed o be empe a u e dependen (8,9).
The hyd ogen bond accep o capaci y,

, can be measu ed by compa ison o ʎmax alues o a
homomo phic pai o sol a och omic dyes such as 4-ni oaniline/N,N-die hyl-4-ni oaniline. In Figu e
4.1 a e illus a ed he 4-ni oaniline (Figu e 4.1a)) and he N,N-die hyl-4-ni oaniline (Figu e 4.1b)).
In ed is ep esen ed he chemical bond ha is he o igin o he sol a och omic ansi ion (10).
Figu e 4.1. Chemical s uc u es o a) 4-ni oaniline and b) N,N-die hyl-4-ni oaniline. The ed line a
he ni o oxygen ep esen he sol a och omic ansi ion.
Measu emen s o he in amolecula cha ge- ans e

→

* by he 4-ni oaniline and N,N-die hyl-4-
ni oaniline ʎmax can deduce he elemen o wa eleng h change due o hyd ogen bonding (10). In
a)
b)
Ionic Liquids in he De elopmen o No el Bioma e ials
Kamle -Ta Sol a och omic Pa ame e s o Fluo ina ed Ionic Liquids
58
Equa ion 4.1., he ela ionship be ween he maximum abso p ion wa eleng h o he sol a och omic
dyes (𝒗
) in kilo Kyse s (cm-1), and he maximum abso p ion wa eleng h o he es compound (ʎmax)
in nanome e s (nm) is ep esen ed (8).
𝒗
=𝟏𝟎𝟕
ʎ𝒎𝒂𝒙 Equa ion 4.1.
The hyd ogen bond accep o abili y (β) can be calcula ed by Equa ion 4.2. (8).
𝜷 = 𝟏.𝟎𝟑𝟓𝝂
𝑵−𝑵−𝒅𝒊𝒆𝒕𝒉𝒚𝒍−𝟒−𝒏𝒊𝒕𝒓𝒐𝒂𝒏𝒊𝒍𝒊𝒏𝒆+𝟐.𝟔𝟒−𝝂
𝟒−𝒏𝒊𝒕𝒓𝒐𝒂𝒏𝒊𝒍𝒊𝒏𝒆
𝟐.𝟖𝟎 Equa ion 4.2.
The me hod used o de e mine he hyd ogen bond dona ion capaci y (

) is simila . The sol a och omic
dyes used in his calcula ion a e Reicha d ’s dye (2,6-Diphenyl-4-(2,4,6- iphenyl-1-
py idinio)phenola e) and 4-ni oaniline. In his case hey ac as a non-HBD solu e. In Figu e 4.2. is
illus a ed he chemical s uc u e o Reicha d ’s dye as well as he chemical bond ha is he o igin o
he sol a och omic ansi ion (10).
Figu e 4.2. a) Chemical s uc u e o Reicha d ’s dye and b) he sol a och omic ansi ion in ed.
Reicha d ’s dye exhibi s a la ge sol a och omic ange. The in amolecula cha ge ans e π → π* is
obse ed a ound 500 nm, om ʎmax = 453 nm in wa e (pola sol en ) o ʎmax = 925 nm in hexane
(nonpola sol en ) (10). The 𝐸𝑇
30 is a pola i y scale based only on Reicha d ’s dye and p oposed by
Dim o h e al. o calcula e he α pa ame e o he Kamle -Ta me hod as shown in Equa ion 4.3. and
Equa ion 4.4. (8,10).
𝑬𝑻
𝟑𝟎 =𝟐𝟖𝟓𝟗𝟐
ʎ𝒎𝒂𝒙 Equa ion 4.3.
𝜶 = 𝟎. 𝟎𝟔𝟒𝟗𝑬𝑻
𝟑𝟎 − 𝟐. 𝟎𝟑 − 𝟎. 𝟕𝟐𝝅∗ Equa ion 4.4.
a)
b)
Ionic Liquids in he De elopmen o No el Bioma e ials
Kamle -Ta Sol a och omic Pa ame e s o Fluo ina ed Ionic Liquids
59
The dipola i y/pola izabili y e alua ion is accomplished by he

*-scale. The

* pa ame e is only
dependen on one dye, N-N-die hyl-4-ni oaniline, and i is calcula ed by Equa ion 4.5. (8).
𝝅∗= 𝟎. 𝟑𝟏𝟒(𝟐𝟕.𝟓𝟐 − 𝒗
𝑵,𝑵−𝒅𝒊𝒆𝒕𝒉𝒚𝒍−𝟒−𝒏𝒊𝒕𝒓𝒐𝒂𝒏𝒊𝒍𝒊𝒏𝒆) Equa ion 4.5.
In his chap e , he hyd ogen bond acidi y (

), hyd ogen bond basici y (

) and dipola i y/pola izabili y
(

*) we e i s calcula ed o cha ac e ize pu e luo ina ed ionic liquids. Fu he mo e, he e ec o wa e
on he Kamle -Ta pa ame e s o FILs was e alua ed o add ess he ele ance o designing
unc ionalized (so-called ask-speci ic) ILs ha ha e been syn hesized wi h a pa icula applica ion in
mind.
4.2 Ma e ials
1-E hyl-3-me hylimidazolium i luo ome hanesul ona e, ≥ 99% mass ac ion pu i y; 1-bu yl-
3-me hylimidazolium i luo ome hanesul ona e, ≥ 99% mass ac ion pu i y; 1-e hyl-3-
me hylpy idinium pe luo obu anesul ona e, >99% mass ac ion pu i y; 1-e hyl-3-me hylimidazolium
pe luo obu anesul ona e >97% mass ac ion pu i y; 1-hexyl-3-me hylimidazolium
pe luo obu anesul ona e, > 99% mass ac ion pu i y; 1-oc yl-3-me hylimidazolium
pe luo obu anesul ona e, > 98% mass ac ion pu i y; choline pe luo obu anesul ona e, 97% mass
ac ion pu i y; e abu ylammonium pe luo obu anesul ona e, 98% mass ac ion pu i y;
e abu ylammonium pe luo ooc anesul ona e > 98% mass ac ion pu i y; 1-e hyl-3-
me hylimidazolium ace a e, > 95 % mass ac ion pu i y; 1-e hyl-3-me hylpy idinium b omide, 99 %
mass ac ion pu i y; 1-e hyl-3-me hylimidazolium chlo ide, ≥ 98 %; we e acqui ed om IoLiTec.
Choline chlo ide, ≥ 98% mass ac ion pu i y was acqui ed om Sigma-Ald ich. The pu i y o all ionic
liquids was e i ied by 1H, 13C and 19F NMR. P io o any use, all samples we e d ied unde a 3∙10-2
To acuum and igo ous s i ing o a leas 48 hou s o a oid ola ile impu i ies. Choline and ace a e-
based ILs we e kep a 313.15 K and he emaining ILs a 323.15 K.
The wa e con en was de e mined using Ka l Fiche coulome ic i a ion me hod (Me ohm 831 KF
Coulome e ) o be less han 100 ppm. The s uc u es and ac onyms o he ionic liquids a e lis ed in
Table 4.1.
Table 4.1. Designa ion and chemical s uc u e o each ionic liquid used along his s udy.
IL designa ion
Chemical s uc u e
1-E hyl-3-me hylimidazolium
i luo ome hanesul ona e
[C2C1Im][CF3SO3]
c
Ionic Liquids in he De elopmen o No el Bioma e ials
Kamle -Ta Sol a och omic Pa ame e s o Fluo ina ed Ionic Liquids
66
4.4.1.3. In luence o he Fluo ina ed Chain Leng h o he Anion
I has been epo ed ha he anionic luo ina ed chain leng h has an in luence on he Kamle -
Ta desc ip o s (18). A luo ina ed anionic g oup is capable o addi ional in e ac ions wi h pola
componen s making hem sui able o enhanced solubili y o hyd ophobic bioac i e compounds (21).
Fo ins ance, Ca doso and Micaelo (22) examined he molecula sol a ion o double-s and DNA
(dsDNA) and single-s anded DNA (ssDNA) in nea ILs based on [BF4]- and [PF6]- anions. The au ho s
ound ha ssDNA bases a e p e e en ially sol a ed by he anions ia hyd ogen bonding wi h he luo ine
a oms. He ein, he dependence o he Kamle -Ta desc ip o s on he anion luo ina ed chain leng h in
imidazolium ([CF3SO3]- and [C4F9SO3]-) and e abu ylammonium-based ([C4F9SO3]- and [C8F17SO3]-)
FILs is e alua ed (see Figu e 4.7). The esul s a e lis ed in Table 4.2.
Figu e 4.7. Kamle -Ta pa ame e s, hyd ogen-bond dono (α), hyd ogen-bond accep o (β), and
dipola i y/pola izabili y (π*), measu ed a * 298.15 K o imidazolium-based ILs and a ** 323.15 K
o e abu ylammonium-based ILs.
Inc easing he luo ina ed chain leng h leads o an inc ease o

alues o bo h amilies being he
imidazolium-based ILs he ones wi h a mo e p onounced abili y o dona e hyd ogen bonds. As
men ioned abo e o ammonium-based ILs, he s abiliza ion o he dipola g ound s a e is mainly
o igina ed om coulombic in e ac ions (17). Consequen ly, [N4444]+ is a poo H-bonding dono due o
he lack o acidic hyd ogens compa ed o he imidazolium based ings (see Table 4.1).
In e abu ylammonium-based ILs, he inc ease o luo ina ed chain leng h p oduces an inc ease on
HBA. These esul s a e no su p ising because

alues o his amily mainly depend on he anion (17).
Dipola i y/pola izabili y ( )
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Hyd ogen bond accepo ( )
0.0
0.2
0.4
0.6
0.8
1.0
1.2
Hyd ogen bond dono ( )
0.0
0.2
0.4
0.6
0.8
1.0
1.2
**
*
**
**
*
**
**
*
*** **
[C2C1Im][CF3SO3]
[C2C1Im][C4F3SO3]
[N4444][C4F3SO3]
[N4444][C8F17SO3]

Ionic Liquids in he De elopmen o No el Bioma e ials
Kamle -Ta Sol a och omic Pa ame e s o Fluo ina ed Ionic Liquids
67
The acidi y/basici y is p opo ional o he cha ge densi y o he compound and o he ela i e size- o-
cha ge a io (7). The [C8F17SO3]- anion is la ge han he [C4F9SO3]- anion, which allows a highe
dispe sion o he nega i e cha ges, p omo ing hyd ogen bonding wi h H+ a ailable on he media. Fo
imidazolium-based FILs, i can be concluded ha HBA does no change by inc easing he luo ina ion
o he anion. In ac , he -CF2 added o he anion co e only inc eases he acidi y main aining he FILs
basici y.
Imidazolium-based ILs wi h [NT 2]- and [PF6]- anions p o ed o be use ul o enhance he solubili y o
biomolecules o se e al p ocesses (1). Thus, a compa ison o he α and β alues ob ained o he
imidazolium-based ILs wi h [CF3SO3]- and [C4F9SO3]- anions is made in Figu e 4.8.
Figu e 4.8. Kamle -Ta desc ip o s

and

o 1-e hyl-3-me hylimidazolium based ILs wi h
luo ina ed anions. The

and

o [CF3SO3]- and [C4F9SO3]- we e ob ained in his wo k. The alues
o *[PF6]- (16) and †[NT 2]- (20) we e ob ained om he li e a u e.
In Figu e 4.8. an acidi y (

) and basici y (

) scale is ep esen ed. Analyzing he ILs o e all i is possible
o obse e he possibili y o manage he inal cha ac e is ics o he compounds hough he di e se
combina ion o he anions. The [C2C1Im][C4F9SO3] p o ed o be he mos acidic and basic in which
hyd ogen bonding is mo e a o able. This esul could be use ul when add essing he design o
unc ionalized ILs wi h a pa icula applica ion in mind.
Fo ins ance, he hyd ogen bonding capaci y o nucleobases is esponsible o co ec DNA base-pai ing
and s uc u e s abiliza ion (22). A aújo e al. (5) in es iga ed he sol a ion o nucleobases and concluded
ha he ionic liquid mus be a good hyd ogen bond accep o and mode a e bond dono o dissol e he
nucleobases. In addi ion, a high-HBA ionic liquid can s ongly coo dina e he HBD g oups o cellulose
and igge solu e-sol en in e ac ions ha a e equi ed o cellulose dissolu ion (8). In some cases, a
s ong hyd ogen bonding abili y is also ela ed o enzyme dena u a ion, which lowe s he enzyma ic
Ionic Liquids in he De elopmen o No el Bioma e ials
Kamle -Ta Sol a och omic Pa ame e s o Fluo ina ed Ionic Liquids
68
ac i i y (1). On he o he hand, in hyd ophobic ILs media (lowes

and

) enzymes can e ain hei
ac i i y and hei s abili y is enhanced in compa ison wi h adi ional sol en s (1).
4.4.2 Kamle -Ta Sol a och omic Pa ame e s o Aqueous Solu ions o
Fluo ina ed Ionic Liquids
Ionic liquids usually ha e high iscosi ies and high pola i ies due o hei cha ged s uc u es and
ela i ely s ong anion-ca ion in e ac ions (2). Howe e , adding wa e in o hyd ophilic ionic liquids a
dec ease in hei iscosi y is no iced (23). Ne e heless, IL + wa e mix u es can s ill exhibi sa is ac o y
ex ac ion e iciency o pola bioac i e compounds (24).
The hyd ogen-bond basici y (

) i is one o he mos impo an pa ame e s e lec ing he hyd ogen bond
accep ing abili y o he IL anion (7). Mos o he ele an p ope ies o ILs ega ding he solu e-sol en
in e ac ion a e signi ican ly de e mined by he na u e o he anion a he han he ca ion (18). In ac , he

pa ame e is widely used o explain (and co ela es wi h) di e se p ope ies, such as sol a ion abili y
and phase equilib ium beha io o ILs (25, 26).
A good example o he applica ion o sol a och omic pola i y scales o ionic liquids a e he s udies
ocused on he cellulose solubili y in 1,3-dialkylimidazolium-based ILs. The measu emen o Kamle -
Ta pa ame e s showed ha ILs cha ac e ized by a high β pa ame e , indica ing an inc ease in he
hyd ogen bonding accep ing capabili y o he anion, displayed inc eased cellulose solubili y (5). The IL
1-e hyl-3-me hylimidazolium ace a e ([C2C1Im][C1CO2] ep esen ed in Table 4.1), cha ac e ized by a
high

pa ame e , has been inc easingly ecognized as a p omising sol en and can be ega ded as an
enzyme- iendly co-sol en o bioca alysis as well as a good sol en o biomac omolecules such as
cellulose and sube in, DNA, p o eins, small solu es such as ca bohyd a es, and nucleic acid bases and
has signi ican abili y o sou gas seques a ion (27). Recen ly, Dohe y e al. (8) demons a ed ha he
β pa ame e p o ides a measu e o he e iciency o ILs o se e as sol en in lignocellulosic biomass
p e ea men . The ex ac ion powe o lignin and yields o e men able suga we e epo ed o inc ease
among wi h he β alue. Mo eo e , hese au ho s epo ed ha he addi ion o wa e in o ILs has he
g ea es impac on he β pa ame e (8) mainly due o he ela i ely poo hyd ogen bond basici y o wa e
(

= 0.14–0.18) (2).
Among ionic liquids, β displays he g ea es a ia ion compa ed o α and π* alues when wa e is added
o he sys em (8). In his sec ion he Kamle -Ta desc ip o s we e measu ed o wa e mix u es wi h
luo ina ed ionic liquids and con en ional ionic liquids (see Table 4.3). In his way, i could be assessed
how IL+ wa e sys em can in luence he hyd ogen bond capaci y and pola izabili y. The main aim o
his s udy is o design an IL ha do no loses he β p ope y in aqueous solu ions, add essing he design
o unc ionalized (so-called ask-speci ic) ILs ha ha e been syn hesized wi h a pa icula applica ion
in mind.
Ionic Liquids in he De elopmen o No el Bioma e ials
Kamle -Ta Sol a och omic Pa ame e s o Fluo ina ed Ionic Liquids
69
Table 4.3. Kamle -Ta pa ame e s hyd ogen-bond dono , α, hyd ogen-bond accep o , β, and
dipola i y/pola izabili y, π*, de e mined o he aqueous solu ions wi h FILs and con en ional ILs a
298.15 K.
Wa e
(w %)
α
RSD
(%)
β
RSD
(%)
π*
RSD
(%)
Wa e
(w %)
α
RSD
(%)
β
RSD
(%)
π*
RSD
(%)
[C2C1Im][CF3SO3]
[C4C1Im][CF3SO3]
Nea
0.62
3.59
0.48
1.25
1.02
0.09
Nea
0.62
3.87
0.48
0.80
1.02
0.09
12
0.74
1.79
0.45
6.74
1.10
1.68
10
0.72
0.19
0.45
0.77
1.08
0.18
31
0.84
0.63
0.39
3.55
1.19
0.35
30
0.78
0.47
0.40
0.59
1.17
0.01
50
0.85
0.29
0.35
2.11
1.25
0.08
50
0.77
0.06
0.36
0.31
1.22
0.01
69
0.80
0.66
0.29
0.59
1.32
0.08
70
0.75
0.03
0.26
4.95
1.31
0.26
[C2C1py][C4F9SO3]
[C2C1Im][C4F9SO3]
Nea
0.62
1.01
0.50
0.48
0.94
0.10
Nea
0.76
0.13
0.48
1.24
0.89
0.05
14
0.86
1.09
0.49
1.59
1.07
0.20
9
0.99
0.13
0.49
1.48
1.01
0.11
31
0.92
0.43
0.49
0.49
1.09
0.50
30
1.00
1.14
0.48
4.53
1.06
0.21
50
0.96
0.31
0.50
0.37
1.08
0.20
50
1.03
0.43
0.49
1.33
1.05
0.53
67
1.07
3.87
0.50
1.15
1.08
0.10
70
0.98
0.32
0.53
0.53
1.06
0.00
[N1112OH][C4F9SO3]
[C2C1Im] C1CO2
10
1.14
0.21
0.42
0.50
1.05
0.32
11
0.49
0.44
0.91
0.15
1.11
0.00
30
1.14
1.02
0.46
8.53
1.06
0.42
22
0.58
0.76
0.67
0.65
1.22
0.17
50
1.14
0.13
0.46
1.83
1.05
0.53
44
0.53
0.14
0.49
1.47
1.31
0.08
69
1.13
0.37
0.48
2.09
1.04
0.21
70
0.82
0.09
0.37
4.25
1.34
0.08
[N1112OH] Cl
[C2C1Im] Cl
24
0.95
0.51
0.48
0.23
1.21
0.61
25
0.52
0.01
0.55
1.69
1.27
0.16
32
0.94
0.04
0.40
0.30
1.24
0.00
30
0.51
0.01
0.47
1.25
1.31
0.07
36
0.96
0.79
0.38
2.95
1.25
0.08
35
0.66
0.96
0.50
1.24
1.31
0.31
51
0.97
0.04
0.30
0.40
1.29
0.00
52
0.69
0.09
0.37
1.65
1.35
0.06
71
0.94
0.26
0.22
0.71
1.32
0.26
72
0.80
0.25
0.20
2.01
1.40
0.24
[C2C1py] B
24
0.54
0.92
0.48
0.71
1.35
0.30
32
0.57
0.45
0.42
0.47
1.37
0.12
35
0.62
0.84
0.45
0.92
1.39
0.00
52
0.70
1.20
0.36
1.98
1.42
0.07
71
0.91
1.84
0.28
2.53
1.39
0.00
Ionic Liquids in he De elopmen o No el Bioma e ials
Kamle -Ta Sol a och omic Pa ame e s o Fluo ina ed Ionic Liquids
70
4.4.2.1 In luence o he Imidazolium, Py idinium and Cholinium Ca ion
In Figu e 4.9 i is possible o obse e he ends o [C2C1Im][C4F9SO3], [C2C1py][C4F9SO3]
and [N1112OH][C4F9SO3] ega ding hei

,

and

desc ip o s. [N1112OH][C4F9SO3] wi h a mel ing
empe a u e o o 436 K (14), is solid a oom- empe a u e, hus measu ed o his nea FIL we e no
accomplish.
Figu e 4.9. Kamle -Ta pa ame e s, hyd ogen-bond dono (α), hyd ogen-bond accep o (β), and
dipola i y/pola izabili y (π*), measu ed a oom- empe a u e o py idinium, imidazolium and choline-
based FILs a di e en aqueous concen a ions a 298.15 K.
The choline-based ILs ha e he highe

alues compa ed o imidazolium and py idinium. Tha esul
is no su p ising since choline i sel has a pe manen dipole momen p omo ed by he non-symme ical
s uc u e and, in pa icula due o i s e minal OH g oup, inc easing he acidi y (28). Then,
[N1112OH][C4F9SO3] has an inc eased abili y o dona e hyd ogen bonds lowed by he imidazolium and
py idinium-based FILs. Fo all FILs ep esen ed in Figu e 4.9, he

and π* alues inc ease only a low
dilu ions and emain s able when inc easing he wa e con en . Thus, he addi ion o wa e in o nea FILs
enhances hei HBD and pola izabili y.
As discussed abo e, he β pa ame e is mainly de e mined by he o igin o he anion (18) and so no
signi ican di e ences a e ound on HBA o he [C4F9SO3]- based FILs. In ac , no clea impac is
obse ed in he

endency in opposi ion o con en ional ILs, whe e he addi ion o wa e has he g ea es
impac on he HBA abili y (26). This beha io will be discussed in sec ion 4.4.2.3 o his chap e .
Wa e (%)
020 40 60 80
Hyd ogen bond dono ( )
0.1
0.4
0.8
1.1
1.5
Wa e (%)
020 40 60 80
Hyd ogen bond accep o ( )
0.1
0.4
0.8
1.1
1.5
[C2C1py][C4FSO3]
[C2C1Im][C4FSO3]
[N1112OH][C4FSO3]
Wa e (%)
020 40 60 80
Dipola i y/pola izabili y ( )
0.1
0.4
0.8
1.1
1.5
Ionic Liquids in he De elopmen o No el Bioma e ials
Kamle -Ta Sol a och omic Pa ame e s o Fluo ina ed Ionic Liquids
71
4.4.2.2 In luence o he Hyd ogena ed Alkyl Chain Leng h on he
Imidazolium Ca ion
In o de o e alua e he e ec o he hyd ogena ed alkyl chain leng h o he imidazolium ing,
he Kamle -Ta desc ip o s o [C2C1Im][CF3SO3] and [C4C1Im][CF3SO3] we e measu ed and a e
ep esen ed in Table 4.3. The ends o bo h FILs a e iden ical as can be seen in Figu e 4.10.
Figu e 4.10. Kamle -Ta pa ame e s, hyd ogen-bond dono (α), hyd ogen-bond accep o (β), and
dipola i y/pola izabili y (π*), measu ed a oom empe a u e wi h he inc ease o hyd ogena ed chain on
imidazolium ca ion a di e en aqueous concen a ions a 298.15 K.
Wi h he addi ion o wa e , he

alues inc eased un il p oximally 20 w % o wa e and hen
emain ela i ely s able. On he o he hand, he π* alues a e d as ically inc eased in bo h cases
indica ing a g ea e hyd ophilici y (20). The

pa ame e o bo h [C2C1Im][CF3SO3] and
[C4C1Im][CF3SO3] dec eased wi h he addi ion o wa e in o he bulk. Fo ins ance, Cláudio e al.
epo ed ha an in oduc ion o luo ina ed g oups om [CH3SO3]- o [CF3SO3]- leads o a dec ease in
IL’s hyd ogen bond basici y o nea compounds (18). The low pola izabili y o he luo ina ed g oups
and hei elec on wi hd awing e ec weaken he hyd ogen bonding abili y wi h he HBD o he
sol a och omic p obe (18). This end can be ela ed o he poo HBD (2) o he wa e and he small
alue o [CF3SO3]- based ILs anion.
Ne e heless, compa ing hese esul s wi h hose ob ained o [C4F9SO3]- (see Table 4.3) i is no iced
ha inc easing he luo ina ed chain e oke he

 a ia ion. This beha io will be discussed in he nex
sec ion.
Wa e (%)
020 40 60 80
Hyd ogen bond dono (
0.1
0.4
0.8
1.1
1.5
[C2C1Im][CF3SO3]
[C4C1Im][CF3SO3]
Wa e (%)
020 40 60 80
Hyd ogen bond accep o
0.1
0.4
0.8
1.1
1.5
Wa e (%)
020 40 60 80
Dipola i y/pola izabili y
0.1
0.4
0.8
1.1
1.5

Ionic Liquids in he De elopmen o No el Bioma e ials
Kamle -Ta Sol a och omic Pa ame e s o Fluo ina ed Ionic Liquids
72
4.4.2.3 In luence o he Fluo ina ed Chain Leng h on he Anion
The in luence o he anion will be discussed o he imidazolium, py idinium and cholinium-
based ionic liquids. The p esence o a luo ina ed anion, and i s chain leng h, e sus con en ional anions
(ace a e ([C1CO2]-), chlo ide (Cl-) and b omide (B -)) will be e alua ed ega ding he

,

and

*
pa ame e s. Focusing on he [C2C1Im]+ ca ion wi h con en ional anions, he ILs become mo e acidic
(inc easing α) and he β dec eases wi h he addi ion o wa e (see Figu e 4.11), as expec ed om
p e ious s udies (29).
Figu e 4.11. Kamle -Ta pa ame e s, hyd ogen-bond dono (α), hyd ogen-bond accep o (β), and
dipola i y/pola izabili y (π*), measu ed a oom o imidazolium-based ionic liquids wi h con en ional
(C1CO2- and Cl-) and luo ina ed anions ([C4F9SO3]- and [CF3SO3]-) a di e en aqueous concen a ions
a 298.15 K.
Howe e , he luo ina ed anions (especially [C4F9SO3]-) p ese e hei basici y along wi h he inc eased
wa e con en . These esul s could be explained by he a o able high elec onega i i y o he luo ine
a om (F-) and by he s ong hyd ogen bond be ween C–F ··· H–O (2.4 kcal.mol-1), hal o he a e age O
··· H s eng h p esen on wa e molecules (21). Thus, he hyd ogen bonding o luo ina ed anions can
be conside ed s able. Conce ning he π* alues, all ionic liquids p esen ed an excellen pola izabili y,
highe han wa e (1.09) (8). In addi ion, [C2C1Im][C4F9SO3] e ains he same

* alue wi h he addi ion
o wa e .
As discussed abo e, high

alues a e ad an ageous o se e al p ocedu es in ol ing
biomac omolecules (27). Ionic liquids based on he ace a e anion ([C1CO2]-) p o ed o be use ul o
lignocellulose p e ea men (8,30) and o nucleobases sol a ion (5,27) due o hei s ong HBA abili y
Wa e (%)
020 40 60 80
Hyd ogen bond dono ( )
0.1
0.4
0.8
1.1
1.5
[C2C1Im][C4F9SO3]
[C2C1Im][CF3SO3]
[C2C1Im] C1CO2
[C2C1Im] Cl
Wa e (%)
020 40 60 80
Hyd ogen bond accep o ( )
0.1
0.4
0.8
1.1
1.5
Wa e (%)
020 40 60 80
Dipola i y/pola izabili y ( )
0.1
0.4
0.8
1.1
1.5
Ionic Liquids in he De elopmen o No el Bioma e ials
Kamle -Ta Sol a och omic Pa ame e s o Fluo ina ed Ionic Liquids
73
(see Table 4.3). Conce ning he ILs basici y (

), he [C2C1Im][C1CO2] has highes

alues up o nea ly
50 w % wa e con en . Then, he [C2C1Im][C4F9SO3] demons a ed o be mo e ad an ageous wi h a
highe

. Conce ning he wa e con en up o 50 w % he ollowing basici y scale acco ding o he anions
could be es ablished: [C1CO2] > Cl ≈ [C4F9SO3] > [CF3SO3]. Howe e , be ween 50 w % and 80 w %
he basici y end changes o: [C4F9SO3] > [C1CO2] > [CF3SO3] > Cl-. This esul shown he amazing
abili y o ILs o “ une” cha ac e is ics acco ding o a pa icula applica ion in mind.
Figu e 4.12 illus a e he in luence o a luo ina ed ([C4F9SO3]-) e sus con en ional (B -) anion o
py idinium-based ILs in e ms o

,

and

* desc ip o s. The b omide anion combined wi h he
py idinium ca ion has being s udied o se e al biochemical p ocesses such as ex ac ion and sepa a ion
o bioac i e compounds om plan s (31). Thus, unde s anding he hyd ogen bonding o his ILs will be
bene icial o enhance ex ac ion and sepa a ion yields.
Figu e 4.12. Kamle -Ta pa ame e s, hyd ogen-bond dono (α), hyd ogen-bond accep o (β), and
dipola i y/pola izabili y (π*), measu ed a oom o py idinium-based ionic liquids wi h a con en ional
(B -) and a luo ina ed anion ([C4F9SO3]-) a di e en aqueous concen a ions a 298.15 K.
One ad an ageous cha ac e is ic o B - anions is hei highly hyd ophilici y which could inc ease ILs
solubili y (32). Thus, he

* alues o [C2C1py] B - a e ema kably highe . Compa ing bo h HBA and
HBD esul s, i is clea ha he luo ina ion o he anion p omo es a highe hyd ogen bonding abili y
(see Figu e 4.12). Conce ning he

alues, a all wa e concen a ions he [C2C1py][C4F9SO3] is
conside ed he mos acidic (inc eased

). Rega dless he

desc ip o , he [C2C1py] B - a ≈ 25 w % has
a basici y simila o [C2C1py][C4F9SO3] bu i d as ically declines wi h he u he addi ion o wa e .
Wa e (%)
020 40 60 80
Hyd ogen bond dono ( )
0.1
0.4
0.8
1.1
1.5
[C2C1py][C4F9SO3]
[C2C1py]B
Wa e (%)
020 40 60 80
Hyd ogen bond accep o ( )
0.1
0.4
0.8
1.1
1.5
Wa e (%)
020 40 60 80
Dipola i y/pola izabili y ( )
0.1
0.4
0.8
1.1
1.5
Ionic Liquids in he De elopmen o No el Bioma e ials
Kamle -Ta Sol a och omic Pa ame e s o Fluo ina ed Ionic Liquids
74
This beha io could be explained by he wa e ’s s ong HBD which sol a e a B - anion a inc eased
wa e concen a ions (22). The same beha io is epo ed o choline-based ILs.
Fo [N1112OH][C4F9SO3] an highe acidi y and basici y is epo ed compa ed o [N1112OH] Cl- (see Figu e
4.13).
Figu e 4.13. Kamle -Ta pa ame e s, hyd ogen-bond dono (α), hyd ogen-bond accep o (β), and
dipola i y/pola izabili y (π*), measu ed a oom o choline-based ionic liquids wi h a con en ional
(Cl-) and a luo ina ed anion ([C4F9SO3]-) a di e en aqueous concen a ions a 298.15 K.
The

is highe o he choline con aining he luo ina ed anion. Rega dless he

pa ame e , un il ≈ 20
w % he [N1112OH] Cl- p esen ed a highe basici y. Then, wi h inc easing wa e concen a ions hei

alues dec ease linea ly. Addi ionally, Jingyi Hu e al. obse ed he same

beha io o chlo ide
imidazolium-based ILs (33). On he o he hand, [N1112OH][C4F9SO3] main ained hei basici y ega dless
adding wa e in o he bulk. The pola izabili y ep esen ed by he

* pa ame e is highe o Cl- choline-
based ILs. Like B - py idinium-based IL (see Figu e 4.12), hose con aining he chlo ide anion ha e
highe solubili y due o Cl- sol a ion by wa e .
4.5 Conclusion
To da e, i is p o en ha ionic liquids can p o ide a new and powe ul pla o m o p o eins,
enzymes and DNA enhanced solubili y, ac i i y and s abili y (1). In his chap e , he hyd ogen bonding
and pola izabili y we e e alua ed o nea and aqueous solu ions o FILs.
Wa e (%)
020 40 60 80
Hyd ogen bond dono ( )
0.1
0.4
0.8
1.1
1.5
[N11112OH][C4F9SO3]
[N11112OH] Cl
Wa e (%)
020 40 60 80
Hyd ogen bond accep o ( )
0.1
0.4
0.8
1.1
1.5
Wa e (%)
020 40 60 80
Dipola i y/pola izabili y ( )
0.1
0.4
0.8
1.1
1.5
Ionic Liquids in he De elopmen o No el Bioma e ials
Kamle -Ta Sol a och omic Pa ame e s o Fluo ina ed Ionic Liquids
75
F om he analysis o he Kamle -Ta desc ip o s o nea FILs, se e al conclusions could be made: i)
imidazolium and py idinium-based FILs ha e simila hyd ogen bonding abili y a 323.15 K; ii)
e abu ylammonium-based FILs achie ed he highe basici y and he lowes acidi y a 323.15 K; iii) he
hyd ogena ed alkyl chain on he imidazolium ca ion has a small in luence on hyd ogen bonding o
[CnC1Im CF3SO3] (n= 2; 4) and [CnC1Im C4F9SO3] (n= 2; 6; 8) a 298.15 K; i ) a u he inc ease on he
luo ina ed chain on he anion p oduces highe HBD while p ese ing he HBA o imidazolium-based
FILs; ) o e abu ylammonium-based FILs luo ina ion o he anion esul s in an inc ease o bo h

and

pa ame e s (highe acidi y and basici y). Finally, all he FILs p esen ed a highe hyd ophilic
beha iou wi h

* alues close o pu e wa e .
The wa e e ec on Kamle -Ta pa ame e s was e alua ed by assessing he

,

and

a di e en
concen a ions a oom- empe a u e. The main pu pose o his s udy was o ind an IL ha do no loses
i s basici y (

) in aqueous solu ions, an impo an p ope y ega ding he solu e-sol en in e ac ion. A
se ies o imidazolium, py idinium and choline-based ILs wi h luo ina ed anions ([CF3SO3] and
[C4F9SO3]) we e es ed and compa ed wi h con en ional ILs such as [C2C1Im] C1CO2, [C2C1Im] Cl,
[C2C1py] B and [N1112OH] Cl. The analysis o he esul s sugges ed ha he inc easing luo ina ion on
he anion ([CF3SO3]- e sus [C4F9SO3]-) p omo es ILs acidi y and a u he s abiliza ion o hei basici y.
In ac , ILs wi h he pe luo obu anesul ona e anion do no lose hei basici y wi h inc eased wa e
concen a ions. He ein, he hyd ogena ed alkyl chain leng h a ec s mainly he HBD abili y and does
no change he HBA end o he [CnC1Im][CF3SO3] (n=2; 4) amily. Finally, he inc eased wa e
con en p omo ed he pola izabili y o all ILs, inc easing hei hyd ophilici y.
These o e all esul s u he s ess ha he IL ca ion and anion, o a la ge ex en , can be used o une he
hyd ogen bonding and dipola i y/pola izabili y o ILs, depending on he desi ed applica ion.
4.6 Re e ences
(1) Si ap agasam, M.; Moni uzzaman, M.; Go o, M. Recen Ad ances in Exploi ing Ionic Liquids o
Biomolecules: Solubili y, S abili y and Applica ions. Bio echnol. J. 2016, 11, 1–14.
(2) Jin, W.; e al. Enhanced Solubiliza ion and Ex ac ion o Hyd ophobic Bioac i e Compounds Using
Wa e /Ionic Liquid Mix u es. G een Chem. 2016, 18, 3549–3557.
(3) Zhao, H. DNA S abili y in Ionic Liquids and Deep Eu ec ic Sol en s J. Chem. Technol. Bio echnol.
2015, 90, 19–25.
(4) Pa el, R.; Kuma i, M.; Khan, A. B.; Recen Ad ances in he Applica ions o Ionic Liquids in P o ein
S abili y and Ac i i y: A Re iew. Appl. Biochem. Bio echnol. 2014, 172, 3701–3720.
(5) A aújo, J. M. M.; Fe ei a, R., Ma ucho, I.M.; Rebelo, L. P. N. Sol a ion o Nucleobases in 1,3-
Dialkylimidazolium Ace a e Ionic Liquids: NMR Spec oscopy Insigh s in o he Dissolu ion
Mechanism. J. Phys. Chem. B. 2011, 115, 10739–10749.
Ionic Liquids in he De elopmen o No el Bioma e ials
Conclusions and Pe spec i es
82
The Kamle -Ta sol a och omic pa ame e s showed ha by a ca e ully selec ion o he FIL anion and
ca ion, hyd ogen-bonding could be managed. Fo nea FILs, py idinium and imidazolium-based FILs
p esen ed simila beha iou s. In addi ion, he inc ease in he ca ion hyd ogena ed alkyl chain leng h, o
he [CnC1Im][C4F9SO3] (n=2, 6, 8) FILs p omo ed an inc ease on acidi y and a dec ease on basici y. Fo
[CnC1Im][CF3SO3] FILs wi h n=2 and 4, no signi ican di e ences whe e no iced. The inc ease o he
anionic luo ina ed chain leng h induced a mo e accen ua ed e ec on he e abu ylammonium-based
FILs, inc easing bo h acidi y and basici y. Howe e , o he imidazolium-based FILs es ed he
hyd ogen-bonding dona ion inc eased bu o he abili y o accep hyd ogen bonds no signi ican
di e ences we e ound. Rega ding he e ec o wa e on he FIL basici y desc ip o , i was shown ha
inc easing he anionic pe luo ina ed alkyl chain leng h ([CF3SO3]- e sus [C4F9SO3]-) p omo es ILs
acidi y and a u he s abiliza ion o hei basici y when compa ed o con en ional ILs. No clea impac
is obse ed in he basici y desc ip o o [C4F9SO3]-based ILs. This esul add ess he ele ance o
designing unc ionalized (so-called ask-speci ic) ILs ha ha e been syn hesized wi h a pa icula
applica ion in mind, e.g. dissolu ion o he apeu ic molecules.
The o e all esul s u he s ess ha ILs cons i u i e ions, o some ex en , can be uned wi h se e al
p ope ies depending on he desi ed applica ion.
5.2 Pe spec i es
Du ing he pas decades he in e es in ionic liquids has inc eased, wi h applica ions in di e se
a eas such as elec ochemis y, chemis y, nano echnology, bio echnology, and in enginee ing
p ocesses, among o he s. The nume ous ad an ages o using ionic liquids as bioma e ials a e
unques ionable. This ac makes hem e y a ac i e mainly in he biomedical ield whe e he use o
bioma e ials o enhance clinical e icacy is e y challenging.
The esul s ob ained in his wo k could help in he design o he mos sui able FIL o applica ion as
su ac an s in biomedical applica ions. Besides, he luo ina ed domains p esen in emulsions can
p omo e a highe solubili y o poo soluble d ug molecules and biomolecules such as enzymes, p o eins
and DNA. Addi ionally, FILs a e a g eene al e na i e o subs i u e a m ul sol en s used nowadays in
he pha maceu ical indus y o he ex ac ion, pu i ica ion and syn heses p ocesses o se e al
biomolecules.
As u u e wo k, he s udy o he in e ac ions be ween FILs and d ug molecules o biomolecules is
equi ed. Also, d ugs and biomolecules solubili y in FILs will be needed o de e mine he e ec i eness
o hese compounds as d ug deli e y de ices. Addi ionally, FIL solubili y should be de e mined in
di e en biological luids such as gas ic and in es inal luid. The cellula iabili y in di e en human
cell lines in o de o unde s and hei beha iou in he mos common ou es o adminis a ion (o al,
in a enous and ansde mal) should be also s udied. Mo eo e , sel -agg ega ion p ope ies o FILs

83
6. Scien i ic Communica ions
84
Ionic Liquids in he De elopmen o No el Bioma e ials
Scien i ic Communica ions
85
6.1 Pape s
In p epa a ion:
1. “E alua ion o Cy o oxici y and Pa i ion P ope ies o Fluo ina ed Ionic Liquids”. Joana C.
Bas os, Nicole M. Viei a, João M. M. A aújo, Sa a Nunes, Ana Ma ias, Isabel M. Ma ucho,
Ca a ina M. M. Dua e, Ana B. Pe ei o, Luís P. N. Rebelo
2. “S udy o he In luence o Hyd ogena ed Alkyl Chain on Agg ega ion and Solubili y o
Fluo ina ed Ionic Liquids using he So -SAFT Equa ion” . Fèlix Llo ell, Ana B. Pe ei o, João
M. M. Aa aújo; Ma ía J. Pas o iza -Gallego, And eia S. S. San os, Joana C. Bas os , Luís P. N.
Rebelo, Manuel M. Piñei o‖ and Lou des F. Vega
3. “Fluo ina ed Ionic Liquids–based Aqueous Biphasic Sys ems: S udy o Pola i y and
Hyd ophobici y Scales” Joana C. Bas os, Sa a Ca alho, Ana B. Pe ei o, Luís P. N. Rebelo
and João M. M. A aújo.
5.2 Pos e s in Scien i ic Mee ings
1. Au ho s: Joana C. Bas os, And eia S. S. San os, João M. M. A aújo, Luis Paulo N. Rebelo,
Ana B. Pe ei o.
Ti le: "De elopmen o Fluo ina ed Ionic Liquids o Biomedical Applica ions"
Cong ess: 5 h Po uguese Young Chemis s Mee ing (5 h PYCheM) and 1s Eu opean Young
Chemis s Mee ing (1s EYCheM)
Place: Guima ães (Po ugal) Da e: Ap il, 2016
2. Au ho s: Joana C. Bas os, Nicole S. M. Viei a, Ana Ma ias, Ca a ina M. M. Dua e, João M.
M. A aújo, Luís Paulo N. Rebelo, Ana B. Pe ei o
Ti le: "E alua ing Fluo ina ed Ionic Liquids as No el D ug Deli e y Sys ems"
Cong ess: 5 h Po uguese Young Chemis s Mee ing (5 h PYCheM) and 1s Eu opean Young
Chemis s Mee ing (1s EYCheM)
Place: Guima ães (Po ugal) Da e: Ap il, 2016
3. Nicole S. M. Viei a, J. C. Bas os, A. Ma ias, C. M. M. Dua e, João M. M. A aújo, Luís P. N.
Rebelo, Ana B. Pe ei o
Ti le: "Fluo ina ed Ionic Liquids o Biomedical Applica ion"
Cong ess: 2nd EuCheMS Cong ess on G een and Sus ainable Chemis y
Place: Lisbon (Po ugal) Da e: Oc obe , 2015
Ionic Liquids in he De elopmen o No el Bioma e ials
Conclusions and Pe spec i es
86
4. Au ho s: N. S. M. Viei a, J. C. Bas os, J. M. M. A aújo, A. Ma ias, C. M. M. Dua e, Luís P.
N. Rebelo, A. B. Pe ei o
Ti le: "Cy o oxici y and Pa i ion Coe icien s o Fluo ina ed Ionic Liquids"
Cong ess: Ibe oame ican Mee ing on Ionic Liquids- IMIL 2015
Place: Mad id (Spain) Da e: July, 2015