Supramolecular Interaction-Assisted Fluorescence and Tunable

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Supramolecular Interaction Assisted Fluorescence and Tunable Stimuli-Responsiveness of L-Phenylalanine Based Polymers Mridula Nandi, Binoy Maiti, Kambalapalli Srikanth, and Priyadarsi De Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.7b02431 • Publication Date (Web): 18 Sep 2017 Downloaded from http://pubs.acs.org on September 18, 2017

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Supramolecular Interaction Assisted Fluorescence and Tunable Stimuli-Responsiveness of L-Phenylalanine Based Polymers

Mridula Nandi,a,b Binoy Maiti,a,b Kambalapalli Srikanthb and Priyadarsi Dea,b,c,* a

Polymer Research Centre, bDepartment of Chemical Sciences, cCentre for Advanced

Functional Materials, Indian Institute of Science Education and Research Kolkata, Mohanpur - 741246, Nadia, West Bengal, India * Corresponding Author: E-mail: [email protected]

ABSTRACT: Supramolecular host-guest interaction between randomly methylated βcyclodextrin (RM β-CD) and side-chain phenylalanine (Phe) and Phe-Phe dipeptide based homopolymers has been employed for amplification of fluorescence emission of otherwise weakly fluorescent amino acid Phe. The host-guest complex has been characterized by 1H and

13

C NMR spectroscopy, two-dimensional (2D) rotating-frame overhauser spectroscopy

(ROESY), FT-IR, UV-visible and fluorescence spectroscopy. To gain insights into the origin of fluorescence in homopolymers, density functional theory (DFT) calculations were performed where phenyl moieties inside the less polar core of β-CD were observed to form ππ coupled complex resulting in enhanced emission. Furthermore the complex forming ability of Phe, the guest molecule, has been employed in tuning cloud point temperature (TCP) of statistical copolymers derived from side-chain Phe/Phe-Phe based methacrylate monomers and N-isopropylacrylamide (NIPAM). By varying the co-monomer feed ratios in statistical copolymer and hence concentration of RM β-CD throughout the polymer chain, host-guest interaction assisted broad tunability in TCP of supramolecular polymeric complex has been achieved.

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INTRODUCTION The cooperative association between supramolecular chemistry and polymers have led to fabrication of smart materials with well-defined supra-structures and properties capable of mimicking biological systems. 1 , 2 On account of associated reversibility the polymer conformations, properties and functions can be adjusted via host-guest chemistry.3 Among several supramolecular hosts available cyclodextrins (CDs) are the most intriguing molecules because of their good water solubility and commercial availability, compatibility with a wide range of hydrophobic guests and ability to recognize selectively different guests such as aromatic, aliphatic and chiral molecules.4,5 CD modified polymers, via host-guest interaction, have been used to develop molecular systems with specific functions in fields spanning water management,6 sensing,7 as well as biomedicine.8 Formation of inclusion complex between host and guest moiety significantly alters the solubility9,10 and spectral properties11,12 of the hydrophobic guest molecules. Considerable attention has been paid on the use of CDs as a means of improving aqueous solubility and spectrofluorometric methods for identification of various analytes.

13

The altered

microenvironment around a sequestrated hydrophobic guest inside CD cavity prevents any non-radiative or fluorescence quenching process, thereby aiding in enhancement in fluorescence emission. 14, 15 For instance, complexation behaviour of several dyes such as acridine red, fluorescein, crystal violet etc. with CDs and calix[n]arenesulphonates as molecular receptors revealed an increase in fluorescence intensity upon complexation with CDs while decrease in fluorescence intensity with the latter.16 A study by Al-Hassan et al.17,18 established that the orientation of the probe inside the CD and cavity size directs the intensity, emission wavelength, nature of the spectra of the fluorescent probes. Recently, Li et al. reported fluorescent supramolecular hyperbranched polymer based on host-guest interaction. Eventhough devoid of any conventional chromophore, the diethylenetriamine (DTA) based


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hyperbranched polymer could emit wide-band fluorescence on account of inclusion complexation.19 Additionally, ‘stimuli’-responsive polymeric materials are extensively investigated with the interest to fabricate systems capable of monitoring temperature and pH, owing to their importance in several fields of science and engineering.20,21 Among various thermoresponsive polymers most explored is poly(N-isopropylacrylamide) (PNIPAM) with lower critical solution temperature (LCST) 32

o

C, i.e. on increase in temperature it undergoes

transformation from soluble to insoluble state.

22 , 23

Till date for tuning of

thermoresponsiveness, polymers have been modified into various statistical,

24

block

copolymers,25 hyperbranched,26 and graft co-polymers.27 Hereof, supramolecular interaction between host and guest provides a facile alternative for tuning the phase transition temperature (also known as cloud point temperature (TCP)) of thermoresponsive polymers,28 eliminating otherwise tedious and extensive ways of copolymer preparation. Cavitands with hydrophilic exterior and hydrophobic cavity, such as CDs, encapsulate hydrophobic guests in thermoresponsive polymer chain and increase hydrophilicity and hence phase transition temperature. Consequently several cavitands such as cucurbit[n]urils, 29 pillar[n]arenes, 30 calixarenes, 31 cyclobis(paraquat-p-phenylene), 32 crown ethers 33 as well as CDs have been investigated for supramolecular control over thermoresponsiveness. Covalent attachments of β-CD to the polymer main chain,34 as end groups35 or through non-covalent36 attachment to polymer chain have been studied for precise tuning of TCP. Although the above mentioned systems were successful in altering LCST, most of them actually resulted in decrease in TCP of thermoresponsive polymer. Moreover there are very few systems with broad tunability of TCP reported in literature that can function as sensors.37,38 Eventhough host-guest interaction between phenylalanine (Phe) based polymer and CD has been reported,39,40 alteration in its spectral properties on complexation or its ability to


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tune LCST of thermoresponsive polymer on complexation have not been given much attention, because hydrophobicity associated with phenyl ring leads to decreased solubility in aqueous solution or reduction in TCP. Among the intrinsic fluorophores in proteins, aromatic Phe is weakly fluorescent with a very low molar extinction coefficient and quantum yield.41 Herein we present a strategy for enhancing fluorescence of side-chain Phe based homopolymer via host-guest interaction with randomly methylated β-CD (RM β-CD). Further increased solubility of Phe/RM β-CD or dipeptide (Phe-Phe)/RM β-CD complex has been employed to tune TCP of thermoresponsive supramolecular polymeric complex from statistical copolymers derived from side-chain Phe/Phe-Phe based methacrylate monomers and N-isopropylacrylamide (NIPAM). The side chain amino acid/dipeptide containing polymers are particularly advantageous because their synthesis involves relatively straightforward method and free amine functionalities inside chains undergo reversible protonation/deprotonation incurring pH-responsivity to polymer chain.42 By varying the comonomer feed ratios in statistical copolymer and hence concentration of RM β-CD throughout polymer chain, host-guest interaction assisted broad tunability in TCP of dual thermo and pH-responsive polymer has been achieved.

EXPERIMENTAL SECTION Materials. Trifluoroacetic acid (TFA, 99.5%) and tert-butyloxycarbonyl (Boc)-Lphenylalanine (Boc-F-OH, 99%) were obtained from Sisco Research Laboratories Pvt. Ltd., India. Randomly methylated β-cyclodextrin (RM β-CD, ≥ 97%) was bought from Tokyo Chemical Industries Co. Ltd., Japan. 4-Dimethylaminopyridine (DMAP, 99%), anhydrous N,N-dimethylformamide (DMF, 99.9%), dicyclohexylcarbodiimide (DCC, 99%), and 2hydroxyethyl methacrylate (HEMA, 97%) were purchased from Sigma and used without any further purification. The N-isopropylacrylamide (NIPAM) (Sigma Aldrich, 97%) was 4 ACS Paragon Plus Environment

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recrystallized twice from a mixture of toluene and hexanes prior to polymerization. 2,2′Azobisisobutyronitrile (AIBN) (Sigma, 98%) was recrystallized twice from methanol. The CDCl3 (99.8% D) and methanol-d4 (CD3OD, 99.8% D) from Cambridge Isotope Laboratories, Inc., USA were used for NMR study. The solvents such as hexanes (mixture of isomers), methanol (MeOH), acetone, ethyl acetate, tetrahydrofuran (THF) and dichloromethane (DCM) were purified by standard distillation procedures. The RAFT chain transfer agent (CTA) 4cyano-4-(dodecylsulfanylthiocarbonyl)sulfanylpentanoic

acid

(CDP)

was

synthesized

following a previously reported procedure. 43 The Boc-phenylalanine methacryloyloxyethyl ester (Boc-F-EMA)

44

and Boc-Phe-Phe-oxyethyl methacrylate (Boc-FF-EMA)

45

were

prepared by previously established synthetic procedure from our group. Characterization Techniques. Two-dimensional (2D) rotating-frame overhauser spectroscopy (ROESY), 1H and

13

CNMR spectra were obtained either on a BrukerAvanceIII

500 MHz spectrometer or on a Jeol 400 MHz spectrometer at 25 oC. The number average molecular weight (Mn) and molecular weight distributions (dispersity (Ð)) of homopolymers were determined in THF by Waters gel permeation chromatography (GPC) instrument consisting of a Model 515 HPLC pump, Model 2414 refractive index (RI) detector and two columns (PolarGel-M guard column (50 × 7.5 mm) and PolarGel-M analytical columns (300 × 7.5 mm)) at 30 oC. The THF mobile phase contained 0.05 w/v% butylhydroxy toluene (BHT) and the flow rate was fixed at 1.0 mL/min. A series of ten near monodisperse poly(methyl methacrylate) (PMMA) standards (peak average molecular weight (Mp) values ranging from 1280 to 199000 g/mol) were used to calibrate the instrument. For copolymers Mn and Ð values were determined in DMF solvent at 40 oC. FT-IR spectrum was recorded on Perkin-Elmer Spectrum 100 FT-IR Spectrometer on KBr pellets. UV-visible spectroscopic measurements were carried out on a Perkin-Elmer Lambda35 spectrophotometer. For cloud point determination, UV-vis spectrophotometer was coupled to a Peltier Temperature


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Programmer for temperature control. Fluorescence measurements were carried out using Fluoromax-3 spectrofluorimeter from Horiba JobinYvon. Theoretical calculations were performed using Gaussian 09 program.46 The structure and orientation of the polymer-β-CD complex were optimized using the B97D functional47 and 6-31G(d)48,49 basis set of density functional theory (DFT) methods. Homopolymer Synthesis. A typical RAFT polymerization was carried out as follows: Boc-F-EMA (400 mg, 1.61 mmol), CDP (17.1 mg, 0.04 mmol), AIBN (0.7 mg, 4.24 µmol; 44.9 mg stock solution of 5.6 mg AIBN in 503.2 mg DMF) and DMF (1.6 g) were taken in a 20 mL septa sealed vial equipped with a small magnetic stir bar, purged with dry nitrogen for 20 min and placed in a preheated reaction block at 70 °C. The polymerization was stopped by cooling the vial in ice-water bath and exposing reaction mixture to air. After quenching, the reaction mixture was diluted with acetone and precipitated from hexanes. The corresponding homopolymerpoly (Boc-F-EMA) (PF) was further reprecipitated around five times from acetone/hexanes and dried under high vacuum for 8 h at 35 °C to obtain faint yellowish polymers. Monomer conversion was determined gravimetrically from the initial weight of monomer taken and weight of purified polymer. A similar procedure was followed for the synthesis of side-chain dipeptide based polymer, poly(Boc-FF-EMA) (PFF) (Scheme S1). Copolymer Synthesis. A typical RAFT copolymerization process was as follows: BocF-EMA (104.5 mg, 0.28 mmol), NIPAM (595.5 mg, 5.26 mmol), CDP (22.4 mg, 0.06 mmol), AIBN (1.0 mg, 5.5 µmol, from stock solution) and DMF (2.8 g) were taken in a 20 mL septa sealed glass vial equipped with a small magnetic stir bar, purged with dry nitrogen for 20 min and placed in a preheated reaction block at 70 °C. After predetermined time, the reaction was stopped, copolymers were purified and monomer conversions were determined following similar procedure as homopolymers. A similar procedure was followed for the synthesis of copolymers of NIPAM and Boc-FF-EMA (Scheme 1).


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Deprotection of Boc-Protected Polymers. Typically, to a homogeneous solution of PF (0.16 g) in 1.0 mL DCM, 0.5 mL TFA was added drop-wise under ice-water bath condition. The solution was kept stirring for 2 h at room temperature. The Boc deprotected polymer (DPF) was precipitated in diethyl ether and dried under vacuum for 8 h at 35 °C. Similarly, PFF was used to prepare corresponding Boc deprotected copolymer DPFF. Also, various copolymers were deprotected under acidic condition at room temperature. Preparation of Supramolecular Inclusion Complex. For inclusion complex formation, to a homogeneous solution of DPF (50.0 mg, 0.13 mmol) in 1.0 mL acetone taken in a 20 mL vial a solution of RM β-CD (149.0 mg, 0.13 mmol) in 2.0 mL acetone was added. Following continuous stirring for 7 days at room temperature, the solution was dialyzed against MeOH using a Spectra/porR dialysis membrane (2kDa molecular weight cut-off (MWCO)) to remove excess RM β-CD. During dialysis, MeOH was changed atleast 5 to 7 times in 2 to 8 h interval. A yellowish solid complex was obtained after rotary evapouration and drying under vacuum for 8 h at 35 °C. Similarly, complexation of RM β-CD with DPFF and the copolymers were carried out following above mentioned procedure. Determination of Phase Transition Temperature. For measurement of cloud point temperature (TCP), the % transmittance (%T) of aqueous solution of copolymer (2.0 mg/mL) was recorded at wavelength (λ) = 500 nm within the temperature range 20-75 oC. The temperature was gradually increased at the heating rate of 2-5oC/min and prior to each measurement the sample was equilibrated for 5 min. The TCP is defined as the temperature where 50% reduction in %T of the polymer solution was observed.

RESULTS AND DISCUSSION Synthesis of Homo- and Co-Polymers. Previously, we have demonstrated effectiveness of CDP for controlled RAFT polymerization of Boc-F-EMA,44 Boc-FF-EMA45


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and NIPAM.50 Thus, in this study we have used CDP to prepare homo- and co-polymers in the presence of AIBN in DMF at 70 oC. Two series of copolymers with different compositions were prepared by varying the co-monomer feed ratios i.e. [NIPAM]/[Boc-F/FFEMA]. But [CDP]/[AIBN] and [monomer]/[CDP] ratios were kept constant at 1/0.1 and 100/1, respectively. Homopolymers were coded as: PF, PFF and PNIPAM which were prepared from Boc-F-EMA, Boc-FF-EMA and NIPAM, respectively. Copolymers were named as PFN or PFFN, where F, FF and N signifies Boc-F-EMA, Boc-FF-EMA and NIPAM, respectively (Table 1). The numbers 5, 10 and 15 after PFN or PFFN in Table 1 stand for the F or FF monomer feed ratios. For example, a copolymer of Boc-FF-EMA and NIPAM with [Boc-FF-EMA]/[NIPAM] = 5/95 feed ratio is designated as PFFN5. To represent polymers after Boc deprotection, the letter ‘D’ was introduced before PFFN5 and written as DPFFN5.

O co O

O

O

O

NH

O

O N H

O

O

O

O

O

NH

co (Boc-FF-EMA)

(Boc-F-EMA)

m

n

O O

N H

H N

O

O

O

CDP, AIBN DMF, 70 oC

O

CDP, AIBN DMF, 70 oC

NIPAM

m

n

O

O

NH

O

O O

co

co n

HN

O O

TFA/DCM

O O

O O

PFNx (x = 5,10,15)

-

TFA

+

H3N

DPFNx (x = 5,10,15)

O

m

n

NH

O O

O

m

O

HN

NH

O

TFA/DCM

O

NH

O

O

O

HN O NH3+

TFA-

DPFFNx (x = 5,10,15)

PFFNx (x = 5,10,15)

O CDP : HO

S NC

S

C12H 25

S

Scheme 1. Synthesis of amino acid/dipeptide based random co-polymers by RAFT polymerization, followed by deprotection of the Boc group.


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Table 1. Results from the synthesis of homopolymers (PF and PFF) and various copolymers from the RAFT polymerization of Boc-F-EMA/Boc-FF-EMA with NIPAM in DMF at 70 oC. Polymer

[Boc-F/FF-

Time

Conv.c

EMA]:

(min)

(%)

Mn,NMRd

Mn,GPCe

F/FF-EMA in (g/mol)

(g/mol)

% of Boc-

Ðe

Mn,theof (g/mol)

copolymerd

[NIPAM] PFa

100:0

210

60

1.00

7000

5800

1.12

6100

PFN5b

5:95

210

96

0.03

11600

15000

1.2

12500

PFN10b

10:90

210

92

0.08

12000

16700

1.17

13000

PFN15b

15:85

210

95

0.14

15400

17500

1.15

14900

PFFa

100:0

300

53

1.00

8000

5500

1.15

7300

PFFN5b

5:95

300

95

N.D

N.D

14500

1.3

13000

PFFN10b

10:90

300

88

0.09

13500

18200

1.15

15000

PFFN15b

15:85

300

89

N.D

N.D

19000

1.15

16000

a

[monomer]/[CDP]/[AIBN] = 25/1/0.1. b[Monomer]/[CDP]/[AIBN] = 100/1/0.1. cDetermined

gravimetrically. dDetermined from 1H NMR study. eMeasured by GPC using PMMA standards. fTheoretical number average molecular weights; Mn,theo = (([monomer]/[CDP] × average molecular weight (MW) of monomer × Conv.) + (MW of CDP)). N.D: not determined.

The homo- and co-polymers were characterized by 1H NMR study. In the 1H NMR spectrum of PF, PFF and their copolymers (Figures S1 and S2), characteristic resonance signals for the different types of protons in the repeating unit of polymer are assigned. For the PF and PFF, the degree of polymerization (DPn) was determined by comparing the integration areas from the terminal –CH2–CH2– protons (from the HOOC–CH2–CH2– C(CN)(CH3)– chain end) at 2.4–2.6 ppm and the repeating unit protons at 4.1–4.5 ppm (for 9 ACS Paragon Plus Environment

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O–CH2–CH2–O– and chiral proton). Then, number average molecular weight (Mn,NMR) values of homopolymers were calculated using respective DPn and molecular weight of the monomers. Compositions of copolymers were calculated from their 1H NMR spectra by comparing the peak intensity of methylene proton (-CH2-Ph) at 3.2-3.0 ppm to the total peak area at 4.44-3.89 ppm for the –O-CH2-CH2-O- (4H) and chiral proton of Boc-F-EMA segment and -CH(CH3)2 proton of NIPAM unit. The –CH2–CH2– (4H) protons of HOOC– CH2–CH2–C(CN)(CH3)– chain ends were clearly observed at 2.42–2.54 ppm in the case of PFNx (x = 5,10,15) copolymers, and can be used to determine Mn,NMR by the chain end analysis method. First, the average number of Boc-F-EMA units (DPn,F) in the copolymer was calculated from the comparison of peak areas at 3.2-3.0 and 2.42–2.54 ppm. Similarly, comparison of the integration areas from the terminal group (4H) at 2.42–2.54 ppm and peak areas at 4.44-3.89 ppm (after subtracting the peak area contributed by PF units in this region) gives the average number of NIPAM units (DPn,N) in the copolymer. Thus, Mn,NMR values of copolymers were determined using the following equation: Mn,NMR = [(DPn,F × MF) + (DPn,N × MN) + molecular weight of CDP], where DPn,F/N and MF/N are the average number of particular monomer unit in the copolymer and the molecular weight of the monomer, respectively.GPC RI traces (Figure S3) of the homopolymers and copolymers are symmetric and unimodal with narrow Ð values (˂ 1.2). The molecular weights (Mn,GPC) determined from GPC analysis are shown in Table 1. Theoretical molecular weights (Mn,theo) were determined from

gravimetric

conversion

(Conv.)

using

the

following

equation:

Mn,theo=

(([monomer]/[CDP] × average molecular weight (MW) of monomer × Conv.) + (MW of CDP)). Table 1 shows that Mn,theo values matched reasonably well with the corresponding Mn,GPC and Mn,NMR, thus indicate controlled nature of the RAFT polymerizations.


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(A)

DPF/RM β-CD *

RM β-CD

CD3OD

(B)

DPFN10 *

CD OD 3

g

DPF

CD3OD

*

PFN10

g

c,d,e

b

a

f

PF 2.58

g

8

7

e c,d

h

6

5

4

ppm

2.52

f

3

2.46

a

CDCl 3

i CDCl3

2.40

a

b

2

1

0

8

7

6

5

4

3

2

1

0

ppm

Figure 1. 1H NMR spectra of (A) PF in CDCl3, DPF in CD3OD and the complex of DPF with RM β-CD in CD3OD, and (B) PFN10 in CDCl3 and its Boc-deprotected form DPFN10 in CD3OD.

Boc-Deprotection and Aqueous Solubility. Because of the hydrophobic Boc groups in the polymers, Boc-protected homopolymers (PF and PFF) and all the copolymers were insoluble in water. Therefore, Boc groups were removed from the polymers in the presence of TFA to increase their aqueous solubility, since deprotection of Boc groups from the sidechain of Boc-protected polymers yielded polymers with –NH3+groups. Successful removal of Boc groups was confirmed from 1H NMR study where the signal coming from tert-butyl protons of Boc group at 1.41 ppm disappeared completely after Boc deprotection (Figure 1 and Figure S4). Additionally, in the FT-IR spectra of DPFF (Figure S5B) the absorption peak at 1520 cm-1 ascribed to N-H bending frequency (amide II band) disappeared after deprotection. After deprotection the free amine group exists in protonated form, thus a small broad band centered around 1541 cm-1 appeared corresponding to bending frequency of N-H of –NH3+ functionality (Figure S5). Similar results were obtained in the FT-IR study with PF and DPF (Figure S5A). After deprotection, the homopolymer DPF showed limited solubility in water; while DPFF, because of presence of two highly hydrophobic phenyl groups in each repeating unit, 11 ACS Paragon Plus Environment

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was still insoluble in water. Solubility test in water revealed among the deprotected random copolymers, DPFFN5 and DPFFN10 were entirely soluble because of high NIPAM content in the copolymer; DPFFN15 was partially soluble but could be fully solubilised at acidic pH. All three deprotected copolymers from Boc-F-EMA-NIPAM system were nicely soluble in water. Nevertheless, it was observed that in the copolymer series, with higher amino-acid content, solubility decreased because hydrophobicity incorporated in the copolymer by bulky phenyl groups of amino acid outweigh both hydrophilicity of NIPAM and solubilising effect of protonated amine (–NH3+) functionality.

Preparation of Supramolecular Inclusion Complex. Cyclodextrins encapsulate hydrophobic guest by virtue of the dimensions of guest molecule and cavity size of a particular type of CD.51 The dimension of aromatic Phe is such that optimum fit is observed for RM β-CD,52 so host-guest complexation of DPF, DPFF and various copolymers with RM β-CD has been studied at room temperature. For DPF, complexation can be visually identified by the gradual change in colour of solution from transparent to bright yellow. However for DPFF and copolymers no such observation could be made. On complex formation, solubility of all the deprotected homo- and co-polymers increased on account of hydrophilicity of RM β-CD. The complexes have been primarily characterized by various spectroscopic methods (vide infra). Eventhough only a few spectral differences were found between the starting polymer and the complexes, they can be characterized by FT-IR technique (Figure 2 and Figure S6).53 Formation of inclusion complex between RM β-CD and phenyl moiety of amino-acid containing polymethacrylate can be identified from the characteristic bands of RM β-CD appearing within the range 1160-1050 cm-1 (corresponding to anti-symmetric stretching of CO-C of cyclic ether). Anti-symmetric stretching of C-O of ester groups appearing at ~1248 12 ACS Paragon Plus Environment

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cm-1 in uncomplexed RM β-CD shifted towards higher wavenumber by 6 cm-1 in the spectrum of complexes and appears at 1254 cm-1. Furthermore, FT-IR spectra of free polymer DPF showed aromatic C=C stretching band at 1681 cm-1, which in the complexed state is shifted to 1649 cm-1.

DPF

% Transmittance (a.u.)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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4000

DPF/RM β−CD

DPFN5

DPFN5/RM β−CD RM β−CD

3000

2000

1000 -1

Wavenumber (cm )

Figure 2. FT-IR spectra of DPF, DPF/RM β-CD, DPFN5, DPFN5/RM β-CD and RM β-CD.

1

H NMR plays an important role in identifying inclusion complexes,54 based upon the

changes in the chemical shifts (∆δ) of the protons,55 induced on each other by the guest and host molecules. Although no such significant change in chemical shift was observed for our polymers on complex formation, the intensity of proton peaks of the phenyl was reduced and broadened as compared to the polymer in free state (Figure 1A). The broadening indicated significant restriction on intramolecular rotation of phenyl ring inside the cavity. 56 The complex has also been characterized by

13

C NMR where peaks from both phenyl ring and

RM β-CD are present (Figure S7). The 2D NMR spectroscopy is an efficient analytical technique to identify CD inclusion complexes and understand the orientation of guest inside the cavity of CD.54 In 2D ROESY spectroscopy, dipolar interactions between protons


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correlating through space are detected as cross-peaks in a 2D spectrum. Typically for generating signals in ROESY experiment a distance less than 4 Å is required between protons. 57 The structure of CD has only H-3 and H-5 located inside the cavity with H-3 located near the wider rim of CD cavity and H-5 near the narrower rim. All other hydrogens (H-1, H-2, H-4 and H-6) are located on the exterior of the cavity. The 2D ROESY spectrum of the complexes (Figure 3 and Figure S8) clearly showed cross-peaks between the inner H-3 and H-5 of the host RM β-CD at 3.59 and 3.81 ppm respectively and protons of the guest phenyl moiety at 7.34 ppm indicating successful encapsulation of phenyl ring. No cross-peak is generated with other protons. This observation corroborates well with that observed from theoretical calculations where the encapsulation is shown to happen from wider rim of host molecule (vide infra).

Figure 3. 2D ROESY NMR spectrum of DPF/RM β-CD complex in CD3OD.


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Spectroscopic Characterization of Inclusion Complex. The optical properties of the guest molecules are significantly modified inside the apolar cavity of RM β-CD.58 UV-vis measurements of DPF in MeOH showed peaks at 254 nm corresponding to n-π* of carbonyl and at 260 nm corresponding to π-π* transition of phenyl (Figure 4A). Other peak at 309 nm corresponds to trithiocarbonate functionality (coming from CTA fragment) at the polymer chain end.44 On addition of RM β-CD absorbance around 280 nm (A = 0.52) was significantly enhanced as compared to the free polymer which indicated some phenomenon within host-guest inclusion complex (Figure 4A). Fluorescence measurements of DPF in MeOH revealed a single fluorescence peak at 305 nm (Figure 4B), the intensity of which decreases with increase in concentration. Also, a weak band at 370 to 480 nm is observed due to the aggregation of side-chain phenyl rings. The fluorescence behavior of the inclusion complexes was significantly different from that of the polymers. In presence of RM β-CD, fluorescence measurements revealed another fluorescence peak at 365 nm along with that coming from the monomeric unit at 305 nm. Figure 4C shows the effect of RM β-CD (2.84 mM) on increasing polymer concentration. With increase in polymer concentration, the intensity of the fluorescence emission from the monomeric unit at 305 nm decreased whereas intensity of the fluorescence emission at 365 nm increased significantly. At concentration 1.0 mg/mL, three-fold increment in intensity of fluorescence emission at 365 nm dominated over emission at 305 nm. For the other homopolymer DPFF in free state, the emission intensity from monomeric unit at 305 nm decreased gradually with increase in concentration (Figure S9A). Fluorescence measurements of the complex DPFF/RM β-CD in MeOH in addition to emission at 305 nm showed weak emission around 426 nm, originating from an aggregated state. Emission from monomeric unit decreased with increase in polymer concentration; but for the aggregated state emission first increased (for 0.5 mg/mL polymer concentration) and


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then further increase in concentration (for 1.0 mg/mL) led to decrease in emission intensity (Figure S9B).59 Because the amino acid/dipeptide content was less in copolymers (≤ 15%), UV-vis and spectrofluorometric studies were not performed with the copolymer complexes.

Figure 4. (A) UV-vis spectra of DPF in absence and presence of 2.84 mM RM β-CD (polymer concentration: 1 mg/mL). Fluorescence spectra of (B) DPF and (C) DPF/RM β-CD at RM β-CD concentration: 2.84 mM. (D) Optimized gas phase geometry of DPF/β-CD calculated in Gaussian 09 using B97D/6-31G(d); grey: carbon atoms, red: oxygen atoms, blue: nitrogen atoms: white: hydrogen atoms.

To understand the origin of fluorescence at longer wavelength, theoretical calculation by DFT was performed (Figure 4D). The optimized structure for the DPF/β-CD complex revealed insertion of phenyl ring through the wider rim of β-CD cavity eliminating chances of 16 ACS Paragon Plus Environment

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possible interaction with hydrogens located towards the exterior and narrower rim of the molecule. This is in agreement with the results obtained in 2D ROESY NMR. In Figure 4D, the optimized structure given clearly shows one of the phenyl ring completely inserted into βCD core while the other lying little above at a spatial separation of 3.22Å; interaction between -NH3+of homopolymer and –OMe of β-CD prevents complete insertion of second phenyl ring into the cavity. Usually in aromatic systems two phenyl rings located at a distance of 3.4 Å or less are more inclined to through space π-π interaction.60 Because the π-π interaction distance is smaller than inner cross-section of β-CD, it can be inferred that in polymer inclusion complex of DPF/RM β-CD two phenyl rings coming from different chains (or repeating units) form phenyl π-π coupled complex or a dimer. This π-π interaction, stabilized by RM β-CD, is responsible for strong fluorescence emission at 365 nm in spectrofluorometric measurements. Because of structural complexity of DPFF/β-CD, optimized structure in DFT couldnot be generated.

co

O

n O

m

O

NH

co

RM β-CD O

O

m

O

NH

O

O +

n O

Acetone 7 days

H3N

DFNx (x = 5,10,15,100)

O +

Thermo-responsive

H3N

pH-responsive

Polymer Inclusion complex

Figure 5. Schematic representation of inclusion complex formation of copolymers in acetone.

pH-Dependent Cloud Point Temperature (TCP) Study. Boc-deprotected copolymers may exhibit pH-induced phase transition behavior in aqueous medium on account of reversible protonation/deprotonation of the primary amine groups in the side-chain of


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copolymers. Thus pH-dependent thermo-responsiveness of copolymers (Figure 5) and their complexes were studied by turbidity measurements of their aqueous solutions by UV-vis spectrometer (Figure 6 and Figure S10). The TCP values measured for different copolymers and their complexes with RM β-CD at various pH are presented in Table 2 and Table S1. In DPFNx series, the TCP remained almost unchanged at pH values 6.5, 6.0 and 5.5 for DPFN5, DPFN10 and their respective complexes (Table S1). But DPFN15 could be solubilised at slightly acidic pH ≤ 5.5 whereas its corresponding complex shows 3 and 5 oC higher phase transition temperature at pH 5.5 and 5.3, respectively. Among the DPFFNx series of copolymers and their respective complexes with RM β-CD, TCP values were determined at three different pH values: 5.3, 4.5 and 4.0. At pH ≤ 4.5 the amino acid content in the copolymer is not sufficient enough to alter TCP which remains nearly same as homopolymer of NIPAM whereas at pH 5.3 TCP decreases. At this pH most of the amine group exists in deprotonated form and hydrophobicity of the phenyl groups in side chain leads to decrease in TCP. Upon complex formation even though TCP increases, the values do not differ much and nature of the curve remains same. Because the copolymer DPFFN10 and its corresponding complex was soluble upto pH 6.0, TCP values were determined at pH 6.0, 5.7 and 5.3. The effect of host-guest inclusion complexation on LCST is prominent at higher pH when most of the amine exists as free primary amine in solution; in acidic pH its effect gets masked by the solubilising effect of –NH3+ functionality. On account of higher phenyl content, the copolymer DPFFN15 could be solubilised only at acidic pH 4.0 while its corresponding complex at pH ≤ 4.5. The LCST is much higher in the complex because of simultaneous effect of protonated amine and host-guest interaction. Note that these phase transitions are reversible both with respect to temperature and pH. Nevertheless, the Tcp values can be tuned to higher temperature if the pH value was decreased. Figure S11 shows the plots of %T versus temperature for heating/cooling cycle at two different pH (pH 5.1 and pH 5.3) for


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DPFN15 and its corresponding complex. Turbidimetry measurements during cooling cycle incase of copolymer complex DPFN15/RM β-CD exhibited recovery of transmittance almost to initial value (observed prior to heating) with a small hysteresis of 2 oC which implies that the

heating/cooling

rate

provides

sufficient

time

for

the

polymer-host

decomplexation/recomplexation equilibrium. Similar hysteresis (of 1-2 oC) is observed for the free copolymer DPFN15, apparently because rehydration of the aggregated hydrophobic polymer chains occur relatively faster and within the heating/cooling rate.

100

(B)

% Transmittance

80

60

40

20

pH=5.5 pH=5.3

0 20

30

40

50

Temperature (oC)

100

100

(D)

(C) 80

% Transmittance

80

% Transmittance

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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60 40

pH=6.0 pH=5.7 pH=5.3

20

0 20

30

60

40

pH=6.0 pH=5.7 pH=5.3

20

0

40

50

o

Temperature ( C)

60

70

20

30

40

50

o

60

70

Temperature ( C)

Figure 6. Plots of %T versus temperature at different aqueous solution pH of (A) DPFN15, (B) DPFN15/RM β-CD complex, (C) DPFFN10 and (D)DPFFN10/RM β-CD complex.


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Table 2. Aqueous solution properties of the deprotected Phe-Phe based copolymers and their corresponding complexes with RM β-CD. TCP(oC)

Material pH 6.0

pH 5.7

pH 5.3

pH 4.5

pH 4.0

DPFFN5

I

I

29

32

32

DPFFN5/RM β-CD

I

I

30

34

35

DPFFN10

33

37

50

N.D

N.D

DPFFN10/RM β-CD

37

39

49

N.D

N.D

DPFFN15

I

I

I

I

52

DPFFN15/RM β-CD

I

I

I

58

70

I - insoluble, N.D: not determined.

CONCLUSIONS In conclusion, an effective and simple strategy has been reported for amplification of fluorescence emission of weakly fluorescent amino acid Phe via supramolecular host-guest interaction of Phe moieties in the DPF homopolymer and RM β-CD. In the complex DPF/RM β-CD, two phenyl rings from adjacent chains (or repeating units) are brought within phenyl π-π interaction distance inside the CD cavity to form a dimer, which gives rise to strong fluorescence emission at 365 nm. Whereas for the DPFF/RM β-CD complex, emission observed from aggregated state at longer wavelength decreases at higher polymer concentration. Host-guest interaction of Phe moieties in the polymers with RM β-CD enhanced the solubility of the polymeric complex, and has been further employed in tuning TCP of two series of statistical copolymers derived from side-chain Phe/Phe-Phe based methacrylate monomers and NIPAM. In either series of copolymer complexes, DPFNx/RM β-CD and DPFFNx/RM β-CD, TCP increases with higher content of host-guest unit because of the intrinsic hydrophilicity of exterior of RM β-CD. By virtue of free amine functionality,


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TCP of copolymer complexes can be adjusted between 26 and 70 oC within pH range 4.0-6.5. The series of copolymers with broad range of TCP may find potential applicability as sensors.61,62

ASSOCIATED CONTENT Supporting Information. 1H (1D and 2D),

13

C NMR and FT-IR spectra of various

homopolymers, copolymers and their respective complexes, GPC RI traces of homopolymers (PF and PFF) and different copolymers of Boc-F/FF-EMA with NIPAM, fluorescence spectra of DPFF and complex DPFF/RM β-CD, table summarizing the aqueous solution properties of deprotected Phe based copolymers and their corresponding complexes and plots of %T versus temperature at different pH for copolymers and their complexes. ACKNOWLEDGMENTS. We are thankful to Board of Research in Nuclear Sciences (BRNS) for financial support (Sanction Number:37(2)/14/36/2014-BRNS/555). We thank Dr. Prasun Kumar Mandal (IISER Kolkata) for scientific discussions and Mr. Debjit Roy for helping with spectrofluorometric measurements. We also thank Dr. Suhrit Ghosh from Indian Association for the Cultivation of Science (IACS), Kolkata for allowing us to use their GPC facility.


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For “Table of Contents” Use Only

Supramolecular Interaction Assisted Fluorescence and Tunable StimuliResponsiveness of L-Phenylalanine Based Polymers Mridula Nandi, Binoy Maiti, Kambalapalli Srikanth and Priyadarsi De*

π- π interaction Fluorescence

Thermoresponsive pH-responsive


Supramolecular Interaction-Assisted Fluorescence and Tunable

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