http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-7-27
![[1860-5397-7-27-i1]](http://www.beilstein-journals.org/bjoc/content/inline/1860-5397-7-27-i1.png?scale=1.5&max-width=1024&background=FFFFFF)
Scheme 1:
Synthesis of copolymers 3D, 3L and CD-complexes 4D, 4L.
The resulting copolymer 3D, 3L
(1:20) is soluble in water below the critical solution temperature
(LCST). However, the presence of D- or L-Phe significantly affects the
LCST value of pure poly(NIPAAm) (32 °C), since the
hydrophilic/hydrophobic balance of the polymer is changed [17,18]. As noted above, incorporation of the hydrophobic phenylalanine moieties into the polymer reduces the LCST to 25 °C for the 3D, 3L (1:20) copolymer, whereas the 3D, 3L (1:10) copolymer is relatively hydrophobic and not water-soluble.
Surprisingly, the polymers 3D, 3L (1:10) become water-soluble due to host–guest interaction with RAMEB-CD yielding 4D and 4L.
To confirm the formation of the proposed inclusion complexes between the copolymers and CD, which was added in excess, the corresponding monomers 2D and 2L were used as models to prove complexation.
Thus, 2D ROESY NMR spectroscopy was performed to show the correlation between the protons of the β-CD and the protons of the guest 2D. Figure 1 indicates as an example the case of 2D where interactions of protons from the phenyl group with protons of the CD cavity are shown, while no interactions with protons of the outer rim are apparent. Furthermore, there is a second interaction of the protons of the double bond of 2D with the CD cavity. Therefore, it can be concluded, that the complex composition with 2D or 2L has a stoichiometry of 1:2.
To assure for further investigations that the complexation also takes place in the copolymer, additional ROESY experiments were carried out (Figure 2).
Furthermore, both a shift of proton signals and the duplication of proton signals can be detected when the spectra of the complex is compared to the pure compounds 2D and 2L (Figure 3).
Figure 3 shows the specific shifts of signals, which occur on complexation. CDs being chiral molecules themselves effect a downfield shift of 0.1 ppm of the aromatic proton signal since the protons are magnetically shielded by the CD cavity. Additionally, each of the aromatic and double bond proton signals, respectively, change from singlets to doublets on complexation.
Obviously, the supramolecular structure changes and former magnetically identical protons become non-equivalent protons and appear as doublets. This can easily be observed in case of aromatic protons at 7.31–7.14 ppm and the proton signal of the double bond at 5.6 ppm and 6.0 ppm, respectively. The signal of the proton next to the double bond (6.3 ppm) remains unffected. The described shift of proton signals can be detected for both enantiomers, but with different intensities as can be observed in Figure 4.
As expected, we found that 1H NMR spectra of complexed compounds 2D and 2L with β-CD show differences in the splitting pattern of the proton signals (Figure 4). Therefore we conclude that the complex stability is different for 2D and 2L and 4D and 4L, respectively.
To further prove the complexation process of β-CD as host and the Phe derivatives 2D and 2L as guests, we visualized the complexation utilising phenolphthalein [19], i.e., the complexation and decomplexation of a dye with β-CD in basic medium can be employed as a method to prove these processes [20]. In basic media, phenolphthalein exhibits its characteristic pink colour, caused by its planar configuration and electron delocalisation.
On adding cyclodextrin to the solution, phenolphthalein becomes colourless in the complexed state. Hydrogen bond formation is accompanied with a conformational change as the planar state of phenolphthalein is reversed which leads to loss of colour. Taking this into account, the addition of a competitive guest molecule should displace the included phenolphthalein and turn the colour of the solution from colourless to pink. Accordingly, the addition of 2D followed by stirring for one hour caused the solution to regain its characteristic pink colour as Figure 5 shows.
Surprisingly, the polymers 3D, 3L (1:10) become water-soluble due to host–guest interaction with RAMEB-CD yielding 4D and 4L.
To confirm the formation of the proposed inclusion complexes between the copolymers and CD, which was added in excess, the corresponding monomers 2D and 2L were used as models to prove complexation.
Thus, 2D ROESY NMR spectroscopy was performed to show the correlation between the protons of the β-CD and the protons of the guest 2D. Figure 1 indicates as an example the case of 2D where interactions of protons from the phenyl group with protons of the CD cavity are shown, while no interactions with protons of the outer rim are apparent. Furthermore, there is a second interaction of the protons of the double bond of 2D with the CD cavity. Therefore, it can be concluded, that the complex composition with 2D or 2L has a stoichiometry of 1:2.
To assure for further investigations that the complexation also takes place in the copolymer, additional ROESY experiments were carried out (Figure 2).
![[1860-5397-7-27-1]](http://www.beilstein-journals.org/bjoc/content/figures/1860-5397-7-27-1.png?scale=2.0&max-width=1024&background=FFFFFF)
![[1860-5397-7-27-2]](http://www.beilstein-journals.org/bjoc/content/figures/1860-5397-7-27-2.png?scale=2.0&max-width=1024&background=FFFFFF)
Figure 2:
2D NMR ROESY experiment showing the correlation between protons of the phenyl moiety of 4D with the β-CD protons.
The NMR experiments clearly show that the complexation takes place in
monomer and polymer solutions, for both enantiomers (also see Supporting Information File 1).Furthermore, both a shift of proton signals and the duplication of proton signals can be detected when the spectra of the complex is compared to the pure compounds 2D and 2L (Figure 3).
Figure 3 shows the specific shifts of signals, which occur on complexation. CDs being chiral molecules themselves effect a downfield shift of 0.1 ppm of the aromatic proton signal since the protons are magnetically shielded by the CD cavity. Additionally, each of the aromatic and double bond proton signals, respectively, change from singlets to doublets on complexation.
![[1860-5397-7-27-3]](http://www.beilstein-journals.org/bjoc/content/figures/1860-5397-7-27-3.png?scale=1.6&max-width=1024&background=FFFFFF)
Obviously, the supramolecular structure changes and former magnetically identical protons become non-equivalent protons and appear as doublets. This can easily be observed in case of aromatic protons at 7.31–7.14 ppm and the proton signal of the double bond at 5.6 ppm and 6.0 ppm, respectively. The signal of the proton next to the double bond (6.3 ppm) remains unffected. The described shift of proton signals can be detected for both enantiomers, but with different intensities as can be observed in Figure 4.
As expected, we found that 1H NMR spectra of complexed compounds 2D and 2L with β-CD show differences in the splitting pattern of the proton signals (Figure 4). Therefore we conclude that the complex stability is different for 2D and 2L and 4D and 4L, respectively.
![[1860-5397-7-27-4]](http://www.beilstein-journals.org/bjoc/content/figures/1860-5397-7-27-4.png?scale=1.6&max-width=1024&background=FFFFFF)
To further prove the complexation process of β-CD as host and the Phe derivatives 2D and 2L as guests, we visualized the complexation utilising phenolphthalein [19], i.e., the complexation and decomplexation of a dye with β-CD in basic medium can be employed as a method to prove these processes [20]. In basic media, phenolphthalein exhibits its characteristic pink colour, caused by its planar configuration and electron delocalisation.
On adding cyclodextrin to the solution, phenolphthalein becomes colourless in the complexed state. Hydrogen bond formation is accompanied with a conformational change as the planar state of phenolphthalein is reversed which leads to loss of colour. Taking this into account, the addition of a competitive guest molecule should displace the included phenolphthalein and turn the colour of the solution from colourless to pink. Accordingly, the addition of 2D followed by stirring for one hour caused the solution to regain its characteristic pink colour as Figure 5 shows.
![[1860-5397-7-27-5]](http://www.beilstein-journals.org/bjoc/content/figures/1860-5397-7-27-5.png?scale=1.6&max-width=1024&background=FFFFFF)
Figure 5:
Complex formation with phenolphthalein and phenylalanine as competitor.
amcrasto@gmail.com
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
amcrasto@gmail.com
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
amcrasto@gmail.comhttp://newdrugapprovals.org/
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO amcrasto@gmail.comhttp://newdrugapprovals.org/
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
