A new dendrimer series: synthesis, free radical scavenging and protein binding studies
Authors: Dhaval Makawana
Man Singh
Journal: RSC Advances (2020)
Discipline: CHEMISTRY
Keywords: TOBT; THBT; TDBT; dendrimers; synthesis
Affiliations: School of Chemical Sciences, Central University of Gujarat, Gandhinagar-382030, India

Abstract:  Tri-o-tolyl benzene-1,3,5-tricarboxylate (TOBT (T0)), tri-4-hydroxyphenyl benzene-1,3,5-tricarboxylate (THBT (T1)), and tri-3,5-dihydroxyphenyl benzene-1,3,5-tricarboxylate (TDBT (T2)), a series of 1st tier dendrimers with a common 1,3,5-benzenetricarbonyl trichloride/trimesoyl chloride (TMC) core, are reported. T0 does not have any replaceable H+ on its terminal phenyl group, acting as a branch. T1 has one phenolic -OH at the para position and T2 has two phenolic -OH groups at the 3 and 5 positions of each terminal phenyl group. During synthesis, these -OH groups at the terminal phenyl groups were protected through tert-butyldimethylsilyl chloride (TBDMSCl) assisted with t-BuOK in DCM, THF, indazole, 4-dimethylaminopyridine (DMAP), and tertiary-n-butyl ammonium fluoride (TBAF). MTBDMSP (mono-tertiary butyl dimethylsilane phloroglucinol), DTBDMSP (di-tertiary butyl dimethylsilane phloroglucinol), and TTBDMSP (tri-tertiary butyl dimethylsilane phloroglucinol) were obtained with &gt;90% yield, and TTBDMSP phenolic derivatives (PDs) were developed to synthesize T0, T1, and T2 dendrimers by deprotecting with TBAF. T0 showed superhydrophobic properties as it did not dissolve in methanol, contrary to T1 and T2, but dissolved in acetone. Their structures were determined using 1H and 13C NMR spectroscopies, and mass spectrometry. Their scavenging activities were studied using UV-Vis spectrophotometry compared with ascorbic acid and protein binding was studied with bovine serum albumin (BSA) and lysozyme (lyso). T0 exhibited exceptional optical activity contrary to T1 and T2, which acted as antioxidants to scavenge free radicals. 

Retracted: No

PubPeer comments:
 In this research article, in section 3.2 u201cScavenging activities and kinetics of the dendrimersu201d on page 21921, there is sentence u2013 u201cA H+ ion accepts the extra electron of DPPH and develops a u2013Nu2013H covalent bond by reduction.u201d How come the H+ ion accepts the extra electron of DPPH and develops a u2013Nu2013H covalent bond? Explanation = The covalent bond is not at all possible in this scenario. This statement by the author is violating the fundamental concept of a covalent bond. To support my view, I am quoting the paragraph describing the concept of u201cCovalent Bondsu201d from Organic Chemistry, 4th Edition (PDF) by Paula Yurkanis Bruice. It is as follow - u201cCovalent Bonds - Instead of giving up or acquiring electrons, an atom can achieve a filled outer shell by sharing electrons. For example, two fluorine atoms can each attain a filled shell of eight electrons by sharing their unpaired valence electrons. A bond formed as a result of sharing electrons is called a covalent bond. (From page 09, Organic Chemistry, 4th Edition (PDF) by Paula Yurkanis Bruice) In this research article, the author is considering a nitrogen atom and H+ ion. Now consider the nitrogen atom of DPPH radical. The nitrogen is the seventh element with a total of 7 electrons. In writing the electron configuration for nitrogen, the first two electrons will go in the 1s orbital. Since 1s can only hold two electrons, the next 2 electrons for N goes in the 2s orbital. The remaining three electrons will go in the 2p orbital. Therefore the electron configuration of nitrogen will be 1s(2) 2s(2) 2p(3). The 2 electrons in 2s orbital form a lone pair. In DPPH radical, out of three electrons in 2p orbital, the two forms the covalent bonds with neighboring atoms of the molecule while one electron remains as unpaired, and therefore it is radical. Means octate of DPPH is not completed. Question = Then how the author is saying that the u201cA H+ ion accepts the extra electron of DPPHu201d and how it is possible for formation of a covalent bond in this case? , 
 On page 21914, in section 1. u201cIntroduction,u201d the author wrote the following sentence u2013 Generally, webdrimers like PAMAM (poly(amidoamine)) or starburst dendrimers with repeated branched subunits of amide and amine functionality, like TTDMM (trimesyol-1,3,5-trimethyl malonate), TSMM (trisurfactantomethylol melamine), and others do not have replaceable hydrogen atoms. **Explanation** = There no literature reference for PAMAM denoted as a u201cwebdrimer.u201d A dendrimer is a well-accepted term for such molecules. Then why is the author trying to impose the self-coined term and replacing well-accepted term? **Question** = What is webdrimer? And why the author is calling the Polyamidoamine (PAMAM) dendrimers as webdrimer instead of dendrimer? , 
 I found several mistakes in the representation of the u201cArrow pushing or electron pushingu201d in various schemes figures in this research article. In Scheme 5 (on page 21916) the representation of the arrow pushing is entirely wrong. The representation should depict the movement of the electron from the imidazole to the dihydroxybenzene. Also, the movement of the electron depicted by the dotted arrow in this scheme is wrong. In Scheme 6 (on page 21916), how come the author is showing the dotted arrow moving from the proton to the oxygen atom of the DTBDMSH??? It is a wrong representation of the mechanism. In Fig. 4 (on page 21922), the representation of the arrow pushing is entirely wrong. **My view** = Arrow pushing or electron pushing is a technique used to describe the progression of organic chemistry reaction mechanisms. Curved arrows describe either formation or fission of covalent bonds. Almost all bonds in organic chemistry are of the 2-centre, 2-electron type, i.e., the bonding of two atoms is defined by the presence of a pair of electrons between them. Therefore, the formation of such a bond must be denoted by an arrow whose head terminates in the space between the two atoms where the electrons will be bonding in the product; conversely, the fission of such a bond must be denoted by an arrow which begins at the bond between the atoms where the electrons are bonding in the reactant. In Fig. 4 (on page 21922), such fission of bond is wrongly represented. In Fig. 8 (on page 21924) how come the author is showing the dotted arrow moving from the proton to the nitrogen atom of the DPPH??? It is a wrong representation of the mechanism. , 
 In this research article, the reported study of the antioxidant activity of dendrimers is ambiguous. **My view** = In this research article, the author is correlating the H+ (proton) releasing activities of T1 and T2 to scavenge DPPH radicals. How is it possible? The scientific literature considered an electron or hydrogen radicals responsible for the scavenging of the DPPH radical. In support of my view, I am mentioning the following paragraph from previously published research article u2013 It is as follow -------- Evaluation of the antioxidant activity of any compound can be carried out either by in vitro or in vivo models. DPPH is a stable free radical that can accept an electron or hydrogen radical to become a stable diamagnetic molecule. Due to its odd electron, the methanolic solution of DPPH shows a strong absorption band at 517 nm. As shown in the Scheme 19, the DPPH radical reacts with a suitable reducing agent producing new bond, thus changing the color of solution. The solution loses color with the increase in the concentration of antioxidant as the electrons taken up by DPPH radical from the antioxidant. Such reactivity has been used to test the ability of compounds plant extracts to act as free radical scavengers. Reduction of the DPPH radicals can be monitored spectrophotometrically by the decrease in absorbance at 517nm. (This paragraph is taken from page 28000, section 5.3 of research article RSC Adv., 2015, 5, 27986u201328006. DOI = 10.1039 c4ra13315c Link = https: pubs.rsc.org en content articlehtml 2015 ra c4ra13315c , 
 In Supporting Information of this research article in u201cFig (S1): 1H NMR of T0u201d the integration of the u201ceu201d proton is missing. , 
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