Polienonlara amin ve amino asitlerin katılması

Yarbaş, Tuğrul
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Fen Bilimleri Enstitüsü
Dialdehitlerin aseton veya aktif metilen içeren baska bilesiklerle kondensasyonuyla elde edilen polidienonlar çözünmezlikleri yüzünden çok az ilgi gÖrmüslerdir. Polidienonlann tam bir sistem elde etmek amacwla incelenmelerine ražmen, ortaya çlkan maddelerin elektriksel iletkenliäinin çok az olduäu bildirilmi§tir. Bu maddeler genellikle düsük birlesmeye. isazeb eden agak. veya koyu kahverengi rengindedirler. Dižer yandan, enonlann karbon—karbon çift baäla.l'l nükleofilik katllma reaksiyonlanna uygundur. Orneäin, aminlerin Michael tipi katllmasl amino ketonlarl olusturur. Amonyaäln mesitiloksit ile reaksiyonu 2 amino izopropil metil keton verir. Bu çahsmada, tereftalaldehidin asetonla kondensasyonu slraslnda o- OHC O CHO + H3C — C - CH3+ fH2 coo- NH NH CH2 CH2 coo- coo- Ortaya çlkan polimerin ilginç bir özelliä•i, amino asitlerin zwitter iyonik karakterini belirten asidik ve bazik su çözeltilerinde çözünebilir- NaOH (katalizör) konsantrasyonunda, fonksiyonlaêtlrllmasl neredeyse nicelikseldir. Aldehitlerin amino grubuyla aldimin ve aldehitamin olu$uran reaksiyonlarl yoäun NaOH çözeltileriyle devam ettirilirler. Bu yolla, glisin ve alanin gibi, amino asit ta.§lyan, 1500—6500 molekül ažlrllkll poliketonlar elde edilmi§tir.
Amino acid containing polymers have found substantial interest in medical applications such, as polymeric drugs, electrodialysis membranes, enzyme carriers, etc. ce-amino acids are, by far, the most important, since they are essential building units of all proteins. With the exception of glycine, all the a- amino -acids posses asymmetric carbon atom, and are optically active in nature. Except glycine, all the ce-amino acids possessing L- configurations are obtained by acid or enzymic hydrolysis of proteins. Proteins are nat urally occurring polymers which are built up of various a- amino acids. These polymers are formed in body by enzymic dehydration of amino acids, in which molecular weights range from 5000 to a million. Labora tory preparation of proteins, which are called polypeptide, is somewhat difficult. For instance, thermal dehydration of cc-amino acids does not give polypeptide, instead this process results in cyclodimerization to give 1,4 diketopiperazines. Laboratory preparation of polypeptide is achieved by stepwise con densation of N- or C-protected amino acids. Thus, an a-- -amino acid, which is N-protected by t-butyloxy carbonyl group, is interacted with another cc-amino acid, which is C- terminated by esterification in the presence of a dehydrating agent such as DCC. This procedure gives a dipeptide. Then, ester group is removed by regioselective hydrolysis with HBr-CHsCOOH and peptide linkage is exterited from this end. - Boc-NH2 -CHfCOOH + H2 N-ÇH-COOR -5gL R R O o Boc-NH-CH:C-NH-CH-COOR -S£». Boc-NH-ÇH-C-NH-ÇH-COOH R R hydrolysis R R (dipeptide) VI Step 1 and step 2 axe repeated with dipeptide and C- terminated amino acid to obtain tripeptide. Thus, a peptide chain can be built up from one end by repeated interaction with esterified amino acid. This requires a final removal of N- protecting group. By this way, Fisher (1901-1907) was able to prepare 18- membered polypeptide chain. Structurally, polypeptides can be regarded as Nylon-2's. Many pro tecting groups have been introduced. Among them, five amino protecting groups are important. These are benzyloxy carbonyl, t- butoxy carbonyl (Boc), triphenylmethyl (trityl), ptoluene sulfonyl (Tosyl, Ts- ) and ph- taloyl. A common protecting group for carboxyl group is its methyl or ethyl esters. It is important that protecting group should be easily introduced and removed under mild conditions, so that the peptide bond is not hydrol- ysed and that no racemisation occurs. A different approach to peptide synthesis is N-carboxyanhydrate (NCA) method. In this method, an a- amino acid is first treated with phosphene in aprotic solvents to give a cvclic carbamic acid anhydride. 0 II R-CH^ + COCU *- R-CH \nh2 I NH\ II 0 The resulting NCA derivative is polymerized by heating in an organic solvent such as dimethylformamide, dioxane, etc., in the presence of a catalyst, e.g. amines, water, etc. The polymerization proceeds via CO2 evolution O II Q n R-CH^ \. A °,0 NH- 9 *" £ NH-CH-cJ + n CO, ^C 11 0 I Jn-1 R The resulting polypeptide consists of one type of amino acid. If a mix ture of different anhydrides is used, the product is a polymer containing different residues in random distribution. vu Recently, polyglutamide membrane obtained by this procedure has been demonstrated to be very efficient in electrodialysis for enantioselec- tive separation of rasemic mixtures of amino acids. Perhaps, the most elegant approach to prepare polypeptides is solid- phase synthesis, which was first introduced by Merrifeld in 1963. In solid-phase synthesis, an amino acid or a peptide is bound chemically to an insoluble chloromethyl styrene-divinyl benzene resin. Then the chain is built up by the procedure in accordance with the method given above. The method may be illustrated as follows: step 1 Boc-NH-CH-COOH I Et3N R solid phase O il step 2 H2-O-C-CH-NH-B0C »- l 1. HCI-CH3 -COOH 2. Et3N step 3 HOOC-CH-NH-Boc "H2° DCC R O o o II II ? CH2-0-C-CH-NH-C-CH-NH-BOC By repeating the steps 2 and 3, a desired length of polypeptide is prepared. When the desired peptide has been synthesized, the esterbound unking it to the resin can be split by dry HBr in trifluoro acetic acid. This method has been automated, that each addition of the appro priate amino acid is carried out automatically at a predetermined time. Some outstanding advantages of the solid-phase method are: i) Because of the use of an insoluble solid support, purification of the products is easily performed by a simple filtration, and washing with a suitable solvent. vui ii) The yields axe generally high. Hi) The time has been considerably shortened. iv) The order of amino acid sequences and the number of the repeating units can be predetermined. A brief insight which we have been concerned so far is devoted to the polymers consisting of amino acids in the main chain. There are few successful models to prepare the polymers with the amino acids as pendant units. One of the all well-known procedure is Mannich reaction of amino acids with formaldehyde and a suitable proton donor such as acetone or malonic acid derivatives. O u CH3-C-CH3 NH, + CH,0 I z CH-R I COOH -^.CH2-CH2-C-CH2-CH2-N^ CH-R I COOH By this procedure, low molecular weight peptides, in which nitrogen of amino acid is a member of the chain, are obtained. Another approach for the direct incorporation of amino acids into polymers is Michael condensation of amino acids via amino groups to the activated double bonds in bisaycryl amides. O O CH2=CH-C-NH-CH2-NH-C-CH=CH2 NH, I CH-R I COOH i N-CH2-CH2-C-NH-CH2-NH-C-CH2-CH2:[- CH-R I COOH CH2=CH-C-N - CHj-CHj-C-N O N-C-CH=CH, N-C-CH2-CH2-N j CH-R I COOH NH2 CH-R I COOH IX o CH2=CH-C-N' O N-C-CH=CH2 N-C-CH2-CH2-N n CH2 i COONa NHa ÇH2 COONa By this method, low molecular weight water soluble amino acid poly mers are obtained. A different method involves preparation of N-acryloyl amino acids and their radical polymerization to give high molecular weight polymers. CH,=CH + I c=o I ci NH2 I CH-R I COOH CH,=CH-C-NH-CH-COOH I R' poly- -eCH2-ÇH^ I C-NH-CH-COOH II I O R In the present study, we have described a new method for incorpora tion of amino acids into polymer. This method is based on Michael-type of addition of amino groups of amino acids to the activated double bonds in polychalgones. Generally, ethylenic bonds in enones are known to be susceptible to the addition of amines, thioles and hydrocyanic acid. For instance, benzal acetone readily reacts with hydroxyl amine to form corresponding hydroxyl amine. <0> - CH II CH c=o I CH, NH2-OH ©- CH-NH-OH I CH, I z c=o I CH, This reaction seems to be general for all enones. A simple dienone, 1,4 benzoquinone also reacts with amines to give amino substituted quinone. R-NHa it O NH-R NH-R oxid. NH-R X The intermediate hydroquinone is reduced by unreacted qiunone in the mixture to form aminoquinone. This reaction has recently been used to obtain thermally stable polyquinones, starting from 1,4 benzoquinone and a suitable aromatic diamine. H#-(Cjy-HH> J^HM^O^-I» U 9 -in o n In the stud^kbenzalacetone was chosen as the..model compound and, its amino acid addition capabiHty was tested by interacting with glycine and L-alanine.. ' O NH2. ff + R-CB *~ (( J>- CH-NH-CH-COOH COOH 9^ c=o uuüh r c=o I CH, H-NMR spectra and potentiometric titration of the resulting product establish the proposed addition compound. At the second step of the study, acetone-terephtalaldehyde polymer was prepared. By adjusting the amount of the catalyst NaOH, we were able to prepare soluble acetone-terephtalaldehyde polymer which has molecular weight 4600. The higher amounts of NaOH in different sol vents resulted in formation of insoluble polymers. H-NMR spectra of the soluble polymer represent a similar pattern with those given by Kaul and Fernandez. In the spectra, the peak around 6, 10 ppm, has been assigned as proton of enolate form by these authors. However, no evidence has been indicated on this point. The same peak is also observed in our case. However, we also observed additional aliphatic proton peaks between 2,5-3,5 ppm. Also the signals of enolate protons are not observed at so much lower frequencies. For this reason, the signal at about 10 ppm cannot be assigned to enolate proton. Instead, it must belong to aldol proton which forms at the first step of interaction with acetone. Because of this fact, aliphatic proton signals are also observed. This signals must represent aldol proton prior to dehydration step. Attempts to addition of glycine and alanine to the acetone-terephtal aldehyde polymer gave different degree of additions ranging from 36-62%, depending on the reaction time and the solvent used. It is interesting to note that, after addition of amino acids, the poly- XI mer becomes totally soluble in water. This is also another clear evidence of amino acid addition to the polymer. Moreover, we have treated the insoluble acetone-terephtalaldehyde polymer with excess of ethanol amine. Ethanol amine behaves both as reagent and solvent. After addition of ethanol amine, the product sur prisingly becomes soluble in ethanol amine itself and it is also soluble in acidified water. This observation clearly indicates that insoluble acetone- terephtalaldehyde polymer is not in crosslinked form. As a consequence, active ethylenic groups in acetone-terephtalalde hyde polymer is suitable for addition of amino acids and various amino compounds, including proteins. And the method presented here offers a new route to prepare amino acid containing polymers. These new polymers are expected to find var ious applications in medicine and physical chemistry, etc.
Tez (Yüksek Lisans) -- İstanbul Teknik Üniversitesi, Fen Bilimleri Enstitüsü, 1996
Anahtar kelimeler
Kimya, Aminler, Amino asitler, Polienonlar, Chemistry, Amines, Amino acids, Polyenones