Amine-hydrochloride initiators

Scheme 12 Polypeptide synthesis using amine-hydrochloride initiators...

The polymerizations initiated by HMDS and N-TMS amines usually complete within 24 h at ambient temperature with quantitative monomer consumption. These polymerizations in general are slower than those mediated by Deming s Ni(0) or Co (0) initiators (about 30-60 min at ambient temperature) [19, 24, 25], but are much faster than those initiated by amines at low temperature or using amine hydrochloride initiators [20]. These HMDS and N-TMS amine-mediated NCA polymerizations can also be applied to the preparation of block copolypeptides of defined sequence and composition [22]. This organosilicon-mediated NCA polymerization, which was also shown by Zhang and coworkers to be useful for controlled polymerization of y-3-chloropropanyl-L-Glu NCA [43], offers an advantage for the preparation of polypeptides with defined C-terminal end-groups. 

Although more studies need to be performed to study the scope and generality of this system, the use of amine hydrochloride salts as initiators for controlled NCA polymerizations shows tremendous promise. The concept of fast, reversible deactivation of a reactive species to obtain controlled polymerization is a proven concept in polymer chemistry, and this system can be compared to the persistent radical effect employed in all controlled radical polymerization strategies [34]. Like those systems, the success of this method requires a carefully controlled matching of the polymer chain propagation rate constant, the amine/amine hydrochloride equilibriiun constant, and the forward and reverse exchange rate constants between amine and amine hydrochloride salt. This means it is likely that reaction conditions (e.g. temperature, halide counterion, solvent) will need to be optimized to obtain controlled polymerization for each different NCA monomer, as is the case for most vinyl monomers in controlled radical polymerizations. Within these constraints, it is possible that controlled NCA polymerizations utilizing simple amine hydrochloride initiators can be obtained. 

The two approaches that have been discussed so far, viz transition-metal-mediated and primary amine hydrochloride initiated NCA ring-opening pol5nnerization. 

Another innovative approach to controlling amine-initiated NCA polymerizations was reported in 2003 by Schlaad and coworkers [20]. Their strategy was to avoid formation of NCA anions, which cause significant chain termination after rearranging to isocyanocarboxylates [11, 12], through use of primary amine hydrochloride salts as initiators. The reactivity of amine hydrochlorides with NCAs was first explored by the group of Knobler, who found that they could react... 

Although more studies need to be performed to study the scope and generality of this system, the use of amine hydrochloride salts as initiators for controlled NCA polymerizations shows tremendous promise. Fast, reversible deactivation of a reactive species to obtain controlled polymerization is a proven concept in polymer chemistry, and this system can be compared to the persistent radical effect employed in all controlled radical polymerization strategies [37]. Like those systems, success of this method requires a carefully controlled matching of the... 

Secondary amines give the aminosilane, with the more hindered amines requiring heating under pressure. With primary amines, the aminosilane is formed initially, but the size of the substituents at nitrogen and silicon determines whether deamination subsequently occurs. Prolonged heating under reflux in the presence of ammonium sulfate, or the precipitated amine hydrochloride as acid catalyst yields the disilazane in good yield. 

The basicity of an amine can be used for purification. The amine is initially more soluble in ether than in water. Addition of dilute HC1 converts it to the water-soluble hydrochloride salt. Neutralization with NaOH regenerates the free amine. 

The anti addition of diethyl 7V,Ar-dibromophosphoramidates to acyclic and cyclic alkenes was achieved in the presence of boron trifluoride, which makes the ionic dissociation of the N —Br bond more labile94,9s. After reduction of the initial /J,lV-dibromo adducts with sodium bisulfite, the /i-bromo-A -hydrophosphoramides 3 precursor of / -bromo amine hydrochlorides 4 were obtained (Table 4). However, a mixture of diastereomers was obtained from (Z)-l-phenyl-l-propene and (E)- and (Z)-l,2-diphenylethylene. Direct assignment of stereochemistry by H NMR of the phosphoroamidates derived from 2-butenes was not possible. Detailed analysis is, however, possible for the H-NMR spectra of the /J-bromo amine hydrochlorides. As determined by 31P NMR spectroscopy all additions to unsymmetrical aliphatic alkenes were not regiospecific. The /f-bromo amine hydrochlorides were converted to 1,2-diamines95. 

Preparatiou. The carbonate (1) is prepared in 65-70% yield by treatment of benzoin (1.0 eq.) and phosgene (1.1 cq.) in benzene with distilled N,N-dimelhylaniline at 5°. After stirring overnight at room temperature the amine hydrochloride is filtered, and the filtrate refluxed for 3 hr. to cydize the initially formed chloroformatc. 

This type of lactam polymerization is initiated under anhydrous conditions with acids or acid salts which do not split off water at the polymerization temperature (e.g., lactam or amine hydrochloride) as well as with some Lewis acids [176, 177]. The activated species is the monomer cation which takes part both in the initiation and propagation reactions. 

Fig. 19. Concentration of amine hydrochloride during cationic polymerization of caprolactam [186], Initiator caprolactam hydrochloride (0.44 mole kg ), or a mixture of benzylamine hydrochloride (0.47 mole kg ) + acetylcaprolactam (0.47 mole kg ). Temperature, 160°C.

Due to the high rate of both disproportionation and aminolytic reactions at elevated temperatures (above 200°C for caprolactam), the equilibrium (90) is attained during the first minutes of polymerization [186, 187]. Hence, the initiation with lactam hydrochloride is practically equivalent to the initiation with an equimolar mixture of an acyllactam with a primary amine hydrochloride (provided that the amine is similar to the growing end group with respect to steric effects and basicity). 

With the present series of monomers, described in Table I, the polymerization methods studied were the same as those described in previous work (2). Again, polymerization of concentrated aqueous solutions of the amine hydrochlorides using the titaneous chloride/ hydrogen peroxide initiation system provided the best polymerization method. Where this technique did not yield polymers, other free-radical initiation systems were equally unsuccessful. Table II gives some examples of the results of these polymerization experiments. 

The non-aqueous potentiometric titration of amine hydrochloride salts, introduced by Pifer-Wollish and used in the assay of various phenothiazine derivatives can be applied to the determination of propiomazine hydrochloride. The procedure involves initial reaction of the amine hydrochloride group with mercuric acetate in an acetic acid medium. The halide is tied up as undissociated HgClg and the acetate ion liberated can be titrated as a base with perchloric acid, hercuric acetate is essentially undissociated in acetic acid and the excess, therefore, does not interfere. 

---