Activated substrates

In other systems electrophiles other than the nitronium ion are involved with activated substrates (in these cases intermolecular selectivity is high, whereas with nitronium salts it is low). 

An advantage that sulfonate esters have over alkyl halides is that their prepara tion from alcohols does not involve any of the bonds to carbon The alcohol oxygen becomes the oxygen that connects the alkyl group to the sulfonyl group Thus the configuration of a sulfonate ester is exactly the same as that of the alcohol from which It was prepared If we wish to study the stereochemistry of nucleophilic substitution m an optically active substrate for example we know that a tosylate ester will have the same configuration and the same optical purity as the alcohol from which it was prepared... 

Fluoroboric acid is used as a stripping solution for the removal of solder and plated metals from less active substrates. A number of fluoroborate plating baths (27) require pH adjustment with fluoroboric acid (see Electroplating). 

Less activated substrates such as uorohaloben2enes also undergo nucleophilic displacement and thereby permit entry to other useful compounds. Bromine is preferentially displaced in -bromofluoroben2ene [460-00-4] by hydroxyl ion under the following conditions calcium hydroxide, water, cuprous oxide catalyst, 250°C, 3.46 MPa (500 psi), to give -fluorophenol [371-41-5] in 79% yield (162,163). This product is a key precursor to sorbinil, an en2yme inhibitor (aldose reductase). 

Fig. 4.56. Schematic diagram of a SERS-active substrate and the measurement arrangement. Alumina nanoparticles are deposited on a glass surface and produce the required roughness. A thin silver layer is evaporated on to the nanoparticles and serves for the enhancement. Organic molecules adsorbed on the silver surface can be detected by irradiation with a laser and collecting the Raman scattered light.

These results demonstrate some interesting chemical principles of the use of acrylic adhesives. They stick to a broad range of substrates, with some notable exceptions. One of these is galvanized steel, a chemically active substrate which can interact with the adhesive and inhibit cure. Another is Noryl , a blend of polystyrene and polyphenylene oxide. It contains phenol groups that are known polymerization inhibitors. Highly non-polar substrates such as polyolefins and silicones are difficult to bond with any technology, but as we shall see, the initiator can play a big role in acrylic adhesion to polyolefins. 

For less activated substrates, specific tests are desirable. These are available in some cases. Thus Amstutz etal. showed that the reaction of 3-, 6-, and 8-bromoquinolines with piperidine at about 200° produced normal substitution products. 

It is quite reasonable to expect the bimolecular two-stage mechanism Sj Ar ) to predominate in most aromatic nucleophilic substitutions of activated substrates. However, only in rare instances is there adequate evidence to rule out the simultaneous occurrence or predominance of other mechanisms. The true significance of the alternative mechanisms in azines needs to be determined by trapping the intermediates or by applying modem separation and characterization methods to the identification of at least the major portion of the products, especially in kinetic studies. 

Stable heterocyclic compounds having the intermediate-complex structure are well known. Where these compounds result from addition of a strongly nucleophilic anion to an A-alkylazinium cation or to a very activated substrate or must pass through a high-energy second... 

Entries 7, 8, and 10 describe so-called Idnetically controlled syntheses starting from activated substrates such as ethyl esters or lactose. In two reaction systems it was possible to demonstrate that ionic liquids can also be useful in a thermodynamically controlled synthesis starting with the single components (Entry 11) [39]. In both cases, as with the results presented in entry 6, the ionic liquids were used with addition of less than 1 % water, necessary to maintain the enzyme activity. The yields observed were similar or better than those obtained with conventional organic solvents. 

The choice of solvent is not trivial and, generally, the reaction medium must be a good solvent for both monomers and polymer product. In addition, to obtain high molecular weight, water needs to be removed from the system to avoid hydrolyzing the activated substrate, since hydrolysis reduces the reaction rate and upsets the stoichiometry of the monomers.61 63... 

Nitrilases catalyze the synthetically important hydrolysis of nitriles with formation of the corresponding carboxylic acids [4]. Scientists at Diversa expanded the collection of nitrilases by metagenome panning [56]. Nevertheless, in numerous cases the usual limitations of enzyme catalysis become visible, including poor or only moderate enantioselectivity, limited activity (substrate acceptance), and/or product inhibition. Diversa also reported the first example of the directed evolution of an enantioselective nitrilase [20]. An additional limitation had to be overcome, which is sometimes ignored, when enzymes are used as catalysts in synthetic organic chemistry product inhibition and/or decreased enantioselectivity at high substrate concentrations [20]. 

Active Substrate. If a new stereogenic center is ereated in a molecule that is already optically active, the two diastereomers are not (except fortuitously) formed in equal amounts. The reason is that the direction of attack by the reagent is determined by the groups already there. For certain additions to the carbon-oxygen double bond of ketones containing an asymmetric a carbon. Cram s rule predicts which diastereomer will predominate (diastereo-selecti vity). ... 

When an optically active substrate reacts with an optically active reagent to form two new chiral centers, it is possible for both centers to be created in the desired sense. This type of process is called double asymmetric synthesis (for an example, see p. 1222). 

Alkyl halides can be hydrolyzed to alcohols. Hydroxide ion is usually required, except that especially active substrates such as allylic or benzylic types can be hydrolyzed by water. Ordinary halides can also be hydrolyzed by water, if the solvent is HMPA or A-methyl-2-pyrrolidinone." In contrast to most nucleophilic substitutions at saturated carbons, this reaction can be performed on tertiary substrates without significant interference from elimination side reactions. Tertiary alkyl a-halocarbonyl compounds can be converted to the corresponding alcohol with silver oxide in aqueous acetonitrile." The reaction is not frequently used for synthetic purposes, because alkyl halides are usually obtained from alcohols. 

Yet another approach uses electrolysis conditions with the alkyl chloride, Pe(CO)s and a nickel catalyst, and gives the ketone directly, in one step. In the first stage of methods 1, 2, and 3, primary bromides, iodides, and tosylates and secondary tosylates can be used. The second stage of the first four methods requires more active substrates, such as primary iodides or tosylates or benzylic halides. Method 5 has been applied to primary and secondary substrates. 

The rate of the reaction with most reagents is proportional to the concentration of NO2, not to that of other species. When the reagent produces this ion in small amounts, the attack is slow and only active substrates can be nitrated. In concentrated and aqueous mineral acids the kinetics are second order first order each in aromatic substrate and in nitric acid (unless pure nitric acid is used in which case there are pseudo-first-order kinetics). But in organic solvents, such as nitromethane, acetic acid, and CCI4, the kinetics are first order in nitric acid alone and zero order in aromatic substrate, because the rate-determining step is formation of NOj and the substrate does not take part in this. 

Ring nitrosation with nitrous acid is normally carried out only with active substrates such as amines and phenols. However, primary aromatic amines give diazonium ions (12-47) when treated with nitrous acid, " and secondary amines tend to give N-nitroso rather than C-nitroso compounds (12-49) hence this reaction is normally limited to phenols and tertiary aromatic amines. Nevertheless secondary aromatic amines can be C-nitrosated in two ways. The N-nitroso compound first obtained can be isomerized to a C-nitroso compound (11-32), or it can be treated with another mole of nitrous acid to give an N,C-dinitroso compound. Also, a successful nitrosation of anisole has been reported, where the solvent was CF3COOH—CH2CI2. " ... 

The reaction with disubstituted formamides and phosphorus oxychloride, called the Vilsmeier or the Vilsmeier-Haack reaction,is the most common method for the formylation of aromatic rings. However, it is applicable only to active substrates, such as amines and phenols. An intramolecular version is also known.Aromatic hydrocarbons and heterocycles can also be formylated, but only if they are much more active than benzene (e.g., azulenes, ferrocenes). Though A-phenyl-A-methyl-formamide is a common reagent, other arylalkyl amides and dialkyl amides are also used. Phosgene (COCI2) has been used in place of POCI3. The reaction has also been carried out with other amides to give ketones (actually an example of 11-14),... 

This reaction is similar to 13-1 and, like that one, generally requires activated substrates. With unactivated substrates, side reactions predominate, though aryl methyl ethers have been prepared from unactivated chlorides by treatment with MeO in HMPA. This reaction gives better yields than 13-1 and is used more often. A good solvent is liquid ammonia. The compound NaOMe reacted with o- and p-fluoronitrobenzenes 10 times faster in NH3 at — 70°C than in MeOH. Phase-transfer catalysis has also been used. The reaction of 4-iodotoluene and 3,4-dimethylphenol, in the presence of a copper catalyst and cesium carbonate, gave the diaryl ether (Ar—O—Ar ). Alcohols were coupled with aryl halides in the presence of palladium catalysts to give the Ar—O—R ether. Nickel catalysts have also been used. ... 

Unlike 14-18, the Heck reaction is not limited to activated substrates. The substrate can be a simple alkene, or it can contain a variety of functional groups, such as ester, ether,carboxyl, phenolic, or cyano groups. It can also be a... 

Because of the nature of the transition state in the pericyclic mechanism, optically active substrates with a chiral carbon at C-3 or C-4 transfer the chirality to the product, making this an enantioselective synthesis (see p. 1451 for an example in the mechanistically similar Claisen rearrangement). ... 

This reaction to bicyclic compounds containing the aziridine group was also observed for other amides, viz., 44c-f, when treated with a catalytic amount of f-BuOK in THF or MeONa in methanol. LDA treatment of the tosyl-activated substrate 44 a gave the five-membered ring product albeit in a low yield (31 %). Remarkably, the carboxamide derived from the cz5-aziridine failed to react with base, probably due to steric hindrance. 

---