Substrate structure

A concise description of the requirements concerning the substrate structure, nature of the introducing group, and reaction medium is discussed in the following text. 

The groups to be substituted as a result of the Sj j l reaction must be stable in the form of the corresponding ion. Other substituents (not participants in the transformation) must be inert electrochemi-cally, that is, they must be insensitive to electron transfer. 

A cation arriving with a nncleophilic anion is another important factor. The nucleophile can attack the substrate in the form of a free ion or an ionic pair. As a rule, lithium salts are less reactive than sodium and potassium salts. Russell and Mndryk (1982) reported several examples of this. The sodium salt of ethyl acetylacetate reacts with 2-nitro-2-chloropropane in DMF yielding ethyl 2-(wo-propylidene) acetylacetate. Under the same conditions, the lithium salt does not react at all. Potassium diethyl phosphite interacts with l-methyl-l-nitro-l-(4-toluylsulfonyl)propane in THF and gives diethyl 1-methyl-l-nitro-l-phosphite. The lithinm salt of the same reactant does not react with the same substrate in the same solvent. 

Transformation of a substrate into its ion-radical enhances the reactivity of the species. Sometimes, this can overcome steric encumbrance of the substituent to be removed. Thus, in the case of l,4-diiodo-2,6-dimethylbenzene the photoinitiated action of the enolate ion of pinaco-lone (Me3CCOCH2 ), led to substitution of both iodines (from positions 1 and 4) (Branchi et al. 

---

The ESDIAD pattern does, however, provide very usefril infomiation on the nature and synnnetry of an adsorbate. As an example, figure A1.7.13(a) shows the ESDIAD pattern of desorbed collected from a 0.25 ML coverage of PF on Ru(OOOl) [89]. The pattern displays a ring of emission, which indicates that the molecule adsorbs intact and is bonded tlirough the P end. It freely rotates about the P-Ru bond so that tlie emission occurs at all azimuthal angles, regardless of the substrate structure. In figure A1.7.13(b), the... 

Mechanism-Control of Stereochemistry. Stereocontrol in a reaction or transform as a result of mechanistic factors rather than substrate structure alone. 

For the preparation of 2,3-dihydroindoles (8) from indoles (7), two reduction methods are known. In the column Reduction Method in the table, the one indicated A represents use of EtsSiH in TFA (79JOC4809) and the other, indicated B, employs NaBHsCN in AcOH (77S859, 88JMC1746). Although both methods are applicable, the former is generally superior to the latter. In some cases, depending on the substrates structures, the reverse cases are also observed. Examples are the reactions marked B in the column. 

Yields of the di- r-methane rearrangement reaction strongly depend on substrate structure, and are ranging from poor to nearly quantitative. Acetone and acetophenone have been used as photosensitizers." ... 

The reaction conditions for the ene reaction of simple starting materials are, for example, 220 °C for 20 h in an aromatic solvent like trichlorobenzene. Lewis acid-catalyzed intramolecular reactions have been described, e.g. with FeCls in dichloromethane at -78 °C." Yields strongly depend on substrate structure. 

In addition dimeric species are formed, being in equilibrium with the monomeric RMgX. The Schlenk equilibrium is influenced by substrate structure, the nature of the solvent, concentration and temperature. 

In general the /3-elimination proceeds by a E2-mechanism. It involves cleavage of trimethylamine and a /3-hydrogen from the original substrate alkyl group see scheme above—2 3. In some cases—depending on substrate structure and... 

The acid-catalyzed addition of an aldehyde—often formaldehyde 1—to a carbon-carbon double bond can lead to formation of a variety of products. Depending on substrate structure and reaction conditions, a 1,3-diol 3, allylic alcohol 4 or a 1,3-dioxane 5 may be formed. This so-called Prins reaction often leads to a mixture of products. 

The Rosenmund reduction is usually applied for the conversion of a carboxylic acid into the corresponding aldehyde via the acyl chloride. Alternatively a carboxylic acid may be reduced with lithium aluminum hydride to the alcohol, which in turn may then be oxidized to the aldehyde. Both routes require the preparation of an intermediate product and each route may have its advantages over the other, depending on substrate structure. 

Alternatively a Mannich-like pathway may be followed (see Mannich reaction), where ammonia reacts with the aldehyde 1 to give an intermediate iminium species, that adds hydrogen cyanide to give the a-amino nitrile 2. The actual mechanistic pathway followed depends on substrate structure and reaction conditions. 

For the mechanistic course of that reaction two pathways are discussed " a concerted [l,3]-sigmatropic rearrangement, and a pathway via an intermediate diradical species. Experimental findings suggest that both pathways are possible. The actual pathway followed strongly depends on substrate structure the diradical pathway appears to be the more important. 

The vinylcyclopropane rearrangement is of synthetic importance, as well as of mechanistic interest—i.e. the concerted vs. the radical mechanism. A reaction temperature of 200 to 400 °C is usually required for the rearrangement however, depending on substrate structure, the required reaction temperature may range from 50 to 600 °C. Photochemical and transition metal catalyzed variants are known that do not require high temperatures. 

In the case of an appropriate substrate structure, the carbenium ion species can undergo a 1,2-alkyl shift, thus generating a different carbenium ion—e.g. 4. The driving force for such an alkyl migration is the formation of a more stable carbenium ion, which in turn may undergo further rearrangement or react to a final product by one of the pathways mentioned above—e.g. by loss of a proton to yield an alkene 3 ... 

Various rules have been devised with partial success (70,30,99), but it is difficult to formulate encompassing generalities in a reaction subject to the influence of so many reaction parameters, The stereochemislrycan be affected importantly by the catalyst (35,36,64,65,77,89,94), solvent (63), substrate structure, and haplophilic effects (77). 

The course of reduction of a variety of anhydrides with platinum and palladium under mild conditions have been discussed in detail 16 0). Products vary with substrate structure, reaction conditions, and solvent... 

If saturation occurs first, the product will be relatively stable toward further reduction but if hydrogenolysis occurs first, the resulting olefin is readily reduced. This ratio depends greatly on substrate structure, the catalyst, and environment. Hydrogenolysis is best achieved over platinum, whereas palladium (77a,82a,122bJ62a), rhodium (I09a), or ruthenium (I0a,I09a) tend to favor olefin saturation. 

The rate ratio of hydrogenation to hydrogenolysis varies with the catalyst, substrate structure, and environment in a partially predictable way. 

The effect of coating, composition and of substrate structure on the oxidation rate is shown in Fig. 12.25 which gives weight-increase/time curves for oxidation in air at 950°C of three steels of different carbon contents. 

The effects on SN2 reactions of the four variables—substrate structure, nucleophile, leaving group, and solvent—are summarized in the following statements and in the energy diagrams of Figure 11.7 ... 

The exact position of the aldol equilibrium depends both on reaction conditions and on substrate structure. The equilibrium generally favors condensation product in the case of aldehydes with no a substituent (RCH2CHO) but favors reactant for disubstituted aldehydes (R2CHCHO) and for most ketones. Steric Factors are probably responsible for these trends, since increased substitution near the reaction site increases steric congestion in the aldol product. 

FIGURE 9.20 Design of multiple ligancl activity, (a) Dual histamine HI receptor and leukotriene receptor antagonist incorporating known antihistaminic properties of cyproheptadine and LTD4. (b) Joint ACE/NEP inhibitor formed from incorporating similarities in substrate structures for both enzymes. From [57],... 

A sequence of straightforward functional group interconversions leads from 17 back to compound 20 via 18 and 19. In the synthetic direction, a base-induced intramolecular Michael addition reaction could create a new six-membered ring and two stereogenic centers. The transformation of intermediate 20 to 19 would likely be stereoselective substrate structural features inherent in 20 should control the stereochemical course of the intramolecular Michael addition reaction. Retrosynthetic disassembly of 20 by cleavage of the indicated bond provides precursors 21 and 22. In the forward sense, acylation of the nitrogen atom in 22 with the acid chloride 21 could afford amide 20. 

Whereas exo-norbornene oxide rearranges to nortricyclanol on treatment with strong base through transannular C-H insertion (Scheme 5.11), endo-norbornene oxide 64 gives norcamphor 65 as the major product (Scheme 5.14) [15, 22]. This product arises from 1,2-hydrogen migration very little transannular rearrangement is observed. These two reaction pathways are often found to be in competition with one another, and subtle differences in substrate structure, and even in the base employed, can have a profound influence on product distribution. 

The effect of substrate structure on product profile is further illustrated by the reactions of cis- and trons-stilbene oxides 79 and 83 with lithium diethylamide (Scheme 5.17) [32]. Lithiated cis-stilbene oxide 80 rearranges to enolate 81, which gives ketone 82 after protic workup, whereas with lithiated trans-stilbene oxide 84, phenyl group migration results in enolate 85 and hence aldehyde 86 on workup. Triphenylethylene oxide 87 underwent efficient isomerization to ketone 90 [32]. 

There are several examples of successful dienol epoxidations (Table 9.2). Catalytic SAE conditions are generally better than stoichiometric for reactive substrates (Entry 1), whilst stoichiometric conditions, on the other hand, are useful for less reactive substrates. Small variations in substrate structure can cause large differences in reactivity and product stability pentadienol could be epoxidized in acceptable yield, whereas hexadienol gave a complex mixture of products (Entries 1, 2). 

---