Isohypsic

Aim for the isohypsic condition of no net change in oxidation level for atoms involved in bond-making and bond-breaking reaction steps (HI = 0). 

If redox reactions cannot be avoided aim for the isohypsic condition. 

As an example, Scheme 4.10 and Table 4.8 summarize the hypsicity analysis for the Craig plan. Hypsicity indices for all plans are given in column 8 of Table 4.7. Figure 4.34 illustrates the change in oxidation level profiles as a function of reaction stage. It turns out that the Campos plan with the highest RME is also the one with an HI closest to the isohypsic condition of HI = 0. In Table 4.8 a check on the computation of 2 made by taking... 

The term carbonyl derivatives covers here several types of organic compounds which, first, can be obtained by simple derivatization of carbonyl compounds 208 under conditions of isohypsic reactions126 and, second, possess an oxidation level of 2, equal to that for carbonyl compounds17. The sense of this generalization is the intention to... 

A. Isohypsic reactions. Conversions occurring without a change in the oxidation level of the carbon atoms. 

B. Non-isohypsic reactions. Conversions occurring with a change in the oxidation level of the carbon atoms. These conversions may proceed as oxidations, leading to an increase in the oxidation level, or as reductions, resulting in the decrease of the oxidation level. 

Almost any isohypsic transformation is feasible within the limits of a given oxidation level, as isohypsic transformations do not affect oxidation status and imply most usual substitution, addition or elimination reactions. 

Non-isohypsic transformations are feasible only for certain types of derivatives, namely those especially apt to undergo oxidation or reduction. 

Isohypsic Transformations. Synthetic Equivalency of Functional Groups of the Same Oxidation Level... 

As we have seen above, alcohols and alkenes are produced routinely in the numerous reactions utilized in the formation of carbon-carbon bonds. These two functionalities are extremely useful for both the same-level oxidation interconversions and reduction-oxidation transitions (as stairways connecting different floors ). Therefore, it is not surprising to see an enormous number of methods developed to capitalize on the diverse options of alkene and alcohol transformations. These methods occupy a key place among the reactions known for isohypsic conversions of level 1 functionalities. 

Isohypsic reactions of alkenes, like electrophilic additions of H2O or HX, represent a conventional pathway for the preparation of alcohols and alkyl halides from alkenes. The scope of their application was originally limited as unsymmetrical alkenes (e.g. 125) gave product mixtures composed of both Markovnikov (M) adducts and anti-Markovnikov (aM) adducts. As was already mentioned above (see Scheme 2.10), an efficient and general method for the conversion of alkenes into alcohols or ethers 126 (Scheme 2.47), with a nearly complete M selectivity, was elaborated using mercury salts as electrophiles in conjunction with the reduction of the formed adducts. It is also... 

As was amply demonstrated in the preceding sections of this chapter, numerous C-C bond-forming reactions are applicable for the preparation of products with a terminal double bond. Thus the sequence (i) introduction of the terminal alkene moiety, (ii) isohypsic double bond transformation leading to the derivatives like 127 or 128, and (iii) the C-C bond-forming step, may be considered as a reliable operation for carbon chain elongation. 

Perhaps the most notable type of isohypsic transformation of carbonyl compounds and alkynes is their conversion into the synthetic equivalents of carbanions according to Scheme 2.48. We have already seen the pronounced role played by these carbanions and their covalent equivalents in constructing... 

The basic route to the synthesis of epoxides and, in general, vicinal bifunctional derivatives is a non-isohypsic (oxidative) transformation of alkenes (to be discussed below), Epoxides can also be formed directly as a result of certain C-C bond-forming reactions such as the Darzens reaction (modification of a classical aldol-like reaction with a-chloro esters 130 as a methylene component)... 

Another isohypsic transformation of special significance involves elimination of H-X elements from allylic derivatives to form 1,3-dienes. Besides being extremely important compounds as monomers, 1,3-dienes occupy a unique position in synthetic practice as components in the Diels-Alder reaction. One of the common routes of synthesis of 1,3-dienes also employs a vinyl Grignard addition to carbonyl compounds as the initial step (Scheme 2.55). Allylic alcohols thus formed can easily undergo 1,2-elimination (in some cases it is preferable first to transform the alcohols into their respective acetates). 

At oxidation level 3, acid chlorides occupy a key position, since they may serve as a nearly universal substrate for an isohypsic transformation into any kind of carboxylic acid derivative. Acid halides are electrophiles that are synthetically equivalent to acyl cations (RCO ). In this capacity they are used for the synthesis of such important compounds as esters, amides (and hence, nitriles), thioesters, etc. (see Scheme 2.57), and for the formation of C-C bonds in the Friedel-Crafts reaction (see above). Acid chlorides may readily lose HCl upon treatment with triethylamine. This isohypsic conversion leads to ketenes, important reagents widely employed in [2 + 2] cycloadditions, as we will see later. 

Non-isohypsic Transformations as Pathways Connecting Different Oxidation Levels... 

Non-isohypsic transformations are especially important in the syntheses of various nitrogen-containing derivatives. A common route for obtaining amines is the reduction of nitrogen-containing derivatives of carboxylic acids (nitriles or amides), aldehydes and ketones (imines) ... 

It is also possible to synthesize amines in a sequence of reactions where the non-isohypsic conversion (reduction) occurs at the nitrogen atom and the oxidation state of the carbon attached to it is not affected ... 

Another non-isohypsic transformation, addition of halogens to a double bond, is probably the oldest known reaction of unsaturated compounds. It is widely used for both industrial and laboratory purposes. The products formed, 1,2-dihaloalkanes, are valuable for conversion into vinyl halides (such as vinyl chloride monomers for the production of PVC) or alkynes ... 

As we have already shown, the creation of novel carbon-carbon bonds usually results in the formation of functionalized derivatives (the Wurtz coupling and Friedel-Crafts alkylation are probably the only exceptions). That is why a set of special reductive methods was devised to remove residual functionality that is unwanted in the final structure. The well-known hydrogenation of alkenes and alkynes belongs to this group of non-isohypsic transformations. Several other pathways available for the reductive removal of various functions will briefly be considered below. 

A thoughtful reader would have noticed that, while plenty of methods are available for the reductive transformation of functionalized moieties into the parent saturated fragments, we have not referred to the reverse synthetic transformations, namely oxidative transformations of the C-H bond in hydrocarbons. This is not a fortuitous omission. The point is that the introduction of functional substituents in an alkane fragment (in a real sequence, not in the course of retrosynthetic analysis) is a problem of formidable complexity. The nature of the difficulty is not the lack of appropriate reactions - they do exist, like the classical homolytic processes, chlorination, nitration, or oxidation. However, as is typical for organic molecules, there are many C-H bonds capable of participating in these reactions in an indiscriminate fashion and the result is a problem of selective functionalization at a chosen site of the saturated hydrocarbon. At the same time, it is comparatively easy to introduce, selectively, an additional functionality at the saturated center, provided some function is already present in the molecule. Examples of this type of non-isohypsic (oxidative) transformation are given by the allylic oxidation of alkenes by Se02 into respective a,/3-unsaturated aldehydes, or a-bromination of ketones or carboxylic acids, as well as allylic bromination of alkenes with NBS (Scheme 2.64). 

As illustrated, the major steps in the conversion of 140 to 139 correspond to non-isohypsic transformations of functional groups the reduction of an aldehyde to a primary alcohol, the oxidation of a secondary alcohol to a ketone, and the oxidation of a primary alcohol to a carboxylic acid. The introduction and removal of the isopropylidene protecting groups and the use of the bacterium Aeetobacter suboxydans (a non-typical oxidizing agent) ensures selectivity in the reactions of the polyfunctional intermediate compounds. 

Then nucleophilic half-reactions for each side are paired only with electrophilic ones on the other to define full isohypsic constructions and the substrates for these (as zp-lists). These substrate zp-lists now become the products for repeating the operation with the next bond defined in the bondset order. When all the bondset bonds have been sequentially treated in this way, there will result the zp-lists of the four generated starting materials and these can now be looked up in the catalog. If all four are found to be available compounds a successful synthetic sequence has been found and is recorded. 

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