Substitution at saturated carbon and

Carbonyl reactions are extremely important in chemistry and biochemistry, yet they are often given short shrift in textbooks on physical organic chemistry, partly because the subject was historically developed by the study of nucleophilic substitution at saturated carbon, and partly because carbonyl reactions are often more difhcult to study. They are generally reversible under usual conditions and involve complicated multistep mechanisms and general acid/base catalysis. In thinking about carbonyl reactions, 1 find it helpful to consider the carbonyl group as a (very) stabilized carbenium ion, with an O substituent. Then one can immediately draw on everything one has learned about carbenium ion reactivity and see that the reactivity order for carbonyl compounds ... 

The mechanistic aspects of nucleophilic substitutions at saturated carbon and carbonyl centers were considered in Part A, Chapters 4 and 7, respectively. In this chapter we discuss some of the important synthetic transformations that involve these types of... 

In this Chapter are described the possible mechanisms of electrophilic substitution at saturated carbon, as a preliminary to the discussion of the kinetics of substitution. Additionally, there is a description of the nomenclature that has been used to date. There has been no general agreement on the nomenclature of the mechanisms of electrophilic substitution at saturated carbon, and the notation used in subsequent chapters in the present work can thus usefully be enumerated here. We deal first of all with the fundamental mechanisms, that is with mechanisms that do not involve rearrangement or nucleophilic (anionic) catalysis. 

SUBSTITUTION AT SATURATED CARBON AND MICHAEL ADDITION AT CARBONYLS... 

Stereochemical course of the reaction. This kind of information was critical in the elucidation of the SnI and Sn2 pathways for nucleophilic substitution at saturated carbon. 

Chapters 1 and 2 dealt with formation of new carbon-carbon bonds by reactions in which one carbon acts as the nucleophile and another as the electrophile. In this chapter we turn our attention to noncarbon nucleophiles. Nucleophilic substitution is used in a variety of interconversions of functional groups. We discuss substitution at both sp3 carbon and carbonyl groups. Substitution at saturated carbon usually involves the Sjv2 mechanism, whereas substitution at carbonyl groups usually occurs by addition-elimination. 

Synthetically important substitutions of aromatic compounds can also be done by nucleophilic reagents. There are several general mechanism for substitution by nucleophiles. Unlike nucleophilic substitution at saturated carbon, aromatic nucleophilic substitution does not occur by a single-step mechanism. The broad mechanistic classes that can be recognized include addition-elimination, elimination-addition, and metal-catalyzed processes. (See Section 9.5 of Part A to review these mechanisms.) We first discuss diazonium ions, which can react by several mechanisms. Depending on the substitution pattern, aryl halides can react by either addition-elimination or elimination-addition. Aryl halides and sulfonates also react with nucleophiles by metal-catalyzed mechanisms and these are discussed in Section 11.3. 

Fig. 23 Entropy effects on intramolecular reactions of polymethylene chains. Plot of 9AS (e.u.) against number of single bonds for (O) nucleophilic substitutions at saturated carbon ( ) electron-exchange reactions (A) quenching of benzophenone phosphorescence. The straight line has intercept +30 e.u. and slope —4.0 e.u. per rotor. The right-hand ordinate reports the purely entropic EM s calculated as exp(0AS /J )...

Oxidative nitration, a process discovered by Kaplan and Shechter, is probably the most efficient and useful method available for the synthesis of em-dinitroaliphatic compounds from the corresponding nitroalkanes. The process, which is an electron-transfer substitution at saturated carbon, involves treatment of the nitronate salts of primary or secondary nitroalkanes with silver nitrate and an inorganic nitrite in neutral or alkali media. The reaction is believed ° °° to proceed through the addition complex (82) which collapses and leads to oxidative addition of nitrite anion to the nitronate and reduction of silver from Ag+ to Ag . Reactions proceed rapidly in homogeneous solution between 0 and 30 °C. 

A. Williams, Concerted Organic and Bioorganic Mechanisms, CRC Press, New York, 2000. W. P. Jencks, How Does a Reaction Choose Its Mechanism , Chem. Soc. Rev. 1981,10, 345. J. P. Richard, Simple Relationships between Carbocation Lifetime and the Mechanism for Nucleophilic Substitution at Saturated Carbon, Adv. Carbocation Chem. 1989, 1, 122. T. W. Bentley and G. Llewellyn, Scales of Solvent Ionizing Power, Prog. Phys. Org. Chem. 1990, 17, 121. 

Substitutions at saturated carbon atoms that are subject to control by remote functionalities may be best illustrated by the ring opening of aziridines [35] and epoxides [36, 37]. 

If R is an alkyl group, reaction (1) leads to the familiar mechanism of nucleophilic substitution at saturated carbon whilst reaction (2) leads to an electrophilic substitution of saturated carbon. Of course for these mechanisms to be followed it is not necessary for a completely developed carbonium ion or carbanion to be formed, and both nucleophilic and electrophilic substitution at saturated carbon may proceed by mechanisms in which the carbon atom undergoing substitution has a carbonium ion character or a carbanion character respectively. 

The possibility of electrophilic substitution at saturated carbon as an independent mechanism was considered by Hughes and Ingold2 in 1935, but this mechanism was not kinetically demonstrated with metal alkyls as substrates until 1955, when Winstein and Traylor3 published their results on the acetolysis of dialkylmercurys. At about the same time, stereochemical studies on electrophilic substitutions at saturated carbon were commenced by Winstein and by Reutov, again using alkylmercury compounds as substrates. Notable studies on the kinetics and stereochemistry of substitution at saturated carbon have been carried out by Ingold and his co-workers and by Reutov and his co-workers. Ingold4... 

When an electrophilic substitution at saturated carbon occurs, either a car-banion is liberated as such or, if no carbanion is actually formed, the carbon atom undergoing substitution has a certain amount of carbanion character . Thus a knowledge of the factors governing the formation and the stability of carbanions might be of help in the understanding of the mechanism of electrophilic substitution at saturated carbon. 

Much of the fundamental kinetic and mechanistic work on electrophilic substitution at saturated carbon has involved the study of reactions in which an organomercury substrate undergoes substitution by an electrophilic mercuric compound. Ingold and co-workers1 have concluded that these mercury-for-mercury exchanges occur only through the one-alkyl (1), the two-alkyl (2), and the three-alkyl (3) mercury exchange, viz. 

Salt effects and co-solvent effects in electrophilic substitution at saturated carbon... 

The difficulty in dealing with solvent influences on reaction rates is that the free energy of activation, AG, depends not only on the free energy of the transition state but also on the free energy of the initial state. It is therefore of considerable interest to dissect solvent influences on AG into initial-state and transition-state contributions. As far as electrophilic substitution at saturated carbon is concerned, the only cases for which such a dissection has been carried out are (a) for the substitution of tetraalkyltins by mercuric chloride in the methanol-water solvent system (see page 79), and (b) for the iododemetallation of tetraalkylleads in a number of solvents (see p. 173). Data on the latter reaction (6) are more useful from the point of view of the correlation of transition-state effects with solvent properties, and in Table 13 are listed values of AG (Tr), the free energy of transfer (on the mole fraction scale) of the tetraalkyllead/iodine transition states from methanol to other solvents. 

Cram, D. J. Langemann, A. Lwowski, W. Kopecky, K. R. Electrophilic substitution at saturated carbon. IV. Competing radical and anionic cleavage reactions./. Am. Chem. Soc. 1959, 81, 5760-5767. 

Substitution at certain unsaturated centers has little direct stereochemical interest, because there is no choice, e.g. substitution at aromatic, acetylenic, and carbonyl carbons must go with retention. On the other hand, stereoselection is possible at ethylenic and allenic carbon, phosphorus (P—O, P=S) and sulfur (S=0) centers. There appear to be important mechanistic differences between substitutions at unsaturated carbon and phosphorus or sulfur. All SE, SH, SN substitutions at such carbon atoms appear to proceed in at least two steps, while those at phosphorus and sulfur may go in one or more steps. For the SN process, comparative data are available here, substitution at unsaturated carbon proceeds with retention, while at phosphorus and sulfur inversion predominates. Substitution at unsaturated phosphorus and sulfur sites was sufficiently similar to other saturated centers that it was considered with them. Because of these mechanistic differences, we shall examine substitutions at unsaturated carbon more closely. 

A. R. Katritzky, B. E. Brycki, Nucleophilic Substitution at Saturated Carbon Atoms. Mechanisms and Mechanistic Borderlines Evidence from Studies with Neutral Leaving Groups, J. Rhys. Org. Chem. 1988, 1, 1-20. 

J. R Richard, Simple Relationships Between Carbocation Lifetime and the Mechanism for Nucleophilic Substitution at Saturated Carbon, in Advances in Carbocation Chemistry (X. Creary, Ed.) 1989,1, JAI Press, Greenwich, CT. 

The actual mode of interaction between Co(III) and the alkane was not elucidated. It could involve electron transfer as described above or it may be an example of a general class of electrophilic substitutions at saturated carbon centers in which attack at a a bond occurs via a trigonal (three-center) transition state,3008 e.g.,... 

Simple nucleophilic substitutions at saturated carbon atoms are fundamental reactions found wherever organic chemistry is practised. They are used in industry on an enormous scale to make heavy chemicals and in pharmaceutical laboratories to make important drugs. They are worth studying for their importance and relevance,... 

In Chapter 17 we introduced nuclrophilic substitution at saturated carbon, using as an example some alkyl bromides. Now, radicals do react with alkyl halides—but not at carbon You ve seen how alkyl halides undergo substitution at bromine with tin radicals. The difference in reactivity between, say, organolithiums and radicals, both of them highly reactive, is nicely illustrated by the way in which they react with enones. 

Electron transfer substitution at saturated carbon has been performed through photochemical initiation involving a charge transfer complex between the nucleophilic anion and a neutral substrate in HMPA, nitrite anion was displaced by azide on a,p-dinitrocumene [217]. 

---