Bond Formation in Organic Chemistry
There are several main types of reaction which result in bond formation:
1. Ionic addition and substitution reactions
2. Radical addition and substitution reactions
3. Cycloadditions (Diels-Alder, 1,3-dipolar, carbene, etc)
4. Rearrangements (Wagner-Meerwein, Cope, Claisen, Wittig, Favorskii, electrocyclic reactions, etc)
By far the most commonly used are the ionic reactions in which nucleophiles react with electrophiles. In the most general sense, to make an X-Y bond, we have these choices:
X:- + Y+ → X-Y
X+ + Y:- → X-Y
The most appropriate choice is determined by the nature of X and Y. If the natural reactivity of the X group is nucleophilic, then the first one is appropriate, if X is naturally electrophilic, then the second one is better. When one or both X and Y are carbon atoms, then we have to consider the substituents on the carbon to find the best approach. For example, let's say we are making: PhO-CH3. Our choices are:
(1) PhO- + CH3+ → PhO-CH3
(2) PhO+ + CH3- → PhO-CH3
Because carbon is in the middle of the first row of the periodic table, it can often be made either nucleophilic or electrophilic, although substituents will typically make one much easier than the other. In this case both are available: a possible synthetic equivalent of the synthon CH3+ is CH3-I and for the synthon CH3- is CH3-MgBr. However for the PhO reaction partner we have only a good synthetic equivalent for PhO- (PhO-Na or any other metal salt of a phenoxide). PhO+ is a sextet species which very difficult to execute in the laboratory, and so the second approach is probably doomed, or at least much less effective. In fact, in general electronegative atoms (N, O) are inherently better at being nucleophiles than electrophiles. This simple example illustrates the basic concepts of the synthon approach - make a bond disconnection, examine the two charged possibilities, identify methods for executing them by taking advantage of the inherent reactivity of the involved functional groups, and select the one which provides the most available, convenient, and/or least expensive reagents for performing the transformation.
In this example (1) can be considered as using "natural" or "inherent" reactivity of the phenoxy group, whereas (2) requires some method for reversing the natural reactivity (umpolung).
The same considerations apply for the formation of C-C bonds - examine the two possible charged combinations, determine which one best fits the inherent reactivity of the substrates, and decide on reagents to execute the process. Consider the reaction below. We would have to form the bond indicated by the arrow.
The two possible disconnections are shown below:
Plan (1) turns out to be relatively straightforward to implement - anions alpha to carbonyl groups (enolates) are easily formed by deprotonation with a strong base, and a variety of acylating agents (MeC(=O)Cl, MeC(=O)OMe) can serve to acylate the enolate. There is a complication - the kinetic acylation site is usually on oxygen to form the enol acetate, although there are several procedures that give predominantly C-acylation.
Executing plan (2) is MUCH more difficult - in fact, it requires umpolung of both reaction partners, and thus becomes untenable in a practical synthesis. For example, the α-chloro ketone might be a possible reagent for the enolonium cation needed for plan (2). However, this is a bifunctional electrophile, and nucleophiles can react at either the C-Cl or the C=O carbon, not to mention deprotonation of the relatively acidic proton α to chlorine. Similarly for the nucleophile - we cannot, in general make lithium or Grignard reagents of the type needed, so an umpolung scheme has to be developed to provide the acyl anion synthon.
This example illustrates the general phenomenon that carbons bearing oxygens or nitrogens usually function best as acceptors (by virtue of the electrophilic reactivity of carbonyl or imine functions), whereas carbons bonded to carbonyl groups or imines tend to be most easily handled as donors (using the ability to form enolates, enols, enamines, or metaloenamines).
