Nucleophiles, alpha

Fischer, H., Klippe, M., Lerche, H., Severin, T., and Wanninger, G. (1990). Electrophilic beta-bromination and nucleophilic alpha-methoxylation of alpha,beta-unsaturated carbonyl compounds. Chem. Ber. 123, 399-404. 

RITCHIE EQUATION ELECTROPHILE NUGLEOPHILIC GATALYSIS NUCLEOPHILIC COMPETITION NUCLEOPHILICITY ALPHA EFFECT ELECTROPHILICITY... 

Nucleophiles alpha effect, 132 hydrazines, 132 hydroxylamines, 132 peroxides, 132... 

The fluorine-destabilised multiple bonds also add nucleophiles easier than their chlorine analogs (ref. 6) and the direction of addition is opposite From nucleophilic alpha-addition to fluorine and beta to chlorine results the relative ease of fluorine substitution inspite of the strong CF-bond, whereas the beta-adducts to chloroacetylenes form triple bonds by a-elimination and rearrangement (ref. 7, Scheme 3). 

Aldehyde and ketone carbonyls can be created via FGIs, and compounds already containing a carbonyl can be functionalized by reaction with either the electrophilic carbonyl carbon (e.g., acyl substitution reactions) or the nucleophilic alpha carbon. Both strategies can be used to give aldehyde and ketone products. 

The instructions for this problem point to a disconnection at the nucleophilic alpha carbon, thereby creating a four-carbon electrophile (RX) and a three-carbon nucleophile (enolate). However, the resulting enolate is not stable. Addition of an ester electron-withdrawing group leads to a starting material that can be further simplified. A second disconnection at the alpha carbon results in the familiar diethyl malonate enolate. Recognizing the TM as a derivative of acetic add can help you recognize the double disconnection that is possible. 

Ultimately, a complete retrosynthesis of a P-amino ketone leads to the three components needed in a Mannich reaction a ketone, an aldehyde, and an amine. The retrosynthesis of a P-amino ketone begins with making a disconnection between the alpha carbon and the carbon bearing the amino group (the beta carbon). This aldol-like disconnection leads to a nucleophilic alpha carbon (enol) and an electrophilic imine carbon (C=N). Further disconnection of the imine affords the two necessary building blocks for its formation an aldehyde and an amine. 

Since the target molecule is an a,P-unsaturated carbonyl, one possible approach would be an aldol reaction. A disconnection can be made directly through the C=C double bond, or a stepwise approach can be taken by first imagining the TM as a P-hydroxy structure that can then be disconnected between the alpha and beta carbons. Either approach leads to the same aldol starting materials a nucleophilic alpha carbon (enolate) and an electrophilic carbonyl carbon (benzaldehyde). 

When the target molecule has a carbonyl, always look to the alpha carbon for a potential disconnection site. The enolate nucleophile (alpha carbon) can react with a variety of electrophiles (ketone, aldehyde, ester, or a,P-unsaturated C=0) to give a variety of functional group patterns. 

Another significant structural effect that inrparts high nucleophilicity is the alpha effect. It is observed that atoms which are directly bonded to an atom with one or rhore unshared pairs of electrons tend to be stronger nucleophiles than would othermse be expected. Examples in Table 5.7 include H02, which is more nucleophilic than HO , and... 

The simplest method for obtaining selective fluonnation is to conduct reactions under conditions that invigorate the electrophilicity of fluorine In practice this method entails the creation of anionic or strongly nucleophilic reactive centers on substrate molecules while suppressing or reducing the tendency toward radical attack Numerous examples of seleetive fluorine attack on carbanionic, amido and carboxylato species are documented Especially abundant is alpha fluonnation of nitroalkanes in polar solvents [42 43, 44, 45 46] (equations 10-14)... 

The effects of the nucleophile on aromatic substitution which are pertinent to our main theme of relative reactivity of azine rings and of ring-positions are brought together here. The influence of a nucleophile on relative positional reactivity can arise from its characteristics alone or from its interaction with the ring or with ring-substituents. The effect of different nucleophiles on the rates of reaction of a single substrate has been discussed in terms of polarizability, basicity, alpha effect (lone-pair on the atom adjacent to the nucleophilic atom), and solvation in several reviews and papers. ... 

The rate of reaction of a series of nucleophiles with a single substrate is related to the basicity when the nucleophilic atom is the same and the nucleophiles are closely related in chemical type. Thus, although the rates parallel the basicities of anilines (Tables VII and VIII) as a class and of pyridine bases (Tables VII and VIII) as a class, the less basic anilines are much more reactive. This difference in reactivity is based on a lower energy of activation as is the reactivity sequence piperidine > ammonia > aniline. Further relationships among the nucleophiles found in this work are morpholine vs. piperidine (Table III) methoxide vs. 4-nitrophenoxide (Table II) and alkoxides vs. piperidine (Tables II, III, and VIII). Hydrogen bonding in the transition state and acid catalysis increase the rates of reaction of anilines. Reaction rates of the pyridine bases are decreased by steric hindrance between their alpha hydrogens and the substituents or... 

Both in the laboratory and in living organisms, the reactions of carbonyl compounds take place by one of four general mechanisms nucleophilic addition, nucleophilic acyl substitution, alpha substitution, and carbonyl condensation. These... 

Carbonyl compounds are in a rapid equilibrium with called keto-enol tautomerism. Although enol tautomers to only a small extent at equilibrium and can t usually be they nevertheless contain a highly nucleophilic double electrophiles. For example, aldehydes and ketones are at the a position by reaction with Cl2, Br2, or I2 in Alpha bromination of carboxylic acids can be similarly... 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

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