CHEM 7784 Biochemistry Professor Bensley Chapters 13.2 and 13.4: Chemical Logic and Common Biochemical Reactions CHEM 7784 Biochemistry Professor Bensley

CHAPTER 13.2 and 13.4 Chemical Logic Today’s Objectives: To learn and understand the Principles of organic chemistry relating to biochemical processes Understand basic oxidation/reduction reactions in biochemical processes

Most biochemical reactions fall within 5 categories: Chemical Reactivity Most biochemical reactions fall within 5 categories: Cleavage and formation of C–C bonds Free-radical reactions Internal rearrangements, isomerizations, and eliminations Group transfers (H+, CH3+, PO32-) Oxidations-reductions (e- transfers)

Covalent bonds can be broken in two ways Chemistry at Carbon Covalent bonds can be broken in two ways Most reactions in biochemistry are thermal heterolytic processes FIGURE 13-1 Two mechanisms for cleavage of a C—C or C—H bond. In a homolytic cleavage, each atom keeps one of the bonding electrons, resulting in the formation of carbon radicals (carbons having unpaired electrons) or uncharged hydrogen atoms. In a heterolytic cleavage, one of the atoms retains both bonding electrons. This can result in the formation of carbanions, carbocations, protons, or hydride ions. Homolytic cleavage is very rare

Nucleophiles and Electrophiles in Biochemistry Nucleophile – electron rich and therefore donors Electrophile – electron seeking FIGURE 13-2 Common nucleophiles and electrophiles in biochemical reactions. Chemical reaction mechanisms, which trace the formation and breakage of covalent bonds, are communicated with dots and curved arrows, a convention known informally as "electron pushing." A covalent bond consists of a shared pair of electrons. Nonbonded electrons important to the reaction mechanism are designated by dots. Curved arrows represent the movement of electron pairs. For movement of a single electron (as in a free radical reaction), a single-headed (fishhook-type) arrow is used. Most reaction steps involve an unshared electron pair.

Examples of Nucleophilic Carbon-Carbon Bond Formation Reactions FIGURE 13-4 Some common reactions that form and break C—C bonds in biological systems. For both the aldol condensation and the Claisen condensation, a carbanion serves as nucleophile and the carbon of a carbonyl group serves as electrophile. The carbanion is stabilized in each case by another carbonyl at the adjoining carbon. In the decarboxylation reaction, a carbanion is formed on the carbon shaded blue as the CO2 leaves. The reaction would not occur at an appreciable rate without the stabilizing effect of the carbonyl adjacent to the carbanion carbon. Wherever a carbanion is shown, a stabilizing resonance with the adjacent carbonyl, as shown in Figure 13-3b, is assumed. An imine (Figure 13-3c) or other electron-withdrawing group (including certain enzymatic cofactors such as pyridoxal) can replace the carbonyl group in the stabilization of carbanions.

Addition–Elimination Reactions Substitution from sp3 carbon proceeds normally via the nucleophilic substitution (SN1 or SN2) mechanism Substitution from the sp2 carbon proceeds normally via the nucleophilic addition–elimination mechanism Nucleophile adds to the sp2 center giving a tetrahedral intermediate Leaving group eliminates from the tetrahedral intermediate Leaving group may pick up a proton

Isomerization Reactions Have Smaller Free Energy Changes Isomerization between enantiomers: G = 0 FIGURE 13-6a Isomerization and elimination reactions. (a) The conversion of glucose 6-phosphate to fructose 6-phosphate, a reaction of sugar metabolism catalyzed by phosphohexose isomerase.

Group Transfer Reactions Proton transfer, very common Methyl transfer, various biosyntheses Acyl transfer, biosynthesis of fatty acids Glycosyl transfer, attachment of sugars Phosphoryl transfer, to activate metabolites, also important in signal transduction

Nucleophilic Displacement Substitution from sp3 phosphorous proceeds via the nucleophilic substitution (usually associative, SN2-like) mechanism Nucleophile forms a partial bond to the phosphorous center giving a pentacovalent intermediate or a pentacoordinated transition state FIGURE 13-8d Alternative ways of showing the structure of inorganic orthophosphate. (c) When a nucleophile Z (in this case, the —OH on C-6 of glucose) attacks ATP, it displaces ADP (W). In this SN2 reaction, a pentacovalent intermediate (d) forms transiently.

Oxidation-Reduction Reactions Reduced organic compounds serve as fuels from which electrons can be stripped off during oxidation FIGURE 13-9 The oxidation states of carbon in biomolecules. Each compound is formed by oxidation of the red carbon in the compound shown immediately above. Carbon dioxide is the most highly oxidized form of carbon found in living systems.

Reversible Oxidation of a Secondary Alcohol to a Ketone Many biochemical oxidation-reduction reactions involve transfer of two electrons In order to keep charges in balance, proton transfer often accompanies electron transfer In many dehydrogenases, the reaction proceeds by a stepwise transfers of proton ( H+ ) and hydride ( :H- )

FIGURE 13-10 An oxidation-reduction reaction FIGURE 13-10 An oxidation-reduction reaction. Shown here is the oxidation of lactate to pyruvate. In this dehydrogenation, two electrons and two hydrogen ions (the equivalent of two hydrogen atoms) are removed from C-2 of lactate, an alcohol, to form pyruvate, a ketone. In cells the reaction is catalyzed by lactate dehydrogenase and the electrons are transferred to the cofactor nicotinamide adenine dinucleotide (NAD). This reaction is fully reversible; pyruvate can be reduced by electrons transferred from the cofactor.

NAD and NADP are Common Redox Cofactors These are commonly called pyridine nucleotides They can dissociate from the enzyme after the reaction In a typical biological oxidation reaction, hydride from an alcohol is transferred to NAD+ giving NADH

FIGURE 13-24a NAD and NADP. (a) Nicotinamide adenine dinucleotide, NAD+, and its phosphorylated analog NADP+ undergo reduction to NADH and NADPH, accepting a hydride ion (two electrons and one proton) from an oxidizable substrate. The hydride ion is added to either the front (the A side) or the back (the B side) of the planar nicotinamide ring (see Table 13-8).