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

2. 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

3. 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)

4. 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

5. 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.

6. 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.

7. 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

9. 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.

10. 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

11. 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.

12. 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.

13. 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- )

14. FIGURE 13-10 An oxidation-reduction reaction
FIGURE 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.

15. 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

16. 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).