Carbonyl functional groups in biology Introduction

Several functional groups contain the carbonyl group
Group
O H HO H H O R H aldehyde

Biological occurence
H OH H OH OH CH2OH glucose H O OH HO HO HO

Group
O

Biological occurence
O NH2

O

OH OH (hemiacetal form)

R

N H amide O

R' O R N H O Gln at C-terminus of peptide O-

R Ocarboxylate

Pi-O

O O R O ester R' R O OH monoacyl glycerol

OH

N pyridoxal phosphate CH2OH O O R R' ketone HO H H H OH OH HO O HO OH OH HO (hemiketal form)

NH2

O R S R'
O S N H

N O N H H N O OH O O O P O P O OOO N N

N

thioester

CH2OH fructose

Ac-S-CoA

O OH O P OO-

Chapter 16

1

Chapter 16

2

In order to understand mechanisms, divide carbonyls into two groups
No leaving group (Class 1):
O R H aldehyde R O R' ketone

Structure of the Carbonyl Group
The carbonyl carbon is sp2 hybridized and is trigonal planar
All three atoms attached to the carbonyl group lie in one plane

With leaving group (Class 2):
O R Cl R O O O R R O S thioester R'

acyl chloride

carboxylate anhydride

O R O ester R'

O R OH carboxylic acid
Chapter 16

O R N H amide R'

3

Chapter 16

4

1

these will give you clues about reactivity Chapter 16 5 Chapter 16 6 Reactions of Carbonyl Compounds with Nucleophiles Carbonyl groups can undergo nucleophilic addition The nucleophile adds to the δ+ carbon The π electrons shift to the oxygen The carbon becomes sp3 hybridized and therefore tetrahedral Hydride ions and carbanions are two examples of nucleophiles that react with the carbonyl carbon Let’s look at a typical nucleophile: Hydride Sources of hydride (H-): NaBH4 (sodium borohydride) LiAlH4 (lithium aluminum hydride) Reaction of an aldehyde and sodium borohydride to give a primary alcohol. ether 2. there is substantial δ+ charge on the carbon OK…. H3O+ OH H H Chapter 16 8 2 . how will it react with a nucleophile?? O + Nu- Remember: Electronegativity trends from first year. O The formation of a tetrahedral intermediate is the first step in many of the mechanisms you’ll see in this chapter (and others too!) Chapter 16 7 H 1. NaBH4.The carbonyl group is polarized. Given the polarity of a carbonyl.

NaBH4. LiAlH4. O HH H OH H2O OH H H How did this happen??? Chapter 16 11 CH3O- H2O CH3OH 12 Chapter 16 3 . H3O+ no reaction Consider the mechanism….What is the mechanism? Aldehydes and ketones (Class 1 carbonyls) react with nucleophiles to give nucleophilic addition products. ether 2. H3O+ OH + CH3-OH The aldehyde generated goes on to be reduced further to the primary alcohol while the alkoxide gets protonated in the workup. Chapter 16 9 Chapter 16 10 What happens when we try this nucleophilic addition on a Class 2 carbonyl? Let’s try the hydride addition on an ester: O OCH3 1. O OCH3 HOH OCH3 O H + CH3O- nucleophilic acyl substitution NaBH4 not a strong enough reducing agent for esters (explanation to come)… need LiAlH4 O OCH3 1. ether 2.

X: R O Nu X Nu 2nd step protonation H+ ONu Chapter 16 OH Nu 13 Chapter 16 14 Chapter 16 Aldehydes and Ketones I. Important to remember: many different reactions with essentially the same mechanism.Addition to aldehydes/ketones 1st step is addition (nucleophilic attack) O δ+ Nu Nu δO- Reaction type #2 . Nucleophilic Addition to the Carbonyl Group Nomenclature of Aldehydes and Ketones (16.You’ll see these two mechanism throughout the course with a number variations on these themes. Reaction type #1 .3) Chapter 16 16 4 .2) Physical Properties (16.Nucleophilic Acyl Substitutions (nucleophilic addition followed by elimination) δ- O δ+ R OX Nu .

4 Ch. Esters and Nitriles Reduction of carboxylic acid to aldehyde is impossible to stop at the aldehyde stage Aldehydes are much more easily reduced than carboxylic acids Reduction to an aldehyde can be accomplished by using a more reactive carboxylic acid derivatives such as an acyl chloride. 16. 16.6 Ch.Ch. 16.4 Relative Reactivity: Aldehydes versus Ketones Aldehydes are generally more reactive than ketones Synthesis of Aldehydes Aldehydes by Oxidation of 1o Alcohols Primary alcohols are oxidized to aldehydes by PCC Chapter 16 17 Chapter 16 18 Ch.4 Synthesis of Aldehydes Aldehydes by Reduction of Acyl Chlorides. 16. ester or nitrile and a less reactive hydride source The use of a sterically hindered and therefore less reactive aluminum hydride reagent is important Chapter 16 19 Chapter 16 20 5 .

5 Reduction of an ester to an aldehyde can be accomplished at low temperature using DIBAL-H As the carbonyl re-forms. 16.4 Acid chlorides react with lithium tri-tert-butoxyaluminum hydride at low temperature to give aldehydes Chapter 16 21 Chapter 16 22 Ch. and 2o Alcohols Ketones can be made from alkenes by ozonolysis Chapter 16 23 Chapter 16 24 6 . an alkoxide leaving group departs Synthesis of Ketones (review .4 Ch.also see Ch.4 Ch.Ch. 8) Ketones from Alkenes. 16. 16. Arenes. 16.

16. 16.6 Synthesis of Ketones (review .1.6 Nucleophilic Addition to the Carbonyl Groups Addition of strong nucleophiles such as hydride or Grignard reagents result in formation of a tetrahedral alkoxide intermediate The carbonyl π electrons shift to oxygen to give the alkoxide The carbonyl carbon changes from trigonal planar to tetrahedral An acid catalyst is used to facilitate reaction of weak nucleophiles with carbonyl groups Protonating the carbonyl oxygen enhances the electrophilicity of the carbon Chapter 16 27 Chapter 16 28 7 . 16.Ch. and Introductory lecture) Addition of a nucleophile to a carbonyl carbon occurs because of the δ+ charge at the carbon Ketones can be made from 2o alcohols by oxidation Chapter 16 25 Chapter 16 26 Ch. 12) Nucleophilic Addition to the Carbonyl Groups (See also Chapter 12. 16.5 Ch.6 Ch.see also Ch.

geminal.9 The equilibrum favors a ketone over its hydrate because the tetrahedral ketone hydrate is sterically crowded The Addition of Hydrogen Cyanide Aldehydes and ketone react with HCN to form a cyanohydrin A catalytic amount of cyanide helps to speed the reaction Chapter 16 31 Chapter 16 32 8 . indicates the presence of two identical substituents on the same carbon) Chapter 16 29 Chapter 16 30 Ch.e. 16.Ch.7 Ch. 16. 16.7 Addition of Water to Aldehydes or Ketones Dissolving aldehydes (or ketones) in water causes formation of an equilibrium between the carbonyl compound and its hydrate The hydrate is also called a gem-diol (gem i.6 Ch. 16.

12 Reaction of Grignard Reagents with Carbonyl Compounds Nucleophilic attack of Grignard reagents at carbonyl carbons is the most important reaction of Grignard reagents Reaction of Grignard reagents with aldehydes and ketones yields a new carboncarbon bond and an alcohol Chapter 16 35 Chapter 16 36 9 . 18.Ch. 16.from Ch. 12 review . 16.8H) Reduction of a cyanohydrin produces a β-aminoalcohol Chapter 16 33 Chapter 16 34 review .from Ch.9 The cyano group can be hydrolyzed or reduced Hydrolysis of a cyanohydrin produces an αhydroxycarboxylic acid (Sec.9 Ch.

cyclic five.and sixmembered ring hemiacetals are Chapter 16 37 Chapter 16 38 Ch.Ch.7 Ch. 16. 16.7 Hemiacetal formation is catalyzed by either acid or base Acetals An aldehyde (or ketone) in the presence of excess alcohol and an acid catalyst will form an acetal Formation of the acetal proceeds via the corresponding hemiacetal An acetal has two alkoxyl groups bonded to the same carbon Chapter 16 39 Chapter 16 40 10 . 16. 16. however.7 Ketones from Nitriles Organolithium and Grignard reagents add to nitriles to form ketones The Addition of Alcohols: Hemiacetals and Acetals Hemiacetals An aldehyde or ketone dissolved in an alcohol will form an equilibrium mixture containing the corresponding hemiacetal A hemiacetal has a hydroxyl and alkoxyl group on the same carbon Acylic hemiacetals are generally not stable.5 Ch.

Ch. 16. however.7 Ch.and 6. 16.7 Acetals as Protecting Groups Acetal protecting groups are stable to most reagents except aqueous acid Example: An ester can be reduced in the presence of a ketone protected as an acetal Thioacetals Thioacetals can be formed by reaction of an aldehyde or ketone with a thiol Thioacetals can be converted to CH2 groups by hydrogenation using a catalyst such as Raney nickel This sequence provides a way to remove an aldehyde or ketone carbonyl oxygen (BF3 is a Lewis acid) Chapter 16 43 Chapter 16 44 11 . favorable Such cyclic acetals are often used as protecting groups for aldehydes and ketones These protecting groups can be removed using dilute aqueous acid Acetals are stable when isolated and purified Acetal formation is reversible An excess of water in the presence of an acid catalyst will hydrolyze an acetal to the corresponding aldehyde (or ketone) Chapter 16 41 Chapter 16 42 Ch.membered ring acetals from ketones is.7 Ch. 16.7 Acetal formation from ketones and simple alcohols is less favorable than formation from aldehydes Formation of cyclic 5. 16.