Chem 335 - Winter 1999 - Organic Chemistry II
Portland State University - Dr. Carl C. Wamser

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Chapter 15 - Carbonyl Compounds

Carbonyl Functional Groups

usually subdivided into two families:

• aldehydes and ketones
• both R groups are C or H

• carboxyl derivatives
• X is some electronegative element
• (halogen, O, N, S, others)

The Carbonyl Group - Structure and Properties

• polar C=O double bond
• O is nucleophilic
  reacts with acids & electrophiles
• C is electrophilic
  reacts with Lewis bases and nucleophiles
• alpha-C-H position is acidic (pKa ~ 20)

Aldehyde Nomenclature

• IUPAC: alkanal
  -al suffix, with carbonyl assumed #1 in parent chain
  
  -carbaldehyde suffix
  (if aldehyde can't be part of the parent)
  e.g., cyclohexanecarbaldehyde
  
• common nomenclature:

formaldehyde
acetaldehyde
propionaldehyde
butyraldehyde
benzaldehyde

Ketone Nomenclature

• IUPAC: alkanone
  -one suffix, with number
  
  -oxo- prefix if necessary
  e.g., 4-oxopentanal
  
• common nomenclature:
  dialkyl ketone
  acetone
  acetophenone
  benzophenone

acyl- as prefix
e.g., acetyl or benzoyl, as in acetylcyclopropane

Precedence Order of Functional Groups

• decides which gets to be the parent compound (suffix)
• lower functional groups must be named as substituents (prefixes)
  
  carboxylic acid
  aldehyde
  ketone
  alcohol
  amine
  thiol

Characteristic Properties

• polar H-bond acceptors, but not H-bond donors
• Mass spec shows alpha cleavage (stable acylium ion RCO+)
  or McLafferty rearrangement (split between alpha and beta carbons)
• NMR shows aldehyde C-H at 9-10 ppm, C=O at 180-210 ppm
• IR shows strong C=O stretch at 1600-1800 cm-1
  exact position depends on ring strain, conjugation
• UV shows weak n -> pi* at ~ 300 nm and pi -> pi* at ~ 200 nm
  exact position and strength of the absorption depends on conjugation

Nucleophilic Addition to Carbonyls

the major reaction of carbonyl compounds

General Trends:

• aldehydes more reactive than ketones
  (due to steric hindrance with ketones)
• aromatic carbonyls less reactive than aliphatic
  (due to conjugation effects)
  
• a large variety of nucleophiles can undergo addition reactions

C nucleophiles: CN-, RLi, RMgX, ylids

O nucleophiles: OH-, H2O, ROH

S nucleophiles: RSH

N nucleophiles: NH3, RNH2 , NH2OH, RNHNH2

H nucleophiles: LiAlH4, NaBH4

Acid Catalysis of Nucleophilic Addition

• protonation generates a more reactive electrophile
  (carbon becomes more receptive to nucleophiles)

• works well to enhance reactivity with weak nucleophiles
• doesn't work for nucleophiles that protonate readily
• base catalysis sometimes observed when base can be used to generate a stronger nucleophile

Hydration Reactions

• as in hydration of C=C double bonds,
  the elements of H and OH are added

• H2O is the nucleophile
• the product is a geminal diol

Hydration is a reversible equilibrium

• formaldehyde in water is mainly dihydroxymethane
• most other carbonyls have unfavorable equilibria
  (very little gem-diol in aqueous solution)
• reaction rate is slow at pH 7
  but faster in acid or in base (catalysis)

Base-Catalyzed Hydration

• OH- is a strong nucleophile

Acid-Catalyzed Hydration

• H+ acts as a catalyst

Comparison of acid and base catalytic effects

• in base, a strong nucleophile is generated by deprotonation
• in acid, the carbonyl is made more receptive to a weak nucleophile
• note that you can't have both at the same time
  (although nature comes close with some enzyme catalysts)

Alcohol Additions

• reversible addition gives a hemiacetal, which is usually unstable

• the hemiacetal undergoes acid-catalyzed substitution (SN1) to an acetal

• ketal (and hemiketal) are terms often used for the corresponding products from ketones
  
• reversible acid-catalyzed equilibrium
  pushed forward by removal of water
  reversed by addition of excess water (hydrolysis)

Acetals as protecting groups

• protecting groups temporarily "cover up" a reactive carbonyl group
  usually to avoid unwanted reactions during other synthetic steps
• ethylene glycol commonly used to form a cyclic acetal

Sulfur Additions - 1,3-Dithianes

• sulfur is a better nucleophile than oxygen
• 1,3-propanedithiol forms a cyclic dithioacetal (a 1,3-dithiane)
• 1,3-dithianes have a relatively acidic C-H bond at C-2
  ( pKa ~ 31 , use RLi as the base )
• the anion of a 1,3-dithiane can be used as a nucleophile
  alkylation creates a new C-C bond
• hydrolysis of the dithioacetal returns the original carbonyl
  but with a new alkyl group (aldehyde -> ketone)
• Umpolung reaction - a normally positive carbon (aldehyde carbonyl)
  has been used as a nucleophile (the dithiane anion)

Amine Additions

• reversible addition gives an aminol, which is usually unstable

• the aminol dehydrates to an imine under acid catalysis

• acid-catalysis limited to mild pH ranges (typically 4 - 6)
• otherwise the amines are all protonated and no longer nucleophilic

Carbon Additions

• cyanide additions gives cyanohydrins
  the nitrile group is convertible to a variety of other functional groups
  
• acetylide additions give alkynols
  
• organometallic reagents add a new C-C bond and make alcohols

• Grignard + formaldehyde --> 1° alcohol
• Grignard + aldehyde --> 2° alcohol
• Grignard + ketone --> 3° alcohol
• useful synthetic reaction
  a new C-C bond is formed
  builds up a larger carbon skeleton
  
• Grignard reagents are incompatible with most other polar functional groups
  (OH, COOH, NH2, etc.) and with atmospheric water and oxygen

Wittig Reactions

• phosphonium ylids are nucleophiles that add to carbonyls to give an alkene

Keto-Enol Tautomerism

• alpha C-H bonds are relatively acidic ( pKa ~ 20 )
• equilibration by acid (protonated carbonyl)
  or by base (enolate anion)
• most carbonyl forms are favored over enol forms
  unless there are stabilizeing effects such as H-bonding and/or conjugation

Alpha-Substitution Reactions

• chiral alpha-carbons can be racemized by acid or base
• deuterium can be exchanged for hydrogen using D2O
• halogens are readily substituted by acid or base catalysis
  with acid - single substitution on the more highly substituted alpha carbon
  with base - multiple substitutions on the less substituted alpha carbon
• haloform reaction - methyl ketones can be cleaved to haloform ( CHX3 )

Reduction Reactions

• to an alkane: Wolff-Kishner or Clemmensen reactions
• to an alcohol: catalytic hydrogenation or hydride additions
  reductions by LiAlH4 or NaBH4 are additions of hydride "H-" as a nucleophile

Oxidation of Aldehydes

• very sensitive to oxidation
  (slow reaction with air by a radical chain mechanism)
• Tollen's test
  Ag+ in aqueous ammonia reduced to metallic silver (mirror)

Oxidation of Ketones

• Baeyer-Villager oxidation to an ester

Glucose Hemiacetals

• the major form of most sugars in aqueous solution is as cyclic hemiacetal isomers

Glucose Acetal Polymers (Starches and Cellulose)

• the storage form of glucose in animals (starches)
  and in plants (cellulose - structural material)