Revising organic chemistry  Doc Brown's  Summary of organic reaction mechanisms

Part III Alcohols, Aldehydes-Ketones and Acid (Acyl) Chlorides

Revision notes include full diagrams and explanation of the mechanisms and the 'molecular' equation and reaction conditions and other con-current reaction pathways and products are also explained.

Revision notes for GCE Advanced Subsidiary Level AS Advanced Level A2 IB Revise AQA GCE Chemistry OCR GCE Chemistry Edexcel GCE Chemistry Salters Chemistry CIE Chemistry revising courses for pre-university students (equal to US grade 11 and grade 12 and Honours/honors level courses)

• MECHANISM Introduction and terms used in organic chemistry

•  MECHANISM INDEX

• Part Ia ALKANES - introduction

  • Free radical chlorination/bromination to give halogenoalkanes (haloalkanes, alkyl halides)

  • Free radical thermal cracking to give shorter alkanes and alkenes

  • Ionic catalytic cracking to give shorter alkanes and alkenes

• Part Ib ALKENES - introduction

  • Electrophilic addition of hydrogen bromide [HBr_{(conc. aq)} and HBr_{(g/non-polar solvent)}] to form halogenoalkanes

  • Electrophilic addition of bromine ...

    • with pure bromine or in non-polar solvent (non-aqueous Br_2(l/solvent)) to give dibromoalkanes

    • or using bromine water [aqueous Br_2(aq)] to give bromo-alcohols

  • Electrophilic addition of sulphuric acid

  • Electrophilic addition of water [acid catalyst] to form alcohols

  • Free radical polymerisation to give poly(alkene) polymers

  • Hydrogenation to give saturated alkanes (in kinetics notes)

• Part II HALOGENOALKANES - introduction (haloalkanes, alkyl halides)

  • Nucleophilic substitution by water/hydroxide ion [S_N1 or S_N2, hydrolysis to give alcohols]

    • with extra notes on kinetics, rds, molecularity, activated complex etc.

  • Nucleophilic substitution by cyanide ion to give a nitrile [S_N1 or S_N2]

  • Nucleophilic substitution by ammonia/primary amine to give primary/secondary amines etc. [S_N1 or S_N2]

  • Elimination of hydrogen bromide to form alkenes [E1 and E2]

• Part III ALCOHOLS - introduction [this page]

  • Conversion of an alcohol to a halogenoalkane

  • Elimination of water from an alcohol to give an alkene [acid catalysed, E1 and E2]

• and Carbonyl compounds - ALDEHYDES and KETONES - introduction

  • Nucleophilic addition of hydrogen cyanide to form a hydroxy-nitrile

  • Addition of hydrogen - reduction with LiAlH₄ or NaBH₄ to give alcohols

  • The iodination of ketones e.g. a 2-one like propanone (a methyl ketone) to give iodo-ketones

• and ACID CHLORIDES - introduction - all nucleophilic addition-elimination reactions

  • Hydrolysis with water to give a carboxylic acid

  • Esterification with alcohols to give an ester

  • Amide formation from reaction with ammonia or primary amines

• Part IV AROMATIC HYDROCARBONS - introduction to arene electrophilic substitutions

  • Nitration to give nitro-aromatics like nitrobenzene

  • Chlorination to chloro-aromatics like chlorobenzene

  • Alkylation to give alkyl-aromatics like methylbenzene [Friedel-Crafts reaction]

  • Acylation to give aromatic ketones [Friedel-Crafts reaction]

  • Sulphonation/sulfonation to give a sulphonic/sulfonic acid like benzenesulphonic acid/benzenesulfonic acid

  • The orientation of products in aromatic substitution (1,5/3,5/4 positions, ortho/meta/para substitution products)

• EMAIL query?comments

• e.g. R₃C-OH + HX ==> R₃C-X + H₂O    [see mechanisms 12 and 13 below]

• or more correctly: R₃C-OH + H₃O⁺ + X^- ==> R₃C-X + 2H₂O

  • because hydrogen halides are fully ionised in water, HX_(g/aq) + H₂O_(l) => H₃O⁺_(aq) + X^-_(aq) 

  • For tertiary halogenoalkanes the reaction is reversible.

  • You can use conc. hydrochloric acid to make a chloroalkane or conc. hydrobromic acid to make a bromoalkane. In fact both HX acids are often made in situ using sodium chloride/potassium bromide/potassium iodide? with moderately concentrated sulphuric acid.

mechanism 13 - substitution of the OH group of an alcohol by a halide ion ('unimolecular' via carbocation)

• [mechanism 13 above] This is effectively, overall an S_N1 nucleophilic substitution reaction [steps (2) and (3)]

  • In step (1) the alcohol is initially protonated by an oxonium ion from the acid.

  • Heterolytic C-O bond fission occurs in step (2) to give a carbocation and water and this is the 'unimolecular' rate determining step.

  • In step (3) the halide ion (chloride Cl^-, bromide Br^- or iodide I^-) rapidly adds to give chloro/bromo/iodo-alkane product.

mechanism 12 - substitution of the OH group of an alcohol by a halide ion (bimolecular)

• [mechanism 12 above] This is effectively an S_N2 nucleophilic substitution reaction via step (2).

  • In step (1) the alcohol is initially protonated by the oxonium ion from the acid solution.

  • Step (2) involves nucleophilic attack by the halide ion on the carbon of the C-O bond.

    • Step (2) is the 'bimolecular' rate determining step (rds).

• FURTHER COMMENTS

  • The general order of reactivity is tert > sec > prim alcohol

    • (CH₃)₃C-OH + HCl (CH₃)₃C-Cl + H₂O 

      • The above reaction with 2-methylpropan-2-ol, occurs with conc. hydrochloric acid at room temperature and is readily reversed on dilution of the product with water.

The acid catalysed elimination of water from an alcohol

• e.g. R₂CH-C(OH)R₂ ==> R₂C=CR₂ + H₂O   [see mechanism 30 below]

• The alcohol can be heated with mod. conc. sulphuric acid or conc. phosphoric(V) acid to produce an alkene.

mechanism 30 - acid catalysed elimination of water from an alcohol

• [mechanism 30 above] It is effectively an E1 elimination reaction since step (2) is the rate determining step.

  • Step (1) The alcohol is protonated by the oxonium ion from the acid solution.

  • Step (2) Heterolytic C-O bond fission occurs to give the carbocation and water.

  • In Step (3) the carbocation is 'deprotonated' to give the alkene and oxonium ion.

  • The double bond is completed from the C-H bonding pair of electrons 'left' as the proton is removed.

• FURTHER COMMENTS

  • This mechanism is the complete reverse of [mechanism 29], the acid catalysed hydration of an alkene.

  • If the C chain >C₃, and not a primary alcohol (-1-ol) you can get isomeric alkenes formed.

    • e.g. butan-2-ol can form but-1-ene or but-2-ene.

      • CH₃CH₂CH(OH)CH₃ ==> {CH₃CH₂CH=CH₂ or CH₃CH=CHCH₃} + H₂O

  • The ease of dehydration of an alcohols is tert > sec > prim e.g. for

    • C₄H₁₀ isomers: (CH₃)₃COH > CH₃CH₂CHOHCH₃ > CH₃CH₂CH₂CH₂OH

    • due to the ease of formation and stability of tert > sec > prim carbocations.

Carbonyl compounds - ALDEHYDES and KETONES

Aldehydes and ketones readily undergo nucleophilic attack because of the highly polar carbonyl bond >C^δ+=O^δ- caused by the big difference in the electronegativity between carbon (2.5) and oxygen (3.5). An electron pair donating nucleophile (Nuc:), will therefore attack the 'positive carbon' (C^δ+) to form a C-Nuc bond. A comparison of electrophilic addition to alkenes with nucleophilic addition to aldehydes/ketones is included in these notes.

• e.g. RR'C=O + HCN ==> RR'C(OH)CN   [see mechanism 7 below]

• The reaction involves mixing an aldehyde (R = H, R' = H or alkyl) or ketone (R and R' are either alkyl or aryl, but NOT H) with buffered potassium cyanide solution to provide a source of negative cyanide ions, the nucleophile. The product of the nucleophilic addition of hydrogen cyanide is a hydroxynitrile (a cyanohydrin).

mechanism 7 - nucleophilic addition of cyanide ion to an aldehyde or ketone

• [mechanism 7 above] The >C^δ+=O^δ- bond is highly polarised because of the great difference in electronegativity between carbon (2.1) and oxygen (3.5).

  • Step (1) The nucleophilic electron pair donating cyanide ion attacks the positive carbon of the polarised C=O bond, forming a C-C bond. The Π electron pair of the original C=O bond moves onto the oxygen to give it a whole negative charge.

  • Step (2) The intermediate formed, RR'C(CN)O^-, is a strong conjugate base and will abstract a proton from water to give the hydroxynitrile product and a hydroxide ion.

• FURTHER COMMENTS

  • Why do alkenes react by electrophilic addition and carbonyl compounds by nucleophilic addition?

    • In alkenes, the electron pair ('rich') donating double bond, is much more likely to react with an electron pair accepting electrophile (Lewis acid) like a positive ion. Electron pair donating nucleophiles, especially if negative (e.g. X^- or OH^-) will tend to be repelled by the high electron density of the Π bond.

    • However, in carbonyl compounds, the highly polar >C^δ+=O^δ- bond, will be susceptible to attack at the positive carbon by electron pair donating nucleophiles

  • In this nucleophilic addition reaction, at the functional group centre of the reaction (>C=O), you change from an unsaturated trigonal planar situation to a saturated tetrahedral bond network about the carbon atom. This carbon atom is, in most cases a chiral carbon and the product therefore can exhibit optical isomerism (R/S isomerism). However the product is usually a 50:50 mixture of the enantiomers (non-superimposable mirror-image forms) i.e. a racemic mixture.

    • Why is the product an optically inactive racemate even if the product is an asymmetric molecule with a chiral carbon?

    • The reason can be clearly argued by considering the mechanism 7 above. The nucleophile attacks the carbon of the polarised carbonyl group (R₂C^δ+=O^δ-) in a trigonal planar bonding situation which changes to a tetrahedral on formation of the C-Nucleophile bond. Quite simply, there is a 50:50 chance of which side of the carbonyl group the nucleophile attacks and therefore a 50:50 chance of which optical isomer is formed as the configuration about the carbon atom changes.

    • Apart from explaining the formation of a racemic mixture, you can also argue, in turn, that the lack of optical activity in the product is itself evidence for an initial attack of the nucleophile at the carbon of the carbonyl group and you might reasonably expect a 2nd order rate expression.

      • rate = k[aldehyde/ketone][CN^-]

      • though I don't know if the kinetics are actually this simple for what seems to be an initial bimolecular rate determining step mechanism!

  • -

Nucleophilic addition of a hydride ion in the reduction of aldehydes/ketones to primary/secondary alcohols

• Lithium tetrahydridoaluminate(III) (lithium aluminium hydride) or sodium tetrahydridoborate(III) (sodium tetraborohydride) reduce aldehydes to primary alcohols and ketones to secondary alcohols.

  •  very simply the reaction is: RR'C=O + 2[H] ==> RR'CHOH

  • Aldehyde: R = H, R' = H or alkyl) or ketone: R and R' are either alkyl or aryl, but NOT H.

mechanism 40 - nucleophilic addition of a hydride ion (via NaBH₄ or LiAlH₄) to an aldehyde or ketone

• [mechanism 40 above] is a considerable simplification of the full mechanism.

  • In step (1) the AlH₄^- or BH₄^- ion act as nucleophiles and donate the 'equivalent' of a  nucleophilic hydride ion :H^- to the positive carbon of the polarised carbonyl bond.

  • In step (2) the intermediate ion is a strong conjugate base and reacts with any proton donor e.g. water (but can be an alcohol ROH or acid H₃O⁺) to form the alcohol product.

  • The real mechanism involves a step-wise replacement of the hydrogen atoms on the reducing reagent with alkoxide groups (RR'CH-O-, e.g. ethoxy CH₃CH₂-O- from reduced ethanal CH₃CHO). This happens because all the intermediates are themselves nucleophilic agents. In the sequence X = B or Al and R₂ =RR' for simplicity)

  • XH₄^- + R₂C=O => [H₃XO-CHR₂]^- = R₂C=O => [H₂X(O-CHR₂)₂]^- = R₂C=O => [HX(-OCHR₂)₃]^- = R₂C=O => [X(-OCHR₂)₄]^- 

  • Then the alkoxide complex reacts with any proton donor (depending on reagent/reaction conditions e.g. the water/ethanol/ acid) to free the alcohol.

    • [X(OCR₂)₄]^- + water/acid/alcohol => 4R₂CHOH + compound of X

The >C=O is polarised because of the difference in electronegativity of the carbon (2.1) and oxygen (3.0). The four reactions described all involve an initial nucleophilic addition at the positive carbon of the polarised bond of the carbonyl group >C^δ+=O^δ- of the acyl chloride. This is followed by the elimination of a small molecule e.g. HCl.

• e.g. R-COCl + 2H₂O ==> R-COOH + H₃O⁺ + Cl^-    [see mechanism 14 below]

• The organic hydrolysis product is a carboxylic acid.

  • The above equation applies to excess water but with limited water you do get fumes of hydrogen chloride gas.

  • R-COCl + H₂O ==> R-COOH + HCl 

  • Acid chlorides tend to fume rather nastily in air as hydrogen chloride fumes are formed, and these will form hydrochloric with any moisture, most noticeably in the eyes!

mechanism 14 - nucleophilic addition-elimination reaction for the hydrolysis of an acyl chloride

• [mechanism 14 above] The mechanism involves several rearrangements and assumes excess water.

  • Step (1) The >C^δ+=O^δ- carbonyl is highly polarised and the positive carbon is attacked by the nucleophilic water molecule, acting as an electron pair donor. The water adds to form a highly unstable ionic intermediate via a C-O bond and simultaneously the ∏ electron pair of the C=O double bond moves onto the oxygen atom to give it a full negative charge.

  • Step (2) The C-Cl bond pair moves onto the chlorine atom which leaves as a chloride ion and simultaneously one of the lone pairs of electrons from the negative oxygen atom shifts back to complete (reform) the C=O carbonyl bond.

  • Step (3) A water molecule abstracts a proton to form the oxonium ion and the carboxylic acid product.

    • If only limited water available, e.g. like when the acid chloride liquid fumes in air, step (3) could be written as a chloride ion removing the proton to form hydrogen chloride i.e.

      • RCOOH₂⁺ + Cl^- ==> RCOOH + HCl

• FURTHER COMMENTS

  • The reaction is effectively, overall, the substitution of the -Cl chlorine atom with an -OH hydroxy group.

Acyl chloride esterification by nucleophilic addition-elimination

• e.g. R-COCl + R'OH ==> R-COOR' + HCl   [see mechanism 15 below]

mechanism 15 - nucleophilic addition-elimination reaction for the esterification of an acyl chloride

• [mechanism 15 above] The mechanism involves several rearrangements and is essentially the same mechanism as for water, i.e. one of the H's is replaced by R'.

  • Step (1) The >C^d+=O^d- carbonyl is highly polarised and the positive carbon is attacked by the nucleophilic alcohol molecule, acting as an electron pair donor. The alcohol adds to form a highly unstable ionic intermediate via a C-O bond and simultaneously the ∏ electron pair of the C=O double bond moves onto the oxygen atom to give it a full negative charge..

  • Step (2) The C-Cl bond pair moves onto the chlorine atom and leaves as a chloride ion and simultaneously one of the lone pairs of electrons from the negative oxygen atom shifts to complete (reform) the C=O carbonyl bond.

  • Step (3) The previously formed chloride ion abstracts a proton to form the oxonium ion and the ester product.

• FURTHER COMMENTS

  • The reaction is effectively, overall, the substitution of the -Cl chlorine atom with an -OR group where R'=alkyl or aryl.

  • The acyl chloride and alcohol usually readily react at room temperature, especially if both are aliphatic. Phenols may require the presence of aqueous sodium hydroxide to facilitate the reaction, especially if the acyl chloride itself is itself a less reactive (than aliphatic) aromatic e.g. C₆H₅COCl. The alkali generates a negative phenoxide ion (e.g. C₆H₅O^- from phenol C₆H₅OH), which is a more powerful nucleophile than the original neutral phenol molecule.

Amide formation via acyl chloride by nucleophilic addition-elimination

• e.g. R-COCl + 2NH₃ ==> R-CONH₂ + NH₄⁺ + Cl^-   [see mechanism 16 below]

mechanism 15 - nucleophilic addition-elimination reaction for an acyl chloride forming an amide from ammonia

• [mechanism 16 above] The mechanism involves several rearrangements and assumes excess ammonia.

  • Step (1) The >C^δ+=O^δ- carbonyl bond is highly polarised and the positive carbon is attacked by the nucleophilic ammonia molecule, acting as an electron pair donor. The alcohol adds to form a highly unstable ionic intermediate via a C-N bond and simultaneously the ∏ electron pair of the C=O double bond moves onto the oxygen atom to give it a full negative charge.

  • Step (2) The C-Cl bond pair moves onto the chlorine atom and leaves as a chloride ion and simultaneously one of the lone pairs of electrons from the negative oxygen atom shifts to complete (reform) the C=O carbonyl bond.

  • Step (3) Another ammonia molecule abstracts a proton to form the ammonium ion and the primary amide product.

• From a primary amine a secondary amide (or N-substituted amide) is formed.

• e.g. R-COCl + 2R'NH₂ ==> R-CONHR' + RNH₃⁺ + Cl^-   [see mechanism 17 below]

  • or less correctly written as: R-COCl + R'NH₂ ==> R-CONHR' + HCl

mechanism 15 - nucleophilic addition-elimination reaction for an acyl chloride forming a secondary amide (N-substituted amide) from a primary amine

• [mechanism 16 above] The mechanism involves several rearrangements and assumes excess of the primary amine and is in principal no different than the reaction with ammonia.

  • Step (1) The >C^δ+=O^δ- carbonyl is highly polarised and the positive carbon is attacked by the nucleophilic primary amine molecule, acting as an electron pair donor. The alcohol adds to form a highly unstable ionic intermediate via a C-N bond and simultaneously the ∏ electron pair of the C=O double bond moves onto the oxygen atom to give it a full negative charge.

  • Step (2) The C-Cl bond pair moves onto the chlorine atom and leaves as a chloride ion and simultaneously one of the lone pairs of electrons from the negative oxygen shifts to complete (reform) the C=O carbonyl bond.

  • Step (3) Another primary molecule abstracts a proton to form an alkylammonium ion and the free secondary amide.

• FURTHER COMMENTS

  • The reaction is effectively, overall, the substitution of the -Cl chlorine atom with an amine/amino (-NH₂) group or a substituted amide (-NHR) group.

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