NEW site: ORGANIC CHEMISTRY MECHANISMS for Alcohols, Alcohol derivative Aldehydes-Ketones, Acid/Acyl chloride chlorides, electrophilic substitution, dehydration, nucleophilic addition elimination, cyanide ion, reduction LiAlH4 NaBH4 derivatives GCE-AS-A2-IB Advanced Level Organic Chemistry at Doc Brown's Chemistry Clinic docborgmechs

docborgmechs3 updated May 1st 2008

Doc Brown's Chemistry Clinic

GCE-AS-A2-IB ADVANCED LEVEL ORGANIC CHEMISTRY

A 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. PLEASE ALLOW TIME for the many graphic images-pictures-diagrams to download!!! © Dr W P Brown

MECHANISM Introduction and terms used in organic chemistry
MECHANISM INDEX
Part Ia ALKANES - introduction
- Free radical chlorination/bromination
- Free radical thermal cracking
- Ionic catalytic cracking
Part Ib ALKENES - introduction
- Electrophilic addition of hydrogen bromide [HBr_{(conc. aq)} and HBr_{(g/non-polar solvent)}]
- Electrophilic addition of bromine ...
  - with pure bromine or in non-polar solvent (non-aqueous Br_2(l/solvent))
  - or using bromine water [aqueous Br_2(aq)]
- Electrophilic addition of sulphuric acid
- Electrophilic addition of water [acid catalyst]
- Free radical polymerisation
- Hydrogenation is dealt with under heterogeneous catalysis (new window)
Part II HALOGENOALKANES - introduction (haloalkanes, alkyl halides)
- Nucleophilic substitution by water/hydroxide ion [S_N1 or S_N2, hydrolysis to alcohol]
  - with extra notes on kinetics, rds, molecularity, activated complex etc.
- Nucleophilic substitution by cyanide ion [S_N1 or S_N2]
- Nucleophilic substitution by ammonia or primary amine [S_N1 or S_N2]
- Elimination of hydrogen bromide [E1 and E2]
Part III ALCOHOLS - introduction [this page]
- Conversion to halogenoalkane
- Elimination of water [acid catalysed, E1 and E2]
and Carbonyl compounds - ALDEHYDES and KETONES - introduction
and ACID CHLORIDES - introduction - all nucleophilic addition-elimination reactions
Part IV AROMATIC HYDROCARBONS - introduction to arene electrophilic substitutions
- Nitration
- Chlorination
- Alkylation [Friedel-Crafts reaction]
- Acylation [Friedel-Crafts reaction]
- Sulphonation
- The orientation of products in aromatic substitution
EMAIL query?comments *

ALCOHOLS

The two reactions described both involve acid catalysis and the initial step in each case involves the protonation of the alcohol, this enables a subsequent nucleophilic substitution to take place.

The acid catalysed conversion of alcohol to haloalkane

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.

organic reaction mechanisms

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.

organic reaction mechanisms

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.

organic reaction mechanisms

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 (2.1) and oxygen (3.0). 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.

Nucleophilic addition of cyanide to aldehydes or ketones to give hydroxy-nitriles

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.

organic reaction mechanisms

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 ∏ 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 ∏ 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

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.

organic reaction mechanisms

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 iodination of ketones (substitution reaction, not a nucleophilic addition)

Propanone readily forms 1-iodopropanone on reaction with acidified iodine solution, as do all 2-ones ('methyl ketones') I assume?
- CH₃COCH_3(aq) + I_2(aq) ==> CH₃COCH₂I_(aq) + H⁺_(aq) + I^-_(aq)
However, the rate expression is: rate = k₂[CH₃COCH_3(aq)][H⁺_(aq)]
- and iodine is not in the rate expression but one of the products is!
- Therefore the reaction is zero order for iodine and it also zero order for bromine in the similar bromination reaction.
This suggests there is a slow rate determining step involving the ketone and the hydrogen ion in the mechanism and what ever happens next e.g. involving the iodine, is much faster. A proposed mechanism is shown below, where R = CH₃ if it was propanone. Note that very little can be absolutely proved in mechanistic detail and you will find variations of this diagram on the web.

The mechanism for propanone, with only one slow step suggested is ...
- Step (1) (CH₃)₂C=O + H₃O⁺ (CH₃)₂C=O⁺H + H₂O
  - The ketone is reversibly protonated on the oxygen (+) by the acid in an acid-base reaction (proton transfer).
- Step (2) (CH₃)₂C=O⁺H (CH₃)₂C⁺-OH
  - The electrons 'between' the C-O partly shift to form a carbocation i.e. the positive charge is transferred from the oxygen to the carbon.
- Step (3) (CH₃)₂C⁺-OH + H₂O CH₃C(OH)=CH₂ + H₃O⁺
  - The carbocation, derived from the protonated ketone, loses a proton and slowly changes into the 'enol'* form.
  - This involves breaking a strong C-H bond, hence a high activation energy and slow speed. The positive charge on the adjacent carbon of the carbocation facilitates in 'pulling' the C-H bond pair to form the C=C bond and release the proton to a water molecule.
  - The rate of formation of the enol thus depends on the concentrations of the ketone and the acid, explaining the rate equation experimentally found. Also note that it is an example of autocatalysis because one of the reaction products is the oxonium ion!
  - * An 'enol' has both alkene and alcohol functional groups and is isomeric with the original ketone. This is an example of functional group isomerism involving a dynamic equilibrium of the two isomers (the original ketone and enol formed) and is sometimes called an example of tautomerism.
- Step (4) CH₃C(OH)=CH₂ + I₂ CH₃C(=O⁺H)-CH₂I + I^-
  - Half of the iodine molecule (an electrophile) then quickly adds to the 'enol' (just like any reactive alkene), and the oxygen then carries the positive charge (not on the carbon as in electrophilic addition to alkenes), and the protonated iodoketone is formed.
- Step (5) CH₃C(=O⁺H)-CH₂I + H₂O CH₃COCH₂I + H₃O⁺
  - Then a water molecule rapidly, and reversibly, removes the proton in another acid-base reaction to leave the iodoketone.
- For the slow step (3), the rate depends on the isomerisation of protonated ketone/carbocation, which in turn will depend on the concentration of the ketone AND the acid providing the H₃O⁺ ion.
Note:
- The same reaction is catalysed by bases and proceeds by a different mechanism and gives different products ultimately. Multiple substitution takes place, initially forming 1-iodopropane, then 1,1-diidopropane, and then 1,1,1-triiodopropane. Finally, the carbon chain splits to give triiodomethane, CHI₃, i.e. its the 'iodoform' reaction given by ethanol, ethanal, and all 2-ones ('methyl ketones').
- The individual products are almost impossible to isolate in the base catalysed reaction, but in the acid catalysed reaction, the rate of halogenation decreases with successive halogen atom substitution, so it is possible to isolate e.g. 1-iodopropanone, 1,1-diiodopropanone and 1,1,1-triiodopropanone and presumably? molecules such as 1,3-diodopropanone may be formed, but I'm not sure on this one?
- This mechanism is often presented, and not unreasonably at UK A level, as a three step mechanism, with Step (1) as the rds and clearly showing the proton's role in this acid catalysed reaction.
  1. Step (1) (CH₃)₂C=O + H⁺ (CH₃)₂C=O⁺H
    - SLOW protonation of the ketone by the hydrogen ion
  2. Step (2) (CH₃)₂C=O⁺H CH₃C(OH)=CH₂ + H⁺
    - FAST deprotonation and rearrangement to give the enol form)
  3. Step (3) CH₃C(OH)=CH₂ + I₂ CH₃COCH₂I
    - FAST equivalent of adding I-I across the carbon-carbon double bond >C=C< and then elimination of HI.

CARBOXYLIC ACIDS and DERIVATIVES - Acyl/acid chlorides

The hydrolysis of acyl chloride by nucleophilic addition-elimination

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

organic reaction mechanisms

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]

organic reaction mechanisms

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]

organic reaction mechanisms

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

organic reaction mechanisms

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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docborgmechs3 updated May 1st 2008