Topic 6 – Alkyl Halide and Carbonyl Compounds Organic Compounds Containing a Halogen

Topic 6 – Alkyl halide and carbonyl compounds Organic compounds containing a halogen

 Compounds are named in standard way, eg:

CH3 H3C CH3 Cl CH3 1 C23

I 4-chlorotoluene (aryl halide) 2-iodo-2-methylpropane (tertiary alkyl halide) 15

CHCl 3 Br Br trichloromethane 2,4-dibromopentane (chloroform) (two secondary alkyl halides)

15 CCl 4 tetrachloromethane (carbon tetrachloride) Br Br (2R,4R)-2,4-dibromopentane (two secondary alkyl halides)

Structure and properties  Dense liquids and solids which are insoluble in water .  The C‐X bond is polar with a slight positive charge (+)   residing on the carbon end of the bond and a slight CX X = F, Cl, Br or I negative charge ( ‐) on the halogen end .

 The carbon‐halogen bond strength decreases in the dipole moment order C‐F > C‐Cl > C‐Br > C‐I.  Alkyl fluorides tend to be less reactive than other alkyl halides, mainly due to the higher strength of the C‐F bond.

Bond length (pm) Bond strength (kJ mol‐1) Dipole moment (D)

CH3‐F 139 452 1.85

CH3‐Cl 178 351 1.87

CH3‐Br 193 293 1.81

CH3‐I 214 234 1.62

1. Nucleophilic substitution

Electrophile: A species that seeks an electron pair Nucleophile: A species that supplies an electron pair

  Nu + H3CX Nu CH3 + X

nucleophile electrophile nucleophilic substitution

Nu + H3CX Nu CH3 + X  

Examples:

A wide range of charged and uncharged nucleophiles may be employed

Nucleophile + H3CI Product + I Product class

  HO + H3CI H3COH + I alcohol

RO + H3CI H3COR + I ether

NC + H3CI H3CCN + I nitrile

RCC + H3CI H3CCCR+ I alkyne

H N 2 + H3CI H3CNH2 + I amine

R3N + H3CI H3CNR3 + I tetraalkylammonium salt

Question: Draw the organic products in the following CN reactions: Br OH

NH2

nd Mechanism – SN2 (2 order)

CH CH H3CH2C 2 3 CH2CH3 ~1/2 ~1/2 CH3OCCBr H3COC Br CH3O Br   H H CH3 H CH3 CH3 leaving nucleophile transition state group electrophile

SN2 reaction favoured by a H Me primary alkyl halide as the CX CX starting material. H H Nu H Nu H methyl halide primary alkyl halide relative rate: 2,000,000 (FAST) 40,000

Me Me

CX CX Me Me Nu H Nu Me

secondary alkyl halide tertiary alkyl halide relative rate: 500 <1 (V. SLOW)

st Mechanism – SN1 (1 order)

2 carbocations have sp hybridised carbons (trigonlal

planar) with a vacant p-orbital CH3 Attack of nucleophile to either side of the planar C Br CH carbocation intermediate H CC 3 is equally likely! 3 CH H C 3 3 CH 3 vacant p-orbital slow

CH 3 CH3 CH3 HO OH C C OH HO C fast fast H C CH 3 3 H3C H3C CH3 CH3 Br planar + carbocation leaving intermediate group

Evidence for SN1 mechanism Intermediacy of a planar carbocation intermediate means that any stereochemistry in the starting material is lost on conversion to the product.

The nucleophilic substitution of (R)-3-bromo-3-methylhexane with methanol leads to racemic methyl ether product

H3C Br CH3 slow + Br

(R)-3-bromo-3-methylhexane planar carbocation intermediate

CH3OH CH3OH rate determining step fast 50% inversion H C OCH H CO CH 50% retention 3 3 3 3 +

(R)-3-methoxy-3-methylhexane (S)-3-methoxy-3-methylhexane

SN1 stands for substitution, nucleophilic, unimolecular.

Unimolecular refers to the fact that only one molecule, the alkyl halide, is involved in the slow rate determining step. The reaction rate is therefore determined by the concentration of the alkyl halide Reaction Rate  [electrophile]

Carbocations

The intermediate in an SN1 reaction is a carbocation.  The C atom has six electrons and a positive charge.

 This is an unstable, highly H3C H3C H3C H reactive intermediate. C CH3 C H C H C H  Not all carbocations have the H3C H3C H H a tertiary alkyl a secondary alkyl a primary alkyl a methyl same relative (un)stability . carbocation carbocation carbocation carbocation most least stable stable increasing stability

H H C 3 CX CX S 1 reaction more likely when a N H H tertiary carbocation is the H H intermediate methyl halide primary alkyl halide relative rate: (V. SLOW) <1 1

H3C H3C CX CX

H3C H3C H H3C secondary alkyl halide tertiary alkyl halide relative rate: 12 (FAST) 1,200,000

Comparison of SN1 and SN2

Summary SN2 reaction: Summary SN1 reaction:

Substitution, nucleophilic, second order Substitution, nucleophilic, first order

The reaction rate is determined by the The reaction rate is determined by the

concentration of both nucleophile and concentration the electrophile only electrophile Involves the two step substitution of an Involves the direct, single step alkyl halide by a nucleophile via a substitution of an alkyl halide by a carbocation intermediate nucleophile with no intermediates The SN1 reaction of chiral compounds

The SN2 reaction proceeds with proceeds with racemisation inversion The rate of the SN1 reaction of alkyl The rate of the SN2 reaction of alkyl halides decreases in the order 3° >> 2° > 1° > methyl halides decreases in the order methyl > 1° > 2° >> 3° Usually only 3° alkyl halides react by this Usually only methyl, 1°and 2° alkyl pathway halides react by this pathway - less crowded

Question: Fill in the missing reagents.

N(CH3)3 I

OH I OCH2CH3 + NaI + NaI

+ NaI C C CH3

2. Elimination of HX

Dehydrohalogenation – require H and X on adjacent carbons.  Generally concentrated reagents and elevated temperatures are used.  Concentrated OH– is used (often KOH in ethanol solvent).

c. OH H3C c. OH H3C heat H3C heat HC CH2 HC CH2 HC CH2 H Br Br H

+ H2O + Br 1-bromopropane 2-bromopropane

Zaitsev’s Rule applies – where there is a choice, the most substituted alkene forms.

+ H O + Br c. OH H3C HC CH CH3 2 H heat H3CCHC CH2 major product H Cl H

H3C H2C HC CH2 + H2O + Br

R R CC H H R H R R R R H H CC CC CC CC H H H H R H R H R R CC R H

unsubstituted monosubstituted disubstituted trisubstituted tetrasubstituted ethylene alkene alkene alkene alkene

Br hot, conc K OH + H2O + K Br Examples of eliminations ethanol

H3C H3C hot, conc H2SO4 COH CCH2 + H2O H3C H3C H3C

hot, conc K OH + H2O ethanol + K Cl Cl major minor trisubstituted C=C bond disubstituted C=C bond 3 carbon substituents 2 carbon substituents

Question: Fill in the reagents in the following sequence of reactions.

OH OH

3. Formation of Grignard reagent

This is the reaction of an alkyl‐ or aryl‐halide and magnesium.

  X = Cl, Br, I R X + Mg R Mg X R = alkyl, aromatic

eg CH3Br + Mg CH3MgBr

+ Mg

I Mg I

Cl MgCl + Mg

Carbonyl Compounds – aldehydes and ketones  The double bond is composed of one σ and one π bond. H  The electron density of a π bond is above and below the plane of the   double bond. CO  The C=O double bond is polarised.  Aldehydes have at least one H attached to the carbonyl group, ketones have two carbon groups attached to the carbonyl group. H  Carbon of the carbonyl group is sp2 hybridised. overlap of electrons in p-orbitals give rise to a -bond

H oxygen has two lone H C O pairs of electrons CO H H

overlap of electrons in sp2-hybridised orbitals gives a -bond in formaldehyde, overlap of electrons in an sp2-hybridised orbital from C and a 1s orbital from H gives a -bond Nomenclature Aldehydes  The longest chain containing the CHO group gives the stem; ending –al.  If substituents are present, start the numbering from the aldehyde group ‐ C1.

Ketones  The longest chain containing the carbonyl group gives the stem; ending –one.  If substituents are present number from the end of the chain so the carbonyl group has the lowest possible number.

 There are non‐systematic names for the common aldehydes and ketone, for example:

H CH CH CH CH3CH2CH2 3 3 2 CO CO CO CO H H H H

formaldehyde acetaldehyde propionaldehyde butyraldehyde (methanal) (ethanal) (propanal) (butanal)

O O

CH 3 C C H CH CO 3 CH3

acetone benzaldehyde acetophenone (propanone) 47

Question: Name the following compounds. O

O O CH2O OO

Reactions of carbonyl group – nucleophilic addition

Dominated by weak and accessible π‐bond  Polarity of C=O directs addition reaction  Reaction conducted in two stages . Nucleophile (eg hydride or carbanion) adds to C . Then O– adds to H+ H H   H H H Nu CO CO CO stage 1 Nu Nu stage 2 H H H

1. Hydride addition (reduction)

– + Use H (LiAlH4 or NaBH4) followed by H  Aldehydes give primary alcohols, ketones give secondary alcohols

Examples:

R  R R  H H H CO H CO H CO H H H primary alcohol

R  R R  H H H CO H CO H CO R R R

secondary alcohol

2. Grignard reaction C nucleophile

This is a very versatile reaction. use Grignard reagent: RMgX

 Can use most organohalide compounds to generate Grignard R Mg X reagent.

 Grignard reagent reacts with aldehydes, ketones and CO2.  Must employ anhydrous conditions. R Mg X

Examples:

H  H H  H H CO H3C H3C CO H3C CO STEP 1 STEP 2 H H H MgBr nucleophilic MgBr acid-base addition reaction methyl formaldehyde an alkoxide a primary magnesium anion alcohol bromide

R  R R  H H CO H3C H3C CO H3C CO

H H H MgBr MgBr methyl other aldehydes secondary magnesium alcohol bromide

R   R R H H H3C CO H C CO H C CO 3 3 R R R MgBr MgBr methyl all ketones tertiary magnesium alcohol bromide

O  OO H H3C C  H3C C H3C C

O  O O H MgBr MgBr methyl carbon dioxide carboxylic magnesium acid bromide

Question: Draw the products of the following sequence of reactions.

Cl conc KOH heat dil H2SO4

2 products, use one in next step

2 Cr2O7 / H

conc H2SO4 1. CH3CH2MgBr heat 2. H

Question: In the Grignard reaction to form 3‐methylhexan‐3‐ol there are three possible ketones that could be used as a starting material. Identify the three ketones and the Grignard reagent they need to react with to give the desired product.