CH 24 Student

Solutions manual for Burrows et.al.
Chemistry3
24
Carboxylic acids and derivatives: nucleophilic acyl substitution and -substitution reactions
Answers to worked examples
WE 24.1 Esters from acyl chlorides (on p. 1104 in Chemistry3) Reaction of morphine with two equivalents of ethanoyl chloride and excess pyridine produces heroin. Give the structure of heroin.
HO
O H HO morphine NMe H
Strategy Draw out the structure of morphine and the reagents, ethanoyl chloride and pyridine, and name the functional groups present. Examine the reagents, deduce their relative reactivity, and draw out the resulting product.
1 OXFORD H i g h e r E d u c a t i o n
Oxford University Press, 2009. All rights reserved.
Solutions manual for Burrows et.al. Chemistry3
Solution Morphine contains four heteroatom-based functional groups; the tertiary amine, phenol, secondary alcohol and ether. In all cases, these functional groups can act as a nucleophile or a base. The phenol and secondary alcohol can be easily functionalised as they both contain acidic O-H groups. Pyridine is a mild base/nucleophile, whereas, ethanoyl chloride is a potent electrophile.
phenol HO O ether secondary alcohol HO morphine base/nucleophile O H tertiary amine NMe H Cl ethanoyl chloride electrophile
N pyridine base/nucleophile
Treatment of morphine with two equivalents of ethanoyl chloride (in the presence of an excess of pyridine) results in esterification of the two OH groups (of the phenol and secondary alcohol) to give the diester product, heroin, as shown below. Ethanoyl chloride acts an electrophile, whereas, pyridine acts a base and a nucleophile catalyst. These reactions involves nucleophilic addition to the carbonyl (C=O) group of ethanoyl chloride, followed by elimination of chloride; these processes are more commonly classed as acyl substitution reactions.
ester HO O O Cl O H HO morphine ester NMe H N O O heroin O H NMe H O
Answer
O O O O H O heroin (also called diacetylmorphine or diamorphine) NMe H
WE 24.3 Transesterification and aspirin (on p. 1114 in Chemistry3) In our bodies, compounds called prostaglandins induce inflammation, pain, and fever. To provide relief from pain, aspirin acts by inhibiting an enzyme that catalyses the formation of prostaglandins. Aspirin reacts with an OH group within the active site of the enzyme to convert it into an ester (in a transesterification reaction), which inhibits the production of prostaglandins. Representing the structure of the enzyme by Enzyme-OH, draw the structures of the products formed in the transesterification reaction.
HO
O O O aspirin
Strategy Draw out the structure of aspirin and the enzymes active site, Enzyme-OH, and name the functional groups present. Locate the ester group in aspirin, and transfer it onto the enzymes active site. Draw out the resulting products. Solution The enzymes active site contains a nucleophilic hydroxyl group (HO-Enzyme). Aspirin contains a carboxylic acid group and an ester group; the carbonyl (C=O) group of the ester is more electrophilic than that of the carboxylic acid. Transesterification of ester group from the aspirin to the enzymes active site, HO-Enzyme, gives the products, salicyclic acid and the enzyme-ester A.
carboxylic acid HO O ester O HO O alcohol aspirin salicyclic acid Enzyme O ester A HO O phenol OH O enzyme
Answer
CO2H OH + O O Enzyme
Answers to boxes
Box 24.1 Oxytocin, the hormone of love (on p. 1092 in Chemistry3) Amino acids links together to form peptides (see box 24.1 in p. 702 in Chemistry3). Draw the structures of the eight amino acids that, when linked together with H2NCH2CONH2, form oxytocin. (Assume the SS bond is not formed at this stage).
OH
O H N N H O NH S H2N S O N O O O oxytocin HN N H O O H N NH
O NH2 O NH2
NH2 O
Strategy Locate and highlight the eight amino acid derived peptides, -NH-CHR-C=O-, embedded in the structure of oxytocin. Remember these are peptides and not amino acids. To convert them back into their parent amino acid; the amide bond, NH-C=O-, needs to be broken and hydrated to give the corresponding amino group, -NH2, and the carboxylic acid, -CO2H. In addition, the disulfide bond, -S-S-, has to be reduced to give the two corresponding thiol bonds, -SH and SH.
Solution There are NINE amino acid peptides in oxytocin. Fragmentation and hydration of the amide bonds, reveals eight different amino acids; all are chiral with the exception of glycine, NH2CH2CO2H. The only amino acid which appears twice in oxytocin is cysteine, NH2CH(CH2SH)CO2H. The structures of all theses amino acids, which make up the structure of oxytocin, are shown below.
OH
O H N N H O NH S H2N S O N O O O oxytocin HN N H O O H N NH
O NH2 O NH2
NH2 O
OH
O OH H2N O NH2 OH H2N SH HS HO NH O H2N OH OH O NH2 NH2 HO O O O H2N OH OH H2N O
O NH2
O NH2
NH2 O
Answer
O Ph NH2 OH OH H2N O O OH H2N O NH2
OH HS SH NH2 HO
NH2
O NH2
H2N HO O O
O NH O OH H2N OH
Box 24.3 Fragrant esters (on p. 1101 in Chemistry3) All six esters (AF) shown above are prepared by reaction of an alcohol with a carboxylic acid in an esterification reaction. For each ester, draw the structures of the precursor alcohol and carboxylic acid. Strategy Locate and highlight the ester group, R1(C=O)-O-R2. To convert them back into their parent carboxylic acid and alcohol; the ester bond, -O=C-O-, needs to be broken and hydrated to give the corresponding alcohol HO-R2, and the carboxylic acid R1(C=O)-OH. Draw out the parent carboxylic acid and alcohol components that make up each ester. Solution Each ester can be fragmented and hydrated to give the corresponding alcohol and carboxylic acid, as shown below.
fragment and hydrate O R1 R2 O O "+H2O" R1 OH R2 HO alcohol
ester group
carboxylic acid
For the six esters, the parent carboxylic acids and alcohols are shown below.
O "+H2O" O A: ethyl butanoate OH butanoic acid HO ethanol O
O "+H2O" O B: octyl ethanoate O OH ethanoic acid HO octanol
O "+H2O" O C: methyl butanoate
O OH butanoic acid HO methanol
O O "+H2O"
O OH HO
D: methyl benzoate
benzoic acid
methanol
O "+H2O" O E: pentyl ethanoate

O "+H2O" H O H OH O
O OH ethanoic acid HO pentanol
HO ethanol
F: ethyl methanoate
methanoic acid
Answer
O + OH O + OH HO B HO A
O OH
O OH +
HO
HO
O + OH HO E
O + H OH HO F
Box 24.5 Combinatorial chemistry (on p. 1107 in Chemistry3) Show how libraries of esters are constructed by reacting methanol, ethanol, and propanol with ethanoyl chloride, propanoyl chloride, and butanoyl chloride. Strategy Esters, like R1(C=O)O-R2, can be synthesised by addition of an alcohol, such as R2OH, to an acid chloride, R1(C=O)Cl, in the presence of a suitable base. Draw out the structures of the above acid chlorides and alcohols. For each acid chloride, use the THREE alcohols, MeOH, EtOH and PrOH, to make THREE esters. As there are THREE acid chlorides, there will be NINE ester products. Draw out the structure of these NINE ester products. 10 OXFORD H i g h e r E d u c a t i o n
O R1 Cl R2 HO alcohol "-HCl" R
1
O R2 O ester
acid chloride
Solution Combining three acid chlorides with three alcohols will make nine esters, as shown below. It is important to note, the total number comes from 3 multiplied by 3 (= 9), and NOT 3 plus 3 (= 6). For example, mixing a series of 5 acid chlorides and 5 alcohols would give a library of 25 (5 5) esters, and a series of 10 acid chlorides and 5 alcohols would give 50 (10 5) esters, and so on.
O Me HO methanol "-HCl" Me Me O methyl ethanoate O Et Me Cl HO ethanol "-HCl" Et Me O ethyl ethanoate O Pr HO propanol "-HCl" Pr Me O
ethanoyl chloride
propyl ethanoate
O Me HO methanol "-HCl" Me Et O methyl propanoate O Et Et Cl HO ethanol "-HCl" Et Et O ethyl propanoate O Pr HO propanol "-HCl" Pr Et O
propanoyl chloride
propyl propanoate
O Me HO methanol "-HCl" Me Pr O methyl butanoate O Et Pr Cl HO ethanol "-HCl" Et Pr O ethyl butanoate O Pr HO propanol "-HCl" Pr Pr O
butanoyl chloride
propyl butanoate
Answer 12 OXFORD H i g h e r E d u c a t i o n
MeOH EtOH PrOH MeCOCl mix
MeOCOMe EtOCOMe PrOCOMe MeOCOEt EtCOCl mix EtOCOEt PrOCOEt MeOCOPr PrCOCl mix EtOCOPr PrOCOPr library 3 library 2 library 1
MeOH EtOH PrOH split
MeOH EtOH PrOH MeOH EtOH PrOH
Box 24.7 Hydrolysis of nitriles to form carboxylic acids (on p. 1117 in Chemistry3) Propose a mechanism for the following reaction, which involves an intermediate imine (see section 9.7 on p.436 in Chemistry3 for the structure of imines).
Ph N MgBr
+
Ph O
then H , H2O
Strategy For each step within your proposed mechanism, you will need to decide whether the reaction involves an electrophile/nucleophile or acid/base combination. Acid and base processes involve proton exchange, whereas, electrophile and nucleophile processes involve bond-breaking and bond-making. Draw a curly arrow from the nucleophile or base to the electrophile or acid (). Solution The Grignard reagent, Ph-MgBr is the nucleophile and ethyl cyanide, EtCN, is the electrophile in this reaction. Nucleophilic addition of the phenyl carbanion, Ph-, (from the nucleophilic Ph-MgBr bond) to the electrophilic nitrile group of ethyl cyanide leads to the trigonal intermediate A. Protonation of this basic iminium ion, in A, using aqueous mineral acid (dilute HCl in H2O), gives the imine B. 13 OXFORD H i g h e r E d u c a t i o n
nucleophile Ph MgBr MgBr
Ph C N electrophile N base A H acid N
Ph
H imine B
Under prolonged acidic conditions, this imine, B, hydrolyses to give the ketone I and ammonium chloride. Protonation of the imine, in C, followed by nucleophilic addition of water to the electrophilic iminium ion D gives the hemi-aminal intermediate E. Intramolecular proton exchange, in E, followed by elimination of ammonia gives the oxonium ion H. Intermolecular proton exchange between the acidic oxonium ion H and basic ammonia gives the required ketone I and ammonium chloride. The mechanism of this process is shown below.
nucleophile H2O imine Ph H N H base C H O Ph NH2 F O Ph Ph NH4 H acid H NH3 base ketone I O Cl acid C N H H electrophile D NH2 base E Ph H O Ph acid H
Answer
imine + N Ph MgBr + H N MgBr H Ph NH Ph
H2O Ph H NH2 O H Ph NH2 H HO Ph NH2 H
Ph HO NH3
NH3 O
Ph
H O
Ph
[Movement of electrons can also be depicted using a negative charge or a non-bonded pair of electrons.]
Answers to end of chapter questions (on p. 1127 in Chemistry3)

1. The following queries are based on the reactions of ethyl ethanoate (1) shown below.
O EtOH OH 2 O OEt 1 O O OEt 5 H+, H2O heat OH 4
EtOH
PhMgBr (two equivalents) then, H+/H2O
NaOEt then, H+
(a)
Give appropriate reagents for converting 1 into 2. Is this an example of an oxidation or a reduction reaction?
Strategy Draw out the starting material and product, assign their oxidation levels, and work out if an oxidation or reduction has occurred. Deduce which functional group has changed during this proposed reaction, and suggest reagents for this transformation.
Solution The starting material 1 and product 2 contains ester and primary alcohol functionality, respectively. This process involves reduction, as there is a decrease in the oxidation level of the carbon atom of the ester group, in 1, from +3 to -1 (in the primary alcohol 2).
ester O C OEt 1 oxidation level of C = +3 LiAlH4 (1st equiv.)
aldehyde O C H A oxidation level of C = +1 LiAlH4 (2nd equiv.) then H+,H2O
primary alcohol H C OH 2 oxidation level of C = -1 H
Reduction of the polar carbonyl group, of ester 1, will require a polar reducing agent. The most suitable reagent for this reduction is lithium aluminium hydride (LiAlH4); the use of a less reactive hydride source, like NaBH4, is NOT acceptable. Two equivalents of LiAlH4 are required; the first equivalent reduces the ester to give the intermediate aldehyde A; the second equivalent reduced this aldehyde to the required primary alcohol 2. Under these conditions, the reaction needs to be worked-up under acidic conditions (H+, H2O) in order to protonate the intermediate alkoxide. For a detailed account of these mechanisms, see p. 1055 in Chemistry3. Answer This process involves reduction; a suitable reagent is LiAlH4, then H+. (b) Give the structure of organic compound 3.
Strategy Draw out the reagents, ethyl ethanoate 1 and phenyl magnesium bromide (PhMgBr), and name the functional groups present. Examine the reagents, deduce their relative reactivity, and draw out the resulting product. Solution Ethyl ethanoate 1 is an ester, and acts as an electrophile in this reaction. The Grignard, phenyl magnesium bromide (PhMgBr) is a nucleophilic equivalent of a phenyl carbanion, Ph-.
electrophile O ester 1 C OEt C OEt Ph MgBr Ph B C Ph ketone C O O OEt MgBr MgBr
nucleophile
Nucleophilic addition of the first equivalent of phenyl magnesium bromide, using its nucleophilic Ph-MgBr bond, to the electrophilic carbonyl group of ethyl ethanoate 1 leads to the tetrahedral intermediate B. Elimination of ethoxide, EtO-, gives the intermediate ketone C.
electrophile O ketone C C Ph C Ph Ph MgBr Ph D O H OH C Ph Ph 3 MgBr MgBr
nucleophile
Nucleophilic addition of a second equivalent of phenyl magnesium bromide to the electrophilic carbonyl group of the intermediate ketone C leads to the tetrahedral intermediate D. Protonation of its basic alkoxide, in D, using aqueous mineral acid (dilute HCl in H2O), gives the tertiary alcohol 3. The mechanisms of these Grignard reactions are given on p. 1061 in Chemistry3. Treatment of esters, like R1CO2R2, with two equivalents of Grignard reagent, such as R3MgBr, leads to the corresponding tertiary alcohol, R1C(OH)R3R3. Answer
Ph Ph OH
(c)
Oxygen-18 labelling is often used to establish the mechanism of a reaction. An 16O oxygen in a starting material is replaced by an 18O atom and the position of the 18O 18 OXFORD H i g h e r E d u c a t i o n
atom at the end of the reaction recorded using mass spectrometry (see section 13.1 on p.606 in Chemistry3). (i) Draw a reaction mechanism to show how 1 is converted into 4 and EtOH.
Strategy For each step within your proposed mechanism, you will need to decide whether the reaction involves an electrophile/nucleophile or acid/base combination. Acid and base processes involve proton exchange, whereas, electrophile and nucleophile processes involve bond-breaking and bond-making. Draw a curly arrow from the nucleophile or base to the electrophile or acid (). Solution The ester 1 is the base, and H+ is the acid. Protonation of the oxygen atom of the carbonyl (C=O) group of this ester 1 with H+ gives the intermediate oxonium ion E. Nucleophilic addition of water (H2O) to this oxonium ion, in E, leads to the protonated intermediate hydrate F. Intramolecular proton exchange between the basic ethoxy group and the acidic oxonium ion, in F, gives the intermediate G. Elimination of ethanol (EtOH), assisted by the non-bonded pair of electrons on the neighbouring hydroxyl (OH) group, gives the protonated ester H. Intermolecular acid-base exchange of H with another molecule of water (from the solvent) gives the required carboxylic acid 4 and ethanol. This mechanism involves the acid-catalysed hydrolysis of ester 1, using an AAc2 mechanism, to give the corresponding carboxyl acid and alcohol components by cleavage of its acyl (Ac) group.
base O C OEt ester 1
acid H
electrophile H O E C OEt H OH2 nucleophile acid H O H C OH
OH C O F
base OEt H acid
OH C O H G O Et
OH2 base (solvent)
H O C OH 4
OH2 (solvent)
HOEt
Answer
O OEt 1 H HO OH H OEt OEt H O H OH 4 + EtOH 5 OH HO OH O H catalyst H OH OEt HO H HO O H
OEt
(c)
(ii)
If 1 is heated with H218O and H+, where does the 18O atom appear at the end of the reaction?
Strategy Non-isotopically labelled water is H2O16. Redraw the hydrolysis mechanism given in part (c)-(i) as given above, and replace H2O with isotopically labelled water H2O18 (or H2O). In each step of this mechanism, carefully label the resulting position of this 18Olabelled oxygen atom. Draw out the final products, and clearly label the 18O-atom(s).
Solution By simply replacing H2O with labelled H2O18 (as shown by H2O in the mechanism below) and following the position of this 18O-labelled oxygen atom throughout this mechanism - the initial product of this hydrolysis is a single 18O-labelled carboxylic acid [18O]-4.
electrophile H O E C OEt H OH2 nucleophile acid OH C O H G H HOEt O Et H O C OH H F
acid O C OEt ester 1 H
OH C O
base OEt H acid
OH2 base (solvent)
H O C OH [18O]-4
OH2 (solvent)
O = 18O isotopic label
Under acidic conditions, this 18O-labelled oxygen atom (on the OH group in [18O]-4) can tautomerise into the C=O18 group, and vice versa, as shown below. In essence, the two 21 OXFORD H i g h e r E d u c a t i o n
oxygen atoms of this carboxylic acid [18O]-4] are indistinguishable under this dynamic equilibrium; both isotopically labelled products are equally preferred.
O H C OH [18O]-4 O = 18O isotopic label C O [18O]-4 OH
However, in the presence of an excess of 18O-labelled water (H2O18), the fully 18O-labelled carboxylic acid [18O2]-4 is preferred. This reaction proceeds via the intermediate hydrate [18O2]-I. For further information about the mechanism of hydrate formation, see p. 1064 in Chemistry3.
O H C OH [18O]-4 H2O C OH [18O2]-I OH OH H H2O C OH [18O2]-4 O
Answer
O
18 18
O and/or OH
18
O
18
OH
OH
(c)
(iii)
If ethyl ethanoate, labelled with 18O as shown below, is heated with H2O/H+, where does the 18O atom appear at the end of the reaction?
O C
18
O C OEt OEt O = 18O isotopic label
Strategy 22 OXFORD H i g h e r E d u c a t i o n
Redraw the hydrolysis mechanism given in part (c)-(i) as given above, and replace ester 1 with isotopically labelled ester [18O]-1. In each step of this mechanism, carefully label the position of this 18O labelled oxygen atom. Draw out the final products, and clearly label the 18O atom. Solution By simply replacing the ester 1 with the labelled ester [18O]-1 (as shown by the mechanism below), and following the position of this 18O-labelled oxygen atom throughout this mechanism; the product of this hydrolysis is the unlabelled carboxylic acid 4 and 18Olabelled ethanol (Et18OH). This reaction proceeds by an AAc2 mechanism where cleavage occurs at its acyl (Ac) group.
electrophile H O E C OEt H H2O nucleophile acid OH C O H G H HOEt O Et H O C OH 4 H F
acid O C OEt ester [18O]-1 H
OH C O H
base OEt
acid
OH2 base (solvent)
H O C OH
OH2 (solvent)
Answer EtO18H (d) Draw a reaction mechanism to show how 1 is converted into 5.
For each step within your proposed mechanism, you will need to decide whether the reaction involves an electrophile/nucleophile or acid/base combination. Acid and base processes involve proton exchange, whereas, electrophile and nucleophile processes involve bond-breaking and bond-making. Draw a curly arrow from the nucleophile or base to the electrophile or acid (). Solution Deprotonation of ethyl ethanoate 1 [pKa (H2O) = 25] using ethoxide, EtO-, as the Brnsted base, gives the thermodynamically less stable enolate J and its conjugate acid, ethanol [pKa (H2O) = 16].
pKa (H2O) = 25 acid H C H H ester 1 H enolate J H OEt pKa (H2O) = 16 O C OEt H C O C OEt
OEt base
The product, -keto ester 5, is derived from two equivalents of ethyl ethanoate 1. Nucleophilic addition of the enolate J (derived from the first equivalent of ester 1) to the electrophilic carbonyl (C=O) group of the second equivalent of ester 1, followed by elimination of ethoxide, EtO-, leads to the required -keto ester 5. {This additionelimination has been depicted using a double-headed curly arrow. If you are unsure about using this type of curly arrow, see p. 1095 in Chemistry3.}
electrophile O H C H H leaving group ester 1 enolate J base OEt K C OEt H C H nucleophile O C OEt H C H H H -keto ester 5 pKa (H2O) = 11 O C C H acid O C OEt
However, as this -keto ester 5 [pKa (H2O) = 11] is more acidic than both ethanol [pKa (H2O) = 16] and ethyl ethanoate 1 [pKa (H2O) = 25]; deprotonation of -keto ester 5 (in L) using ethoxide, EtO-, as the Brnsted base, gives the more thermodynamically stable enolate K. External protonation of enolate K, using an acid work-up gives the required keto ester 5 (in the absence of base).
base H C H H H OEt H enolate L H acid
O C C
O C OEt H H H+ H C
O C C H H
O C OEt
-keto ester 5
Answer
O EtOH EtO 1 EtO H EtO + 1 O O OEt EtO O O OEt
O EtO 5
O H EtO
O EtOH EtO
H OEt
[Movement of electrons can also be depicted using a negative charge or a non-bonded pair of electrons.] (e) Draw the major enol form of compound 5.
Enols are unstable tautomers of carbonyl-containing molecules; their enol content is usually less than 1% due to the strength of their carbonyl (C=O) double bond in their keto-form (a ketone or an aldehyde). In order to form an enol, the carbonyl-containing molecule must have an alpha C(sp3)-H bond. Draw out both molecules and include all alpha C(sp3)-H bonds. As enols are constitutional isomers of carbonyl-containing molecules, they can be easily drawn by replacing each H-C(sp3)-C=O unit for a C=C-OH unit. If there are two or more alpha C(sp3)-H bonds, draw out each enol separately and consider their stability. As enol formation is thermodynamically unfavoured, molecules that have two or more carbonyl groups you will only need to consider mono-enol formation. Solution There are two chemically different alpha C(sp3)-H bonds, namely, Ha and Hb, which can lead to three potential enols M (derived from Ha) and, N and O (derived from Hb). The more substituted enols N and O are more thermodynamically stable than enol M due to conjugation (between their C=C and C=O bonds) and increased hyperconjugation from their neighbouring CH3 groups. In all cases, intramolecular hydrogen bonding between the enolic OH group and the neighbouring carbonyl (C=O) bond helps to stabilise these enols. Enol N is slightly more stable than enol O as its remaining ester group is more stable; a carbonyl group of an ester is more stable than that of a ketone due to resonance stabilisation. The relative amount of these enols N and O (in a sample of this -keto ester 5) is approximately 50%. For further information about hyperconjugation; see p. 870 in Chemistry3.
O Ha Ha C C Ha Hb C
O OEt Hb
-keto ester 5 H-bond H O H C H H C C H O C OEt H H H conjugation enol M enol N enol O H C O C C H O C OEt H H H H C O C C H-bond H-bond H O C OEt
Answer
OH O OEt
3.
(a)
The following queries relate to the formation of lactone 7 from keto-ester 6.

O O O OEt 6 1. NaBH4 then, H+ 2. H+, heat MgSO4 7 O
(i) Suggest a mechanism to explain the formation of 7. Strategy For each step within your proposed mechanism, you will need to decide whether the reaction involves an electrophile/nucleophile or acid/base combination. Acid and base processes involve proton exchange, whereas, electrophile and nucleophile processes involve bond-breaking and bond-making. Draw a curly arrow from the nucleophile or base to the electrophile or acid (). Solution Sodium borohydride, NaBH4, is a nucleophilic hydride, H-, equivalent. The ,-ketoester 6 is the electrophile in this reaction; the carbonyl (C=O) group of the ketone component is more electrophilic than its ester component. Nucleophilic addition of hydride, H-, from sodium borohydride (NaBH4), using its nucleophilic H-B bond to the electrophilic carbonyl group of the ketone component of ,ketoester 6, followed by elimination of ethoxide (EtO-) gives the required lactone 7. Magnesium sulphate (MgSO4) is used to remove traces of ethanol (EtOH) and water (H2O) to promote the thermodynamic lactonisation. {This addition-elimination has been depicted using a double-headed curly arrow. If you are unsure about using this type of curly arrow, see p. 1095 in Chemistry3.}
electrophile ketone O O ester OEt 6 nucleophile H H B H Na
nucleophile O
A O electrophile OEt
H H B H H borane
Na
H sodium borohydride O O OEt H
Answer
O O EtO OEt H B H H H 6 7 BH3 O EtO O O O
(a)
(ii)
Explain why the reaction of 1 with NaBH4 is chemoselective.
Strategy For this reaction to be chemoselective (or chemical selective), the reagent must be able to distinguish between different chemicals or functional groups through reactivity, and it must be selective; i.e., chemoselective. If there is a choice within its mechanism, then it will always be selective. Solution This carbonyl reduction is chemoselective as it occurs ONLY on the carbonyl (C=O) group of the ketone component of ,-ketoester 6 and NOT its ester component. This difference in reactivity is due to the relative stability of these carbonyl (C=O) containing functional 29 OXFORD H i g h e r E d u c a t i o n
groups; a ketone is more reactive (less stable) and more electrophilic than an ester as it is NOT resonance stabilised. {For additional information on resonance stabilisation of esters, see p. 1096 in Chemistry3.} Answer NaBH4 selectively reduces the C=O bond of the ketone because the carbonyl carbon atom of the ketone is a better electrophile than the carbonyl carbon atom of the ester. In the ester group, the positive mesomeric effect (+M) of the EtO group reduces the electrophilicity of the carbonyl carbon atom. (a) (iii) Give the structure of the organic product from reaction of 1 with LiAlH4 then H+.
Strategy Lithium aluminium hydride, LiAlH4, is a nucleophilic hydride, H-, equivalent. The ,ketoester 6 is the electrophile in this reaction; the carbonyl (C=O) group of the ketone component is more electrophilic than the ester component. LiAlH4 has higher ground-state energy than NaBH4, and is therefore more reactive and nucleophilic. It is primarily used to reduce less electrophilic carbonyl (C=O) groups, such as esters and amides, in which NaBH4 fails. Draw the structure of the product derived from the reduction of both carbonyl (C=O) group of ,-ketoester 6. Solution Reduction of the more electrophilic ketone component of the ,-ketoester 6, using LiAlH4, leads to the secondary alcohol B. This chemoselective reduction is faster than the corresponding reduction of the ester component. However, this intermediate secondary alcohol, in B, has the potential to cyclise to form the corresponding lactone 7. Using an excess of LiAlH4, the carbonyl (C=O) groups of the ester (in B) and/or the lactone 7 are reduced to give the corresponding primary alcohol (in C).
Reduction of the ,-ketoester 6, using an excess of LiAlH4, gives the 1,5-diol C as the major product.
lactone ketone O ester O OEt H 6 secondary alcohol slow LiAlH4 then, H+ H C OH primary alcohol OH H H B fast LiAlH4 OEt and/or H 7 secondary alcohol OH ester O O O
Answer
OH OH
(b)
The following queries relate to the formation of compound 10.

O O OMe OMe Me O 8 9 10 Me O Me O Me MeO then H+ Me Me O
(i)
Suggest a mechanism to explain the formation of 10.
Strategy For each step within your proposed mechanism, you will need to decide whether the reaction involves an electrophile/nucleophile or acid/base combination. Acid and base 31 OXFORD H i g h e r E d u c a t i o n
processes involve proton exchange, whereas, electrophile and nucleophile processes involve bond-breaking and bond-making. Draw a curly arrow from the nucleophile or base to the electrophile or acid (). Solution By examining the reagents, the ester 8 is an electrophile, ketone 9 is either an electrophile or an acid, and methoxide, MeO-, is either a nucleophile or a base. However, methoxide, MeO-, must be the active component of this mixture, and it has to initially act as a base (as nucleophilic additions to either 8 or 9 are not product determining steps).
electrophile O H OMe H OMe O ester
8
electrophile O Me H acid ketone

9
nucleophile/base
OMe methoxide
Me
Me
Deprotonation of ketone 9 [pKa (H2O) = 20] with methoxide, MeO-, as the Brnsted base, gives the thermodynamically less stable enolate A and methanol [pKa (H2O) = 16].
electrophile O O Me C Me Me 9 base OMe methoxide C H H Me acid H Me C Me A C H H OMe O H MeO MeO C O 8 C
Me Me
pKa (H2O) = 11 O O O acid C C C C Me B OMe base H H
OMe Me C Me Me
O O C C H O C
OMe
enolate C H OMe
The product triketone, 10, is derived from the addition of this enolate A to the diester 8. Nucleophilic addition of this enolate A to one of the two electrophilic carbonyl (C=O) groups of the diester 8, followed by elimination of methoxide, MeO-, leads to the intermediate -ketoester B. {This addition-elimination has been depicted using a doubleheaded curly arrow. If you are unsure about using this type of curly arrow, see p. 1095 in Chemistry3.} However, this intermediate B [pKa (H2O) = 11] is more acidic than both methanol [pKa (H2O) = 16] and the original ketone 9 [pKa (H2O) = 20]; deprotonation of intermediate B using methoxide, MeO-, as the Brnsted base leads to more thermodynamically stable enolate C.
nucleophile O Me C Me Me H MeO C O enolate C electrophile OMe base D Me Me C C C O C pKa (H2O) = 5 acid O C H Me C C O O C
H acid
O base O C C C Me O H OMe C H
+
O O C Me Me C Me 10 H C C O C
Me Me
enolate E
Intramolecular nucleophilic addition of this enolate, in C, to the electrophilic ester, followed by elimination of methoxide, MeO-, leads to the intermediate triketone D. However, this intermediate D [pKa (H2O) = 5] is acidic and subsequent deprotonation with methoxide, MeO-, as the Brnsted base leads to the most thermodynamically stable enolate E. External protonation of this enolate, E, using an acid work-up gives the required triester 10 (in the absence of base).
nucleophile O Me C Me Me H MeO C O enolate C electrophile OMe base D Me Me C C C O C pKa (H2O) = 5 acid O C H Me C C O O C
H acid
O base O C C C Me O H OMe C H
+
O O C Me Me C Me 10 H C C O C
Me Me
enolate E
Answer
O O MeOH H OMe + MeO2C 9 8 O O MeOH H MeO2C MeO O O O O MeO
MeO
O MeO H O
O H 10
10
O + MeOH
(b)
(ii)
Draw two different enol forms of compound 5.
Strategy Enols are unstable tautomers of carbonyl-containing molecules; their enol content is usually less than 1% due to the strength of their carbonyl (C=O) double bond in their keto-form (a ketone or an aldehyde). In order to form an enol, the carbonyl-containing molecule must have an alpha C(sp3)-H bond. Draw out both molecules and include all alpha C(sp3)-H bonds. As enols are constitutional isomers of carbonyl containing molecules, they can be easily drawn by replacing each 35 OXFORD H i g h e r E d u c a t i o n
H-C(sp3)-C=O unit for a C=C-OH unit. If there are two or more alpha C(sp3)-H bonds, draw out each enol separately and consider their stability. As enol formation is thermodynamically unfavoured, molecules that have two or more carbonyl groups you will only need to consider mono-enol formation. Solution There is ONLY one alpha C(sp3)-H bond within the triester 10; however, this can lead to TWO different enols, endo-F and exo-G. Both are equally favoured.
O H O O H O O H O
Me O 10 Me Me O endo-F "endo-" means internal to the ring Me
Me Me O exo-G "exo-" means external to the ring Me
Me Me
Answer
OH O O OH
5. In nature, aromatic compounds are formed by the cyclization of polyketide chains (containing alternating C=O and CH2 groups) in the presence of enzymes. The polyketide chains have a thioester group (RCOSR) at the end of the chain, which, like esters, react in Claisen-type reactions. For example, thioester 1 is converted into phloracetophenone. Phloracetophenone, obtained from the plant Curcuma comosa, has been shown to lower cholesterol levels in animals.
O O O SR O
HO O SR
O 14 polyketide
O 15 O O O HO O OH
O phloracetophenone
OH
(a)
Propose a mechanism that explains how compound 2 is converted into phloracetophenone.
Strategy For each step within your proposed mechanism, you will need to decide whether the reaction involves an electrophile/nucleophile or acid/base combination. Acid and base processes involve proton exchange, whereas, electrophile and nucleophile processes involve bond-breaking and bond-making. Draw a curly arrow from the nucleophile or base to the electrophile or acid ().
Solution This sequence of reactions consists of three stages. Stage 1 (1415) involves classical keto-enol tautomerisation; stage 2 (15A) involves a Claisen-type condensation; and stage 3 (AB) involves keto-enol tautomerisation. The enol tautomer of phloracetophenone B is more thermodynamically stable than its keto tautomer A.
O O O SR O HO O SR stage 2
stage 1
keto-enol tautomerisation O 14 polyketide O 15 O O
Claisen-type condensation
O O HO OH
stage 3
keto-enol tautomerisation O A phloracetophenone OH B
Nucleophilic addition of the conjugated enol to the electrophilic carbonyl (C=O) group of the thioester, 15, followed by elimination of thiolate, RS-, leads to the intermediate oxonium ion, C. {This addition-elimination has been depicted using a double-headed curly arrow. If you are unsure about using this type of curly arrow, see p. 1095 in Chemistry3.} Deprotonation of oxonium ion C using the basic thiolate, RS-, gives the keto-tautomer of phloracetophenone A. For further information about Claisen reactions, see p. 1121 in Chemistry3.
nucleophile HO O leaving group SR electrophile O step 2 Claisen-type condensation O 15
base acid H O O SR O O O
O C
O A phloracetophenone
Answer
H HO SR O O O O SR O
O 15 H O O
SR
O O -RSH O
O phloracetophenone
(b)
For phloracetophenone, explain why the position of the equilibrium lies heavily to the right.
O O O HO O OH
stage 3
keto-enol tautomerisation O A phloracetophenone OH B
Strategy Stage 3 (AB) of this reaction sequence involves keto-enol tautomerisation. The enol tautomer of phloracetophenone B is more thermodynamically stable than its ketotautomer A. Account for this stability. Solution Enol-tautomer B is aromatic, and is more stable than its non-aromatic keto-tautomer A. This electronic stability is due to the cyclic and planar nature of the substituted benzene ring which contains 6-pi electrons with non-interrupted (continuous) conjugation.
Answer Enolisation of the three C=O bonds produces a stable aromatic ring.
2.
Nylon-6,6 is a synthetic polyamide. It is formed by heating hexane-1,6-diamine with hexanedioic acid in a condensation polymerization reaction.
O H2N hexane-1,6-diamine NH2 OH HO O hexanedioic acid High temperature
O H N N H O nylon-6,6 n n H2O
(a)
Why is the formation of nylon-6,6 called a condensation polymerization?
Strategy A condensation reaction involves the addition of two or more molecules to give one or more products and water as the byproduct. Examine the above reaction, and deduce if water (H2O) is produced. Solution Nylon-6,6 involves sequential amide bond formation, by condensing a primary amine with a carboxylic acid. The byproduct of this process is water (H2O). As both starting materials contain two identical functional groups [di-amines (in hexane-1,6-diamine) and dicarboxylic acids (in hexanedioic acid)], therefore polymerisation will occur.
O R
1
O OH NH2 R2 R
1
R2 N H
H2O water
carboxylic acid
primary amine
amide
Answer Two molecules of the monomer combine with the elimination of a molecule of water.
(b)
Why does the formation of nylon-6,6 from hexane-1,6-diamine and hexanedioic acid require heating?
Strategy Condensation reactions require heat to remove the byproduct, water (H2O), from the reaction vessel in order to drive the equilibrium over. Addition of an amine (base) to a carboxylic acid (acid) will form a more stable ammonium salt.
O R
1
O OH NH2 R2 R1 O NH3 R2
carboxylic acid
primary amine
ammonium salt
Solution Addition of hexane-1,6-diamine to hexanedioic acid [pKa (H2O) = 5], gives the more stable diammonium salt A [pKa (H2O) = 9]. At low temperature, the equilibrium favours formation of the ammonium salt A. However, at high temperature, this proton exchange is reversible. Formation of nylon-6,6 occurs by nucleophilic addition of the diamine, hexane-1,6-diamine, to the electrophilic dicarboxylic acid, hexanedioic acid, followed by elimination of water (H2O). This process is unfavourable. However, by continually removing the byproduct, water (H2O), from this equilibrium, through heating to >100oC forces this water to evaporate, and therefore drives the equilibrium towards the required product, nylon-6,6.
O O O A H3N O NH3
Low temperature O H2N hexane-1,6-diamine NH2 OH HO O hexanedioic acid High temperature
O H N N H O nylon-6,6 n n H2O
Answer At room temperature, the amine and carboxylic acid react to form a salt, not an amide bond.
(c)
If hexanedioic acid is replaced by hexanedioyl dichloride, then reaction with hexane-1,6-diamine forms nylon-6,6 at room temperature. Why does the polymerization using hexanedioyl dichloride take place under milder reaction conditions?
Strategy The rate-limiting step for amide formation is the nucleophilic addition of the amine to the electrophilic carboxylic acid derivative. For both reactions outlined above, the nucleophile, 43 OXFORD H i g h e r E d u c a t i o n
hexane-1,6-diamine, is the same. This reaction appears to be faster for the more electrophilic hexanedioyl dichloride.
O OH HO O hexanedioic acid hexanedioyl chloride Cl O O Cl
Draw out the reagents, hexanedioyl dichloride and hexanedioic acid, and account for their relative electrophilicity. Solution Hexanedioyl chloride is a better electrophile than hexanedioic acid for this condensation reaction as its chlorine (-Cl) atom is strongly electron-withdrawing (-I effect > + M effect). The non-bonded pairs of electrons on this chlorine atom are poorly electron-donating [into the carbonyl (C=O) group of hexanedioyl chloride] due to poor 3p(Cl)-2p(C) orbital overlap. The electronegativity of this chlorine atom is responsible for the overall electrophilicity of this acid chloride. Even though the oxygen atom in hexanedioic acid is more electronegative than the chlorine atom in hexanedioyl chloride, hexanedioic acid is less electrophilic than hexanedioyl chloride. This is due to better quality orbital overlap of a non-bonded pair of electrons on the oxygen atom with its neighbouring carbonyl (C=O) group; 2p(O)-2p(C) orbital overlap in hexanedioic acid is better quality than 3p(Cl)-2p(C) orbital overlap in hexanedioyl chloride.
O OH HO C O +M effect > -I effect less electrophilic hexanedioic acid Cl C O -I effect > +M effect more electrophilic hexanedioyl chloride O Cl
Nucleophilic addition of hexane-1,6-diamine, to the more electrophilic hexanedioyl chloride is preferred, and therefore this reaction will proceed faster at a lower temperature.
Answer Acyl chlorides have a particularly electrophilic carbon atom and react rapidly with amines in nucleophilic acyl substitution reactions. (c) Nylon-6,6 is recycled by hydrolyzing all of the amide bonds to reform the monomers, and then re-polymerizing. Hydrolysis of amide bonds under basic conditions requires heating in a concentrated aqueous solution of hydroxide ion. As shown below, two reaction pathways are possible.
pathway A RHN O H R O R O O H N H R
O R R N H R
HOH O OH NHR
-OH
HO
O HOH R
O NHR pathway B R
O R O HN
(i)
Use curly arrows to show the movement of electrons in paths A and B.
Strategy Copy out these pathways, and for each step within these mechanisms, you will need to draw a curly arrow from the nucleophile or base to the electrophile or acid (). Solution 45 OXFORD H i g h e r E d u c a t i o n
For pathway A: Lone-pair assisted elimination of the amide, RHN-, using the non-bonded pair of electrons on the alkoxide, gives the intermediate carboxylic acid, RCO2H. Deprotonation of this carboxylic acid, using the basic amide, RHN-, gives the more stable carboxylate and primary amine, RNH2. The curly arrows for these processes are shown below.
pathway A RHN O R OH NHR R O H O R O O H N H R
For pathway B: Deprotonation of the alcohol (OH) group using the non-bonded pair of electrons on the hydroxide (HO-) leads to the intermediate di-anionic alkoxide. Lone-pair assisted elimination of the amide, RHN-, using the non-bonded pair of electrons on the alkoxide, gives the intermediate carboxylate, RCO2-. Deprotonation of the byproduct, water (H2O), using basic amide, RHN-, gives the more stable hydroxide, HO-, and primary amine, RNH2. The curly arrows for these processes are shown below.
pathway B H OH R NHR HOH R NHR R O O R HN H O HOH -OH R O H N H R OH
Answers
Path A O R OH R N H R O O H R O NHR O + H N H R
Path B O R O N H O + R O H N H R + OH H R OH HOH + R N H O O R R O H O H O + NHR
[Movement of electrons can also be depicted using a negative charge or a non-bonded pair of electrons.] (d) (ii) Under what conditions would you expect path B be favoured over path A?
Strategy For pathway B to occur, hydroxide, HO-, is required (as shown in the original scheme). Solution Pathway A is the more favourable pathway, as it does not proceed via the unstable intermediate di-anionic alkoxide B. However, under very basic conditions (high pH), pathway B will become more favoured.
unstable O R B O NHR
Answer
Path B will be favoured over path A when using a particularly high concentration of hydroxide ion. Solutions provided by J. Eames ([email protected])

CH 24 Student

Uploaded by

Copyright:

Available Formats

CH 24 Student

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

CH 24 Student

Uploaded by

Copyright:

Available Formats

Solutions manual for Burrows et.al.

Solutions manual for Burrows et.al. Chemistry3

Solutions manual for Burrows et.al. Chemistry3

ester HO O O Cl O H HO morphine ester NMe H N O O heroin O H NMe H O

Solutions manual for Burrows et.al. Chemistry3

Solutions manual for Burrows et.al. Chemistry3

Solutions manual for Burrows et.al. Chemistry3

Solutions manual for Burrows et.al. Chemistry3

O OH H2N O NH2 OH H2N SH HS HO NH O H2N OH OH O NH2 NH2 HO O O O H2N OH OH H2N O

Solutions manual for Burrows et.al. Chemistry3

Solutions manual for Burrows et.al. Chemistry3

O "+H2O" O B: octyl ethanoate O OH ethanoic acid HO octanol

O "+H2O" O C: methyl butanoate

O OH butanoic acid HO methanol

O "+H2O" O E: pentyl ethanoate

O OH ethanoic acid HO pentanol

Solutions manual for Burrows et.al. Chemistry3

Solutions manual for Burrows et.al. Chemistry3

Solutions manual for Burrows et.al. Chemistry3

Solutions manual for Burrows et.al. Chemistry3

MeOH EtOH PrOH MeCOCl mix

MeOH EtOH PrOH split

MeOH EtOH PrOH MeOH EtOH PrOH

Solutions manual for Burrows et.al. Chemistry3

nucleophile Ph MgBr MgBr

Ph C N electrophile N base A H acid N

Solutions manual for Burrows et.al. Chemistry3

imine + N Ph MgBr + H N MgBr H Ph NH Ph

H2O Ph H NH2 O H Ph NH2 H HO Ph NH2 H

Solutions manual for Burrows et.al. Chemistry3

Answers to end of chapter questions (on p. 1127 in Chemistry3)

PhMgBr (two equivalents) then, H+/H2O

Solutions manual for Burrows et.al. Chemistry3

ester O C OEt 1 oxidation level of C = +3 LiAlH4 (1st equiv.)

aldehyde O C H A oxidation level of C = +1 LiAlH4 (2nd equiv.) then H+,H2O

primary alcohol H C OH 2 oxidation level of C = -1 H

Solutions manual for Burrows et.al. Chemistry3

electrophile O ester 1 C OEt C OEt Ph MgBr Ph B C Ph ketone C O O OEt MgBr MgBr

Oxford University Press, 2009. All rights reserved.

Solutions manual for Burrows et.al. Chemistry3

Solutions manual for Burrows et.al. Chemistry3

base O C OEt ester 1

electrophile H O E C OEt H OH2 nucleophile acid H O H C OH

base OEt H acid

OH2 base (solvent)

Solutions manual for Burrows et.al. Chemistry3

acid O C OEt ester 1 H

base OEt H acid

OH2 base (solvent)

O = 18O isotopic label

Solutions manual for Burrows et.al. Chemistry3

O = 18O isotopic label

O C OEt OEt O = 18O isotopic label

Solutions manual for Burrows et.al. Chemistry3

acid O C OEt ester [18O]-1 H

OH2 base (solvent)

O = 18O isotopic label

Solutions manual for Burrows et.al. Chemistry3

Solutions manual for Burrows et.al. Chemistry3