Part IA Student Handout 2 2021-22 Cambridge Natural Science PDF

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Reactions and Mechanisms inOrganic ChemistryPart IAStudent Lecture Notes andQuestions: Part 2Deborah A. [email protected] 245Blank for further information to be addedBlank for further information to be added12 Steric Hindrance Adjacent to a Ring Double Bond: Influence on StereochemicalApp...

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Reactions and Mechanisms in Organic Chemistry Part IA Student Lecture Notes and Questions: Part 2 Deborah A. Longbottom [email protected] Office 245

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The Department of Chemistry endeavours to develop an inclusive, supportive and intellectually stimulating environment for our undergraduate community. Athena SWAN is an ongoing programme to address the underrepresentation of women in the sciences. The Silver Award recognises the progress that the Department has made in recent years, and the actions that benefit not only our female students, but all our undergraduate chemists. For more information see www.ch.cam.ac.uk/athena-swan. Your colleagues in previous years suggested that they would like to know a bit more about their lecturers, so this year each lecturer has been asked to provide some biographical notes. We hope that this will illustrate the different backgrounds of our staff and the varied routes that have brought them to the Department. I said at the end of my bio page in the first handout that I’d give a more personal account in the second one. The question about this second part is how best to do it? How to show life events bumping up against career changes and challenges. I’ve tried to do it below, where the typical career pathway is given on top of the horizontal line and the corresponding personal events are shown below the line.

Year$at$ Postdoc$ GlaxoSmith (San$Diego)$ Kline$ March$ Sept$19972002-Dec$ Aug$1998$ 2003$

My#professional#and#personal# careers#distilled#into#a#timeline#

Degree (Durham) year$at$Li Pharmace icals$

PhD$ ambridge

2nd$postdoc$ (Cambridge),$ Teaching$ Fellow$(25%),$ DoS$(Trinity$ College)$

Oct$ 3$ July$1997$

Oc 98$– Nov$2001$

Jan 4– Sept$2007$

1994$–$ 1997$

Nov$ 2001$

Jan$ 2 $

Married$ to$Steven$ Moss$

Partner$of$ Steven$ Moss$ Steven$ Moss$sends$ letter$ renewing$ contact$ (moving$to$ Cambridge)$

Head$of$Graduate$ Education$and$ Undergraduate$Teaching$ Fellow$(Chemistry)$

Teaching$Fellow$(50%,$ Chemistry),$College$ Teaching$Officer$(50%$ Homerton$College)$

Director$of$Education$$ (School$of$the$Physical$Sciences),$ Head$of$Graduate$Education$and$ Teaching$Fellow$(Chemistry)$

Oc 07– April$2014$

June$ 2008$

May$ 0$

Alexander$ born$ William$ born$

May 4– April$2018$

Jan$ Sept$ 2$ 2012$

Sept$ 2 $

Alex$ William$$ starts$ starts$ primary$ primary$ school$$ school$$

Feb$ May$ 5$ 2015$

May 8$–$ present$$ Aug$ 2 $

Lawrence$starts$ primary$school,$$ William$starts$ Secondary$School$

awrence$ born$

Dad$dies$ $(Motor$Neurone$Disease)$ Steve’s$Dad$dies$ $(long$term$complex$ health$problems)$

Sept$ 20

Mum$dies$ unexpectedly$ $(heart$attack)$

The main take-home messages I think this might have are as follows: it is (hooray!) possible to have a career and children (if you want them and all the associated additional work/pleasure they create!); life can be very complicated and you can only just try your best to do what makes you simultaneously happy and fulfilled in your career and in your home life (this sounds simple but is absolutely not!); you never know what is around the corner and annoyingly we don’t have any control over when such important events as births and deaths occur: all we can do is our best to blend the impact that they have into our own unique tapestry of life…….

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INDEX: PART 2 8. NUCLEOPHILIC SUBSTITUTION AT THE CARBONYL GROUP: REACTIONS

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8.1 Hydride Reducing Agents

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8.1.1 Reduction of acid chlorides/anhydrides to alcohols with sodium borohydride

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8.1.2 Reduction of esters to alcohols using lithium aluminium hydride

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8.1.3 Reduction of amides to amines using lithium aluminium hydride

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8.1.4 Reduction of carboxylic acids to alcohols using borane

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8.1.5 Summary of reduction chemistry

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8.2 Organometallic Reagents

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8.2.1 Reaction with acid halides/anhydrides and esters

90

8.2.2 Reaction with carbon dioxide to form carboxylic acids

91

8.2.3 Summary of organometallic chemistry

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8.3 Water

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8.3.1 Acid-mediated hydrolysis of esters and amides

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8.3.2 Base-mediated hydrolysis of esters and amides

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8.3.3 Hydrolysis of esters and amides: summary

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8.4 Alcohols

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8.5 Summary of Methods to Make Carbonyl Derivatives, Alcohols and Amines

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8.6 Common Mistakes in Carbonyl Chemistry

101

8.6.1 Reduction of amides with lithium aluminium hydride

101

8.6.2 Carboxylic acids

101

9. HARD AND SOFT NUCLEOPHILES AND ELECTROPHILES

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10. NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON: SN1 AND SN2 REACTIONS

107

10.1 Substrate Structure

109

10.1.1 Steric hindrance

110

10.1.2 Factors which influence carbocation stability in SN1 reactions

111

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10.1.3 Factors which influence transition state stability in SN2 reactions

116

10.1.4 Summary of Factors

118

10.1.5 Stereochemical consequences of the SN1 and SN2 reaction processes

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10.1.6 The importance of hybridisation state: no SN1 and SN2 at sp2 centres

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10.2 Nucleophile

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10.2.1 SN1 reaction process: the nucleophile is not important

122

10.2.2 SN2 reaction process: the nucleophile is very important

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10.3 Leaving Group

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10.3.1 Halides: F, Cl, Br, I

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10.3.2 OH derivatives

126

10.3.3 Epoxides

129

10.3.4 Leaving groups: summary

130

10.4 Solvent

131

10.4.1 SN1 reaction process: polar, protic solvents are best

131

10.4.2 SN2 reaction process: polar, aprotic solvents are best

131

10.4.3 Solvent types and dielectric constants

132

10.5 Summary

133

10.6 Retrosynthetic analysis

133

11. C=C DOUBLE BOND FORMATION: ELIMINATION MECHANISMS

134

11.1 Rate of Reaction

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11.2 Orbitals

135

11.3 Stereochemical Outcome

136

11.4 Leaving Group

138

11.5 Factors Which Determine Whether Elimination or Substitution Occur

138

11.5.1 Substrate structure

139

11.5.2 Basicity of the nucleophile

140

11.5.3 Size of the nucleophile

141

11.5.4 Temperature

142

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11.6 Summary and Retrosynthesis

142

12. REACTIONS OF p-BONDS: ELECTROPHILIC ATTACK AND HYDROGENATION

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12.1 Electrophilic Addition of H–X

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12.1.1 A symmetrical double bond

145

12.1.2 An unsymmetrical double bond

145

12.2 Bromination and Iodination

147

12.2.1 Mechanism

147

12.2.2 Stereochemical outcome

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12.3 Halohydrin Formation and Reaction

148

12.3.1 Mechanism

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12.3.2 Stereochemical outcome

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12.3.3 Reaction to form an epoxide

149

12.4 Epoxidation

149

12.4.1 Mechanism

150

12.4.2 Stereochemical outcome

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12.5 Hydroboration: Addition of Water with Opposite Regioselectivity

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12.5.1 Mechanism

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12.5.2 Stereochemical outcome

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12.6 Steric Hindrance Adjacent to a Ring Double Bond: Influence on Stereochemical 154 Outcome 12.7 Summary and Retrosynthetic Analysis

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Appendix A: Mechanism for Formation of an Acid Chloride from a Carboxylic Acid 156 and Thionyl Chloride (SOCl2) Appendix B: Hydrogenation

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SUPERVISION PROBLEMS: PART 2

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8. NUCLEOPHILIC SUBSTITUTION AT THE CARBONYL GROUP: REACTIONS Having now covered the principles of reacting nucleophiles at the carbonyl group in some detail, it is important to gather some knowledge of which kind of nucleophiles can be used and the mechanisms/products of those reactions. This section is more complicated than the one on aldehydes and ketones because the functionalities we are considering do vary in their reactivity and outcomes but a lot of this follows the same principles as before and should be relatively straightforward. The topic will be covered in the following order, which matches what was done previously with aldehydes and ketones, and will incorporate reaction of each type of carbonyl compound (acid chlorides, anhydrides, esters, carboxylic acids and amides) with: 8.1 8.2 8.3 8.4

Hydride Reducing Reagents Organometallic Reagents Water Alcohols

8.1 Hydride Reducing Agents You may remember from Section 5.2 (page 28) that nucleophilic attack by the hydride ion itself, H¯, is not a known reaction. The species does exist, e.g. NaH, but for reasons relating to orbital overlap, it usually acts as a base. In fact, the mildest reducing agent that can be used as a source of hydride is sodium borohydride, NaBH4, and the general reaction with ketones follows the usual two step series: nucleophilic attack followed by protonation (see pages 28-30 for full discussion): O R1

H R2

H

R1

H O R2

H

X

OH R1 R 2

+ BH 3

B H

H H

This brings about the question of how to reduce other carbonyl derivatives, which is not universally possible with sodium borohydride. In fact several reducing agents can be employed, the optimum reagent varying for each particular process: 8.1.1 Reduction of acid chlorides/anhydrides to alcohols with sodium borohydride 8.1.2 Reduction of esters to alcohols using lithium aluminium hydride 8.1.3 Reduction of carboxylic acids to alcohols using borane 8.1.4 Reduction of amides to amines using lithium aluminium hydride

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8.1.1 Reduction of acid chlorides/anhydrides to alcohols with sodium borohydride In terms of their reactivity towards incoming nucleophiles, aldehydes and ketones sit between anhydrides and esters: O

O

O

O

> R

Cl

R

>

Most Reactive

R1

R

R

O

O

O

>

> R

NR1R 2

R

OR1

Least Reactive

Reduced by NaBH 4

Therefore, the more reactive acid chlorides and anhydrides will react readily with NaBH4. However, esters and amides, which are less reactive towards nucleophiles than aldehydes and ketones will not react (amides) or will only be reduced very slowly (esters) by NaBH4. For acid chlorides and anhydrides, the mechanisms of reduction are the same and involve the addition of two equivalents of hydride overall to furnish alcohol products:

O

O

O

NaBH 4

or R

O

R

R

R

OH

Cl

The mechanism by which this occurs is as follows (shown for the acid chloride but exactly the same steps occur for the anhydride):

O

H H

H

O O

R

Cl

R

R

R

Cl H H H

H

X

H

B H

O

H

B H

H H

H H R

OH

Following the initial addition of hydride, because we have a good leaving group present now (pKa of HCl = –7), the reaction does not stop at this tetrahedral intermediate. Instead, chloride is expelled, reforming the carbonyl group and the first product we make is an aldehyde. However, this is not the end of the reaction because NaBH4 reduces aldehydes as well and the aldehyde is reduced exactly as seen previously 29) to the alkoxide, which can be protonated either by the reaction solvent (often an alcohol) or upon work-up. 1,2 The sodium/lithium ions have been omitted from the mechanisms in this section for clarity but be aware that they provide coordination to the carbonyl group and the counterion to O¯ when it is formed.

1

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8.1.2 Reduction of esters to alcohols using lithium aluminium hydride For reasons discussed previously, esters and amides are less reactive than ketones and aldehydes and therefore, a stronger reducing agent is required to react with them. The reducing agent most commonly used for this process is lithium aluminium hydride:

The reaction mechanism to reduce esters to alcohols with this reagent is directly analogous to the previous reduction of acid chlorides and anhydrides to alcohols but with Li+ replacing Na+ and AlH4¯ replacing BH4¯: Aldehyde O OR1

R H Al H

H

H

O R R1 O Tetrahedral Intermediate

H H

O Note 1

– R1 O R

H

R

O

H

X

Note 2

H Al H

H H

H

H H R

OH

There are also two important points to make regarding this process: Note 1: as for sodium borohydride, reaction here does not stop at the aldehyde for two reasons: • •

LiAlH4 can also be the source of more than one hydride (see page 30 for analogous NaBH4 process) the aldehyde is more reactive than the ester starting material: it therefore reacts in preference to the ester with LiAlH4.

Note 2: reactions of LiAlH4 are not done in alcoholic solvents.3 For this reason, unlike the sodium borohydride reductions, where protons are available from the solvent, the proton in the final protonation step here only appears during the work-up, after the reaction itself is complete. 8.1.3 Reduction of carboxylic acids to alcohols using borane Carboxylic acids can also be reduced but this reaction is usually carried out with borane: LiAlH4 usually reduces carboxylic acids relatively slowly4 and NaBH4 will not work, as it is not reactive enough.

2

It is not possible to make aldehydes from acid chlorides using this method, i.e. stop the reaction at the aldehyde, because sodium borohydride can be the source of more than one hydride (page 30). Therefore it is difficult to add exactly one equivalent of sodium hydride and anyway, the borohydride will not readily distinguish between the aldehyde and the acid chloride, as both are reactive. 3 Lithium aluminium hydride is very reactive and has caused many a laboratory fire through careless handling! It is incompatible with water and should only be used as a reducing agent when one of this strength is necessary. 4 The reason for this is that the first step which occurs when a carboxylic acid reacts with LiAlH4 is actually removal of the acidic proton, leaving behind the carboxylate anion. Although it is coordinated to the lithium counterion, it is less reactive than other carbonyl derivatives because essentially, the hydride is attacking an already negative species: the carboxylate anion. See Section 8.6.2a in ‘Common Mistakes in Carbonyl Chemistry’ (page 102).

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The mechanistic detail of carboxylic acid reduction is more complicated than can be required at Part IA level so in this case, just a very basic knowledge of the reaction process mediated by borane will be required:

O R

O

BH 3 –3H2 (g)

OH

R

BH 3 O

OH

R

B 3

3 equivalents

Triacylborate

8.1.4 Reduction of amides to amines using lithium aluminium hydride Although mechanistically, two equivalents of hydride are still added to the amide starting material, the product of reduction of amides is different from all the other reductions covered here: amides produce amines when they are reduced, not alcohols as all the other carbonyl compounds do and they do so by the following mechanistic pathway:

O

H NR1R 2

R

H

AlH3

O

O R1

Al H

H H

R1

R2 N

Note 1

Iminium ion

R

R

N

N H

AlH3

R

R1

R2

R2

H

H

Tetrahedral Intermediate

Al H

H H

H H Note 2 R

NR1R 2

The mechanistic difference arises because the tetrahedral key intermediate does not have such a good leaving group as the ester does (N¯ vs O¯) and associated with this, there are two important points to make: Note 1: The oxyanion coordinates the available AlH3 (Lewis acidic), formed when one hydride has been lost from AlH4¯, following which the nitrogen lone pair can expel oxygen, rather than the other way around. 5 Note 2: The iminium ion which is then formed is analogous to the aldehyde in the reduction of esters by LiAlH4 and is reduced very quickly to the amine product, rather than an alcohol. If you would like to compare this correct mechanism and product with the incorrect mechanism that gives the alcohol, please have a look at Section 8.6.1 in ‘Common Mistakes in Carbonyl Chemistry’ (page 101).

5 Don’t worry too much about the exact nature of the group that is lost here. There are several possibilities, e.g. singly (following loss of hydride) or doubly charged anion (less likely) etc but the detail of this is not important at this level.

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8.1.5 Summary of reduction chemistry The information on reduction can be summarised simply, as shown in the table below:

O R

O Cl

R

O

O O

R

O R1

R

OR1

R

O

O R

NR1R 2

R

OH

NaBH4

Y

Y

Y

Slow

N

N

LiBH4*

Y

Y

Y

Y

N

N

LiAlH4

Y

Y

Y

Y

Y**

Slow (use BH3)

* LiBH4 has reactivity in between NaBH4 and LiAlH4. It can be used in alcoholic solutions and has chemoselectivity for esters over amides; **All the products from reduction in this table are alcohols, with the exception of the amide reduction with LiAlH4, which gives an amine. As a general principle, always use the mildest...