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Home , Nucleophilic addition

CHM2C3-A/B Retrosynthesis Dr JS Snaith, Dr LR Cox THE UNIVERSITY A Summary of Useful Reactions from CHM1C3 and CHM2C3-A OF BIRMINGHAM

General

The reactivity of all three classes is dominated by the readily available cloud of π electron density, resulting in very rapid reaction with .

Alkenes

The typical reaction is . This occurs in a Markovnikov fashion, ie. it proceeds through formation of the more stable carbocation (carbenium ion). Remember, the order of stability for carbocations is tertiary > secondary > primary>methyl. The attacks the more positive end of the (X-Y) (work this out on the basis of ) to give a carbocation and the anion (eg Y-). The intermediate is then intercepted by the anion Y-. Remember atoms like bromine can use one of their lone pairs to stabilise the carbocation, giving a cyclic bromonium ion. This opens up with inversion (like SN2) to give the anti product. Some common reactions that you will find useful are shown below.

Reactions of

Br H HBr H via H not secondary carbocation more stable than primary

Br Br2 Br

Br

OH OsO4 then NaHSO3 OH

OH NaOH, H O mCPBA O 2 + or H3O OH

O R2 3 1 O R2 R1 R O then Ph3P

H H HBR2 H2O2, NaOH (eg BH ) 3 BR2 OH

H2, Pd-C H H Formation of alkenes

There are many methods available for forming alkenes, some of which you will have seen from earlier courses. In the case of 1,2-substituted alkenes, stereoselectivity issues ((E) or (Z) stereoisomers) are also important and need to be considered.

1. From alkynes

H2, Lindlar catalyst RR' RR' (Z)

Na, NH3 (liquid) R' RR' R

(E)

2. Wittig reaction

X R'

i) PPh3 ii) base

(Z)-selective when R' = alkyl R' R O Ph3P R' R (E)-selective when R' = electron-withdrawing group phosphonium

3. Elimination

Elimination can proceed through three basic mechanisms, E2, E1 and E1cb. The E2 elimination pathway is particularly useful because it proceeds in a stereospecific fashion with antiperiplanar arrangement between the H−C−C−LG (LG = leaving group). Elimination is a common side-reaction in nucleophilic substitution reactions.

Me Ph Ph LG Me requires H-C and C-LG bonds E H Me to adopt an antiperiplanar arrangement 2 D Me D B B H LG only proceeds when a stabilised carbocation can be formed E1 (e.g. tertiary carbocation)

OOH O O OH particularly common in base-mediated E cb dehydration of aldol products 1

H

B

Common leaving groups include halides and sulfonates:

RClRBr RI leaving group capacity: I- > Br- > Cl-

OO R' = Me (mesylate) R'SO2Cl S ROH ROR' R' = pMePh (tosylate)

poor leaving good LG group Alkynes

Electrophilic addition reactions of alkynes are less useful than for alkenes. The initially formed vinyl carbocation is relatively unstable and thus slow to form. The product alkene often reacts (to form an alkane) faster than the alkyne, and so a mixture of alkene and alkane products may form. Some of the reactions that are synthetically very useful are summarised below.

OH O H O, H SO , HgSO keto- tautomerism R 2 2 4 4 R R

1. strong base eg NaH, NaNH , BuLi RRR'2 2. Electrophile eg R'-I

Aromatics

Reaction with electrophiles dominates, but this time we see substitution products rather than addition products. Because of the aromatic stabilisation energy the intermediate carbocation loses a proton to regain the aromatic ring rather than being attacked by a . Some important reactions involving aromatics:

O reduction eg NO2 H , Pd-C NH2 R 2

Friedel Crafts RCOCl, acylation AlCl3, heat HNO3, H2SO4, heat Friedel Crafts alkylation

R-X, AlX3 (X=Cl, Br) Br2, FeBr3

R Br (reversible reaction - (Cl2, FeCl3 to give to reverse boil in H2SO4, heat the chloride) or steam distil)

SO3H

Diazotisation

Nitration of aromatics is a very useful reaction, since the nitro aromatics may be transformed into a wide variety of products. Reduction affords the corresponding aniline, and diazotisation of this gives a very reactive diazonium salt which is synthetically very versatile. Below are some representative examples.

OH

I

H2O, H2SO4 95 ˚C KI - NH Cl 2 N2 nitrous acid, HONO (made in situ from NaNO2, HCl, 0 ˚C) CuX H3PO2 X H (X=Cl, Br, CN) Nucleophilic Substitution Reactions

There are two important nucleophilic mechanisms, SN1 and SN2. The most important of these for synthesis is the SN2 substitution. This reaction is a stereospecific process which proceeds with inversion of configuration. A variety of leaving groups can be used (see above in the section on elimination reactions).

Nu

Nu good for primary and secondary SN2 alkyl halides and sulfonates LG Nu

LG Nu Nu good for tertiary SN1 alkyl halides and sulfonates

Alkyl halides and sulfonates are commonly used in nucleophilic substitution reactions. They are easily formed from the corresponding .

R'SO2Cl PPh3 , X2 R OSO R' ROH RX 2 X = Cl, Br, I

Chemistry of the

Formation by oxidation and reduction

Jones (CrO3, H2SO4, acetone)

PDC [Cr(VI)]

H OH ROH RO RO

NaBH4 or LiAlH4

PDC R R ROH RO

NaBH4 or LiAlH4

Aldehydes and

Nucleophilic Addition

The chemistry of and ketones is characterised by nucleophilic addition reactions. A wide range of can be used. Common sources include NaBH4 and LiAlH4 (NaBH4 more chemoselective than LiAlH4, which reduces most functional groups containing the C=O group). Common Carbon-nucleophiles are organolithium and organomagnesium (i.e. Grignard) reagents. Reaction proceeds through a tetrahedral intermediate which is quenched on aqueous work-up to provide an product.

R'Li OR OH O OH R'MgX NaBH4 OR RR' R R R R R LiAlH4 or

Aldehydes and ketones are good electrophiles. Sometimes we need to mask this reactivity to allow us to perform reactions elsewhere in the molecule. We therefore need a protecting group to temporarily mask the C=O group. Acetals are the most common protecting groups for aldehydes and ketones. They are readily prepared under mildly acicic (Brønsted or Lewis acids can be used) conditions and are readily hydrolysed back to the parent carbonyl compound by aqueous acid.

2 eq. R' OH OH OH LA or H LA or H protection protection R' R' O OO O O R R R R RR aldehyde acetal or ketone deprotection deprotection

H2O, LA or H H2O, LA or H

Carboxylic Acid Derivatives

These functional groups all contain a C=O group and are therefore also electrophilic. However, their reactivity towards nucleophilic attack depends on the substituent(s) attached. order of reactivity towards nucleophilic addition

O O O O O O

RCl ROR R OR' RNR'2 ROH acid chloride acid anhydride ester

most electrophilic least electrophilic

Thus acid chlorides can be used to prepare all of the less reactive carboxylic acid derivatives by reaction with the relevant partner e.g. for ester synthesis react an acid chloride with an alcohol, for amide synthesis react the acid chloride with the appropriate .

Mechanism of nucleophilic addition / elimination

Carboxylic acid derivatives react with nucleophiles in a similar fashion to aldehydes and ketones, proceeding via a tetrahedral intermediate. However the presence of a leaving group means that the carbonyl group can be reformed by expulsion of the leaving group. In the case of esters, the initial product from the reaction with a Grignard or organolithium reagent is a ketone. This is more electrophilic than the ester starting material and therefore tends to react further. It is therefore generally quite difficult to prepare ketones from carboxylic acid derivatives.

nucleophilic addition elimination ketone product reacts further

O MgBr O PhMgBr Ph O MeO Me OMe Me OMe Me Ph

tetrahedral intermediate PhMgBr

Ph OH Me Ph Uses of Carboxylic Acids

The presence of an acidic proton in the carboxylic acid renders these functional groups very weak electrophiles. Reaction with a nucleophile invariably just results in the nucleophile behaving preferentially as a base and forming the corresponding carboxylate salt (acid-base reaction).

O PhMgBr O PhH Me OH Me O MgBr

However under acidic conditions the alcohols react with carboxylic acids to generate the corresponding ester. You should know the mechanism of this reaction (the acid is required as a catalyst to create a good leaving group). Note that this reaction is an equilibrium process. To drive the reaction over to the right-hand side it is important to either remove the water side-product that is formed (or use a vast excess of the alcohol).

O ROH, cat. H O Me OH Me OR

α,β-Unsaturated Carbonyl Compounds

Enones and enoates are ambident electrophiles in that there is more than one site at which nucleophiles can react. In general, hard nucleophiles (e.g. organolithium and Grignard reagents) react in a 1,2-fashion i.e. directly at the carbonyl carbon, whereas soft nucleophiles (e.g. sulfides and organocopper reagents) react in a 1,4-fashion thereby preserving the carbonyl group in the product.

R' O R'2CuLi O R'Li / R'MgX OH R' R soft Nu R hard Nu R 1,4-addition 1,2-addition

Enolates

Enolates are formed by treating a carbonyl compound containing an α-C−H group with a base. The pKa of the α- C−H determines what type of base to use. To get complete enolisation use a base (B-) whose conjugate acid (B−H) has a much higher pKa that the α-C−H that you are wishing to abstract. To get partial enolisation choose a base whose conjugate acid has a pKa similar to that of the proton you are wishing to abstract.

ONa O OLi NaOEt, EtOH LDA, THF, -78 °C

partial enolisation complete enolisation

Some Important pKa Values of Carbonyl-Containing Molecules

OO O O O O OEt EtO OEt NC CN H H H 9.0 11.0 12.7 11.2

O O O N H H H H OEt NMe2

20 24.5 25 30 Enolates as Nucleophiles

Enolates are ambident nucleophiles in that they can react at either terminus of the functional group. Most electrophiles react at carbon; the most important exception is silyl electrophiles which react preferentially at oxygen to provide silyl enol ethers.

OLi O E E E = alkyl halides, aldehydes, estersetc

C-alkylation

OLi OSiMe3

Me3SiCl

O-alkylation

Important Reactions involving Enolates

OLi O RX R particularly good for primary RX alkylation and activated RX such as MeI, ally bromide and benzyl bromide

OLi O OH RCHO R dehydration can be a competing reaction

The high reactivity of lithium enolates can cause selectivity problems in these reactions. It is possible to temper the reactivity by changing the metal. For example, zinc enolates are less basic than their lithium analogues but still retain high nucleophilicity in their reaction with aldehydes.

O OZnBr O OH Br Zn RCHO R

zinc Reformatski aldol reaction

1,3-Dicarbonyl Compounds are also very important enolate nucleophiles. Regioselective enolisation is straightforward and the enolate products are good, soft nucleophiles that react with a range of activated alkyl halides and in a 1,4-fashion with α,β-unsaturated carbonyl compounds. β-Keto esters are very useful latent enolate equivalents since the ester is readily removed by a saponification / decarboxylation process.

O O O O Na O O O NaOEt RX i) NaOH OEt OEt OEt EtOH ii) H heat R R O

O O OEt

O Silyl enol ethers are relatively mild soft nucleophiles which react with strong electrophiles. Unlike most enolates, they are stable to strong Lewis acids which allows their use in a range of important reactions:

Hosomi-Sakurai reaction

O OSiMe3 O OO X good route to 1,5-dicarbonyls LA LA alkylation with tertiary RX

Mukaiyama O aldol reaction LA RH

O OH R

Other Important Reactions involving Enolates

O O O O i) NaOEt, EtOH OEt OEt OEt ii) H work-up a good method for preparing β-keto esters

O O O NaOEt, EtOH Robinson annelation an important method for preparing rings

This hand-out summarises some of the most important areas of organic chemistry that you have covered in years 1 and 2. It contains many of the reactions that you will find useful when proposing syntheses of organic moelcules. However, it is by no means exhaustive; you will often need to refer to text books and your original lecture notes to find the reagents and reaction conditions that you desire for carrying out a synthetic transformation.