Nucleophilic Addition to Aldehydes and Ketones: Mechanisms and Applications, Exams of Organic Chemistry

Download Nucleophilic Addition to Aldehydes and Ketones: Mechanisms and Applications and more Exams Organic Chemistry in PDF only on Docsity! Section J – Aldehydes and ketones J3 NUCLEOPHILIC ADDITION Key Notes Nucleophilic addition involves the addition of a nucleophile to an aldehyde or a ketone. The nucleophile adds to the electrophilic carbonyl carbon. Charged nucleophiles undergo nucleophilic addition with an aldehyde or ketone to give a charged intermediate which has to be treated with acid to give the final product. Neutral nucleophiles require acid catalysis and fur- ther reactions can take place after nucleophilic addition. Related topics Nucleophilic addition – charged nucleophiles (J4) Nucleophilic addition – nitrogen nucleophiles (J6) Nucleophilic addition – oxygen and sulfur nucleophiles (J7) Definition Overview Definition As the name of the reaction suggests, nucleophilic addition involves the addition of a nucleophile to a molecule. This is a distinctive reaction for ketones and R C O (R'orH) Nu R C O (R'orH) Nu R C OH (R'orH) Nu H3O Fig. 1. Nucleophilic addition to a carbonyl group. Fig. 2. Synthesis of imines, enamines, acetals, and ketals. R C O (R'orH) Nu R C OH (R'orH) Nu H H Nu = NHR -H R C NR (R'orH) Imine Nu = NR2 -H R C NR2 (R'orH) Enamine Nu = OR R C OR (R'orH) OR Acetal / ketal aldehydes and the nucleophile will add to the electrophilic carbon atom of the carbonyl group. The nucleophile can be a negatively charged ion such as cyanide or hydride, or it can be a neutral molecule such as water or alcohol. Overview In general, addition of charged nucleophiles results in the formation of a charged intermediate (Fig. 1). The reaction stops at this stage and acid has to be added to complete the reaction (Topic J4). Neutral nucleophiles where nitrogen or oxygen is the nucleophilic center are relatively weak nucleophiles, and an acid catalyst is usually required. After nucleophilic addition has occurred, further reactions may take place leading to structures such as imines, enamines, acetals, and ketals (Topics J6 and J7; Fig. 2). 174 Section J – Aldehydes and ketones Hydride addition Reducing agents such as sodium borohydride (NaBH4) and lithium aluminum hydride (LiAlH4) react with aldehydes and ketones as if they are providing a hydride ion (:H–; Fig. 6). This species is not present as such and the reaction mechanism is more complex. However, we can explain the reaction by viewing these reagents as hydride equivalents (:H–). The overall reaction is an example of a functional group transformation since the carbon skeleton is unaffected. Aldehydes are converted to primary alcohols and ketones are converted to secondary alcohols. The mechanism of the reaction is the same as that described above for the Grignard reaction (Fig. 7). The hydride ion equivalent adds to the carbonyl group and a negatively charged intermediate is obtained which is complexed as a lithium salt (Step 1). Subsequent treatment with acid gives the final product (Step 2). It should be emphasized again that the mechanism is actually more complex than this because the hydride ion is too reactive to exist in isolation. J4 – Nucleophilic addition – charged nucleophiles 177 H C O H H3C MgI C CH3 H OH H H3C C O H H3C MgI C CH3 H OH H3C H3C C O CH3 CH3CH2 MgI C CH2CH3 CH3 OH H3C 1. H3O2. 1o Alcohol 1. 2o Alcohol H3O2. H3O2. 3o Alcohol Formaldehyde Aldehyde Ketone 1. Fig. 4. Synthesis of primary, secondary, and tertiary alcohols by the Grignard reaction. CH3CH2 C O H CH3 C CH3 H OH CH3CH2 CH3CH2 C O H H3C Li Li H3O Fig. 5. Nucleophilic addition with an organolithium reagent. Fig. 6. Reduction of a ketone to a secondary alcohol. R C O R' C H R' OH R b) H3O 2o Alcohol a) LiAlH4 or NaBH4 Ketone Cyanide addition Nucleophilic addition of a cyanide ion to an aldehyde or ketone gives a cyanohydrin (Fig. 8). In the reaction, there is a catalytic amount of potassium cyanide present and this supplies the attacking nucleophile in the form of the cyanide ion (CN–). The nucleophilic center of the nitrile group is the carbon atom since this is the atom with the negative charge. The carbon atom uses its lone pair of electrons to form a new bond to the electrophilic carbon of the carbonyl group (Fig. 9). As this new bond forms, the relatively weak π bond of the carbonyl group breaks and the two electrons making up that bond move onto the oxygen to give it a third lone pair of electrons and a negative charge (Step 1). The intermediate formed can now act as a nucleophile/base since it is negatively charged and it reacts with the acidic hydrogen of HCN. A lone pair of electrons from oxygen is used to form a bond to the acidic proton and the H–CN σ bond is broken at the same time such that these electrons move onto the neighboring carbon to give it a lone pair of electrons and a negative charge (Step 2). The products are the cyanohydrin and the cyanide ion. Note that a cyanide ion started the reaction and a cyanide ion is regenerated. Therefore, only a catalytic amount 178 Section J – Aldehydes and ketones H R C O H R C O H H H R C OH H H  " δ δ + " Step 1 Step 2 Fig. 7. Mechanism for the reaction of a ketone with LiAIH4 or NaBH4. Fig. 9. Mechanism for the formation of a cyanohydrin. H3C C CH3 O C N C N C CH3 O H3C H H3C C O CH3 C N H C C N N δ Cyanohydrin + +δ Step 1 Step 2 H3C C CH3 O H3C C OH CH3 C N HCN / KCN1) 2) H2O Cyanohydrin Fig. 8. Synthesis of a cyanohydrin. of cyanide ion is required to start the reaction and once the reaction has taken place, a cyanide ion is regenerated to continue the reaction with another molecule of ketone. Cyanohydrins are useful in synthesis because the cyanide group can be converted to an amine or to a carboxylic acid (Topic O4; Fig. 10). Bisulfite addition The reaction of an aldehyde or a methyl ketone with sodium bisulfite (NaHSO3) involves nucleophilic addition of a bisulfite ion (–:SO3H) to the carbonyl group to give a water soluble salt (Fig. 11). The bisulfite ion is a relatively weak nucleophile compared to other charged nucleophiles and so only the most reactive carbonyl compounds will react. Larger ketones do not react since larger alkyl groups hinder attack (Topic J5). The reaction is also reversible and so it is a useful method of separating aldehydes and methyl ketones from other ketones or from other organic molecules. This is usually done during an experimental work up where the products of the reaction are dissolved in a water immiscible organic solvent. Aqueous sodium bisulfite is then added and the mixture is shaken thoroughly in a separating funnel. Once the layers have separated, any aldehydes and methyl ketones will have undergone nucleophilic addition with the bisulfite solution and will be dissolved in the aqueous layer as the water soluble salt. The layers can now J4 – Nucleophilic addition – charged nucleophiles 179 R R' C O R R' C HO CN R R' C HO CH2NH2 R R' C HO CO2H LiAlH4 H3O HCN / KCN Fig. 10. Further reactions of cyanohydrins. R C O H R C O H SO3H SO3H Na Na R C OH H SO3 Na R C O HH2O + + SO2 H Water soluble (g) Fig. 11. Reaction of the bisulfite ion with an aldehyde. Fig. 12. The Aldol reaction. R R' C O R R' C OHa) b) H3O CH C O R" R" CH C O R" R" carbon, the more reactive it is to nucleophiles. Therefore, propanal is more reactive than propanone. Electron inductive effects can be used to explain differing reactivities between different aldehydes. For example the fluorinated aldehyde (Fig. 2) is more reactive than ethanal. The fluorine atoms are electronegative and have an electron- withdrawing effect on the neighboring carbon, making it electron deficient. This in turn has an inductive effect on the neighboring carbonyl carbon. Since electrons are being withdrawn, the electrophilicity of the carbonyl carbon is increased, making it more reactive to nucleophiles. Steric factors Steric factors also have a role to play in the reactivity of aldehydes and ketones. There are two ways of looking at this. One way is to look at the relative ease with which the attacking nucleophile can approach the carbonyl carbon. The other is to consider how steric factors influence the stability of the transition state leading to the final product. Let us first consider the relative ease with which a nucleophile can approach the carbonyl carbon of an aldehyde and a ketone. In order to do that, we must con- sider the bonding and the shape of these functional groups (Fig. 3). Both mole- cules have a planar carbonyl group. The atoms which are in the plane are circled in white. A nucleophile will approach the carbonyl group from above or below the plane. The diagram below shows a nucleophile attacking from above. Note that the hydrogen atoms on the neighboring methyl groups are not in the plane of the carbonyl group and so these atoms can hinder the approach of a nucleophile and thus hinder the reaction. This effect will be more significant for a ketone where there are alkyl groups on either side of the carbonyl group. An aldehyde has only one alkyl group attached and so the carbonyl group is more accessible to nucleophilic attack. 182 Section J – Aldehydes and ketones C C O H C H O H3C F F F Trifluoromethyl group is electron withdrawing and increases electrophilicity Methyl group is electron donating and decreases electrophilicity a) b) Fig. 2. Inductive effect of (a) trifluoroethanal; (b) ethanal. Fig. 3. Steric factors. O H H O H H C C H H H C H C H C H Ethanal Nu: Propanone Nu: We shall now look at how steric factors affect the stability of the transition state leading to the final product. For this we shall look at the reactions of propanone and propanal with HCN to give cyanohydrin products (Fig. 4). Both propanone and propanal are planar molecules. The cyanohydrin products are tetrahedral. Thus, the reaction leads to a marked difference in shape between the starting carbonyl compound and the cyanohydrin product. There is also a marked difference in the space available to the substituents attached to the reac- tion site – the carbonyl carbon. The tetrahedral molecule is more crowded since there are four substituents crowded round a central carbon, whereas in the planar starting material, there are only three substituents attached to the carbonyl carbon. The crowding in the tetrahedral product arising from the ketone will be greater than that arising from the aldehyde since one of the substituents from the aldehyde is a small hydrogen atom. The ease with which nucleophilic addition takes place depends on the ease with which the transition state is formed. In nucleophilic addition, the transition state is thought to resemble the tetrahedral product more than it does the planar start- ing material. Therefore, any factor which affects the stability of the product will also affect the stability of the transition state. Since crowding is a destabilizing effect, the reaction of propanone should be more difficult than the reaction of propanal. Therefore, ketones in general will be less reactive than aldehydes. The bigger the alkyl groups, the bigger the steric effect. For example, 3-pen- tanone is less reactive than propanone and fails to react with the weak bisulfite nucleophile whereas propanone does (Fig. 5). J5 – Electronic and steric effects 183 C CH3 CH3 O C OH CH3 NC CH3 C CH3 H O C OH H NC CH3 large Propanone (planar molecule) Propanal (planar molecule) HCN (Tetrahedral) HCN (Tetrahedral) small Fig. 4. Reactions of propanone and propanal with HCN. a) CH3CH2 C O CH2CH3 C CH3 O H3C b) Fig. 5. (a) 3-Pentanone; (b) propanone. Section J – Aldehydes and ketones J6 NUCLEOPHILIC ADDITION – NITROGEN NUCLEOPHILES Key Notes Primary amines react with aldehydes and ketones to give an imine or Schiff base. The reaction involves nucleophilic addition of the amine followed by elimination of water. Acid catalysis aids the reaction, but too much acid hinders the reaction by protonating the amine. Secondary amines undergo the same type of mechanism as primary amines, but cannot give imines as the final product. Instead, a proton is lost from a neighboring carbon and functional groups called enamines are formed. Aldehydes and ketones can be converted to crystalline derivatives called oximes, semicarbazones, and 2,4-dinitrophenylhydrazones. Such deriva- tives were useful in the identification of liquid aldehydes and ketones. Related topics Nucleophilic addition (J3) Nucleophilic addition – charged nucleophiles (J4) Nucleophilic addition – oxygen and sulfur nucleophiles (J7) Imine formation Enamine formation Oximes, semicarbazones and 2,4-dinitrophenylhy- drazones Imine formation The reaction of primary amines with aldehydes and ketones do not give the products expected from nucleophilic addition alone. This is because further reaction occurs once nucleophilic addition takes place. As an example, we shall consider the reaction of acetaldehyde (ethanal) with a primary amine – methylamine (Fig. 1). The product contains the methylamine skeleton, but unlike the previous reactions there is no alcohol group and there is a double bond between the carbon and the nitrogen. This product is called an imine or a Schiff base. The first stage of the mechanism (Fig. 2) is a normal nucleophilic addition. The amine acts as the nucleophile and the nitrogen atom is the nucleophilic center. The nitrogen uses its lone pair of electrons to form a bond to the electrophilic carbonyl carbon. As this bond is being formed, the carbonyl π bond breaks with both elec- trons moving onto the oxygen to give it a third lone pair of electrons and a nega- tive charge. The nitrogen also gains a positive charge, but both these charges can H3C H C O R H C NHCH3 H CH3NH2 Imine Fig. 1. Reaction of ethanal with methylamine.