Name: carbonyl attack by strong and weak nucleophiles
Uploaded: 2023-04-30T10:18:28.000Z
Duration: 1 min 18 s
Channel: JoVE

In the carbonyl group, the electrophilicity of carbon&#8212;arising from its bonding with the more electronegative oxygen&#8212;makes the carbonyl group susceptible to a nucleophilic attack.
The strength of the attacking nucleophile determines the type of mechanism involved during their addition to the carbonyl group.
Strong nucleophiles directly attack the carbonyl carbon, moving the &#960; electrons to the carbonyl oxygen to give the more basic alkoxide intermediate. 
In the subsequent step, the negatively charged oxygen atom is protonated to give the addition product.
Weaker nucleophiles are less likely to add directly to the carbonyl group. The electrophilicity of the carbonyl carbon must be significantly enhanced to invite a nucleophilic attack.
This is done using an acid catalyst to generate a protonated carbonyl species: an oxonium cation. As the positive charge shifts from oxygen to carbon, the oxonium ion is resonance stabilized, and the carbon atom becomes strongly electrophilic.
The weak nucleophile then readily adds to the activated carbonyl group to give the addition product.

nucleophilic addition to the carbonyl group: general mechanism

Nucleophilic Addition to the Carbonyl Group: General Mechanism

The carbonyl carbon in an aldehyde or ketone is the site of a nucleophilic attack due to its electron-deficient nature. Depending on the strength of the incoming nucleophile, the reaction occurs via different mechanistic pathways.
A stronger nucleophile can directly attack the electrophilic center, the carbonyl carbon. The HOMO orbital of the nucleophile interacts with the LUMO (&#960;* antibonding) orbital present on the carbonyl carbon. This interaction breaks the &#960; bond and shifts the &#960; bonding electrons onto the carbonyl oxygen, forming a basic alkoxide anion. The basic alkoxide ion intermediate abstracts a proton, forming the addition product as depicted in the following figure.
<img alt="Nucleophilic acyl substitution; reaction mechanism diagram; organic chemistry; equilibrium process." src="/files/ftp_upload/12329/12329_PT_Figure_1.svg" style="text-align: center; height: 170px;" data-altupdatedat="1761830439000" data-alt="Figure1" />
On the other hand, a weak nucleophile cannot directly attack the electrophilic carbonyl carbon. For the weak nucleophile to react, the electrophilicity of the carbonyl carbon needs to be enhanced substantially. Thus, the aldehyde or ketone is treated with an acid catalyst to improve the electrophilicity of carbonyl carbon. As shown in the figure below, the acid catalyst protonates the carbonyl oxygen forming an oxonium cation. The oxonium cation is resonance stabilized by delocalizing the positive charge onto the adjacent carbonyl carbon atom. This delocalization of the positive charge increases the electrophilicity of the carbonyl carbon, leading to the attack of the weak nucleophile.
<img alt="Nucleophilic acyl substitution mechanism; chemical reaction diagram; showing electron flow and intermediates." src="/files/ftp_upload/12329/12329_PT_Figure_2.svg" style="text-align: center; height: 140px;" data-altupdatedat="1761830439000" data-alt="Figure2" />

The carbonyl carbon in an aldehyde or ketone is the site of a nucleophilic attack due to its electron-deficient nature. Depending on the strength of the ...

nucleophilic-addition-to-the-carbonyl-group-general-mechanism

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JoVE Core

Organic Chemistry

Unit 1

Aldehydes and Ketones

KEY TERMS AND CONCEPTS

carbonyl attack by strong and weak nucleophiles

A carbonyl group in an aldehyde or ketone is a common target for nucleophilic attack. The carbonyl carbon is electron-deficient, so it acts as the electrophilic site in the reaction. Depending on the strength of the incoming nucleophile, the pathway can change.

A strong nucleophile can attack the carbonyl carbon directly. Its HOMO, or highest occupied molecular orbital, interacts with the LUMO, the π* antibonding orbital, on the carbonyl group. This breaks the π bond and moves the π electrons onto the oxygen, forming a basic alkoxide anion. The alkoxide then abstracts a proton to give the addition product.

A weak nucleophile cannot attack the carbonyl carbon easily on its own. In that case, the aldehyde or ketone is first treated with an acid catalyst to make the carbonyl more reactive. The acid protonates the carbonyl oxygen and forms an oxonium cation.

The oxonium cation is stabilized by resonance, which spreads the positive charge onto the nearby carbonyl carbon. This makes the carbonyl carbon more electrophilic. The weaker nucleophile can then attack the activated carbonyl center.

Carbonyl Attack by Strong and Weak Nucleophiles

carbonyl-attack-by-strong-and-weak-nucleophiles

structures of aldehydes and ketones

Aldehydes and Ketones: Carbonyl Polarity

Aldehydes and ketones are carbonyl compounds with a polar C=O bond. Common examples include vanillin, cinnamaldehyde, and acetone. Vanillin gives vanilla its flavor, cinnamaldehyde gives cinnamon its smell, and acetone is found in nail polish removers. These two groups differ by the atoms attached to the carbonyl carbon. In an aldehyde, the carbonyl group is directly linked to at least one hydrogen atom. In a ketone, the carbonyl group is connected to two carbon atoms. The carbonyl carbon in...

iupac nomenclature of aldehydes

Naming Aldehydes in Organic Chemistry

Aldehydes are named using IUPAC rules in organic chemistry. For an acyclic aldehyde, the longest carbon chain that contains the aldehydic, or –CHO, group is chosen as the parent chain. The name changes by replacing the final “e” in the hydrocarbon name with “al.” A seven-carbon example is heptanal, which comes from heptane. Numbering starts at the aldehydic carbon in an open chain. That carbon is given locant 1, but the 1 is not written in the name. Any substituents on the chain are written as...

iupac nomenclature of ketones

Naming Ketones in IUPAC System

Ketones are named with IUPAC rules by changing the ending "e" in the longest hydrocarbon chain to "one." For acyclic ketones, the carbonyl carbon gets the lowest possible locant, or position number. A five-carbon ketone is therefore named pentan-2-one, not pentan-4-one. IUPAC also allows the locant to be placed before the parent name, so 2-pentanone is an acceptable alternate name. Cyclic ketones are numbered from the carbonyl carbon. The numbering then continues in the direction that gives...

common names of aldehydes and ketones

Naming Aldehydes and Ketones by Common Terms

Some aldehydes and ketones are still known by common names that were used before IUPAC naming. These older names are often based on history and are still widely recognized in chemistry. Common names for aldehydes usually come from the names of their matching acids. For example, acetaldehyde gets its name from acetic acid, formaldehyde from formic acid, and benzaldehyde from benzoic acid. Aliphatic ketones are named by adding the word ketone to the names of the groups on each side of the...

ir and uv&ndash;vis spectroscopy of aldehydes and ketones

ir-and-uvvis-spectroscopy-of-aldehydes-and-ketones

Aldehyde and Ketone IR Peaks Explained

Infrared spectroscopy helps identify bonds and functional groups in aldehydes and ketones. It is also called vibrational spectroscopy because it measures bond vibrations. In these molecules, the carbonyl group, or C=O bond, gives an absorption around 1710 cm -1 . Aldehydes and ketones do not always absorb in exactly the same way. The C=O vibration of an aldehyde occurs at a lower frequency than the same bond in a ketone. An aldehyde also shows two extra peaks from its aldehydic C–H bond in the...

nmr spectroscopy and mass spectrometry of aldehydes and ketones

nmr-spectroscopy-and-mass-spectrometry-of-aldehydes-and-ketones

Aldehyde and Ketone Spectra in NMR

Aldehydes and ketones can be identified by their NMR spectra and mass spectra. Their carbonyl group changes how nearby atoms appear in these tests. That makes the patterns useful for telling these compounds apart. In 1H NMR spectroscopy, the hydrogen on an aldehyde carbonyl carbon is a key clue. It is strongly deshielded because it sits close to the electrophilic carbonyl carbon, so its signal appears around 10 ppm. The alpha hydrogens can split this aldehydic proton signal. For example, one...

preparation of aldehydes and ketones from alcohols, alkenes, and alkynes

preparation-of-aldehydes-and-ketones-from-alcohols-alkenes-and-alkynes

How Aldehydes and Ketones Form in Organic Reactions

Aldehydes and ketones form from alcohols, alkenes, and alkynes through different organic reactions. Alcohols are the most common starting materials for making these carbonyl compounds. The product depends on the type of alcohol and the oxidizing agent, which is a chemical that adds oxygen or removes hydrogen. Primary alcohols can become aldehydes when they react with a weak oxidizing agent. If a strong oxidizing agent is used, the primary alcohol can be over-oxidized to a carboxylic acid. That...

preparation of aldehydes and ketones from nitriles and carboxylic acids

preparation-aldehydes-ketones-from-nitriles-carboxylic

Making Aldehydes and Ketones from Acids

Carboxylic acids and nitriles can be turned into aldehydes and ketones by using the right reducing conditions. Strong reducers such as lithium aluminum hydride (LAH) are not ideal for making an aldehyde from a carboxylic acid, because the aldehyde forms and then quickly over-reduces to a primary alcohol. Milder aluminum hydride reagents help stop that over-reduction. Lithium tri-tert-butoxyaluminum hydride [LiAlH(O-t-Bu)3] and diisobutylaluminum hydride [DIBAL-H] can convert carboxylic acid...

preparation of aldehydes and ketones from carboxylic acid derivatives

preparation-of-aldehydes-and-ketones-from-carboxylic-acid-derivatives

Controlled Reduction of Aldehydes and Ketones

Aldehydes and ketones can be made from carboxylic acid derivatives by careful reduction. The key idea is to use reagents that reduce the starting material without pushing the reaction too far. Strong reducing agents can over-reduce aldehydes to alcohols, so the choice of reagent matters. Carboxylic acids are not efficient for making aldehydes with LAH, which stands for lithium aluminum hydride. Acid chlorides and esters are easier to reduce than the parent acids. These derivatives can react...

A carbonyl group in an aldehyde or ketone is a common target for nucleophilic attack. The carbonyl carbon is electron-deficient, so it acts as the electrophilic site in the reaction. Depending on the strength of the incoming nucleophile, the pathway can change. A strong nucleophile can attack the carbonyl carbon directly. Its HOMO, or highest occupied molecular orbital, interacts with the LUMO, the π* antibonding orbital, on the carbonyl group. This breaks the π bond and moves the π electrons...

aldehydes and ketones with water: hydrate formation

aldehydes-and-ketones-with-water-hydrate-formation

Why Water Adds to Carbonyl Compounds

Water can add to aldehydes and ketones through a nucleophilic addition reaction. This reaction forms hydrates, which are also called 1,1-diols or geminal diols. The process is reversible, so the product can change back to the starting carbonyl compound. Hydrate formation depends on the structure of the carbonyl group. The rate increases when fewer alkyl groups are attached to the carbonyl carbon. Simple aldehydes, such as formaldehyde, form the hydrate very readily. The reaction is also...

aldehydes and ketones with alcohols: hemiacetal formation

aldehydes-and-ketones-with-alcohols-hemiacetal-formation

Alcohol Addition to Carbonyls: Hemiacetals

Alcohols can add to the carbonyl carbon of aldehydes and ketones. This reaction forms a hemiacetal, also called a half acetal. In a hemiacetal, one carbon is directly bonded to both an OH group and an OR group. Hemiacetal formation is very slow under neutral conditions because alcohols are poor nucleophiles. A nucleophile is a species that donates electrons to form a new bond. The reaction can be sped up in either acidic or basic media. In acidic conditions, catalysts such as sulfuric acid or...

protecting groups for aldehydes and ketones: introduction

protecting-groups-for-aldehydes-and-ketones-introduction

Selective Protection of Aldehydes and Ketones

Protecting groups help chemists shield aldehydes and ketones during reactions. A protecting group is a compound that binds to a specific functional group, or reactive part of a molecule, when other functional groups are also present. This lets chemists carry out chemoselective reactions, which means a reaction can be directed at one group instead of another in a molecule with several reactive sites. Aldehydes and ketones can be protected even when other carbonyl groups, such as esters or...

acetals and thioacetals as protecting groups for aldehydes and ketones

acetals-and-thioacetals-as-protecting-groups-for-aldehydes-and-ketones

Using Acetals to Shield Carbonyl Groups

Acetals can shield carbonyl groups such as aldehydes and ketones during an organic reaction. They form when two equivalents of alcohol react with a carbonyl compound. This makes them useful when one functional group must be protected while another part of the molecule reacts. Acetals are stable to bases, nucleophiles, oxidizing agents, and reducing agents. They are also easy to make and easy to remove. Mild acid hydrolysis can break the acetal and restore the original aldehyde or ketone. This...

aldehydes and ketones with hcn: cyanohydrin formation overview

aldehydes-and-ketones-with-hcn-cyanohydrin-formation-overview

Cyanohydrins from Carbonyl Compounds and HCN

Cyanohydrins form when a carbonyl compound reacts with hydrogen cyanide or cyanide ions. The product has both a –CN group and a –OH group on the same carbon atom. This reaction is a nucleophilic addition, which means the cyanide ion attacks the carbonyl carbon. Cyanide ions are strong nucleophiles and strong bases. They can come from HCN in water, but HCN is a weak acid, so only a small amount of cyanide ions forms. To raise the cyanide ion concentration, a small amount of base or salts such...

aldehydes and ketones with hcn: cyanohydrin formation mechanism

aldehydes-and-ketones-with-hcn-cyanohydrin-formation-mechanism

Cyanide Catalysis in Carbonyl Reactions

Cyanide catalysis in carbonyl reactions helps form cyanohydrins from aldehydes and ketones. A cyanohydrin is a molecule that contains both a hydroxyl group and a nitrile group. In this reaction, cyanide ions react with the electrophilic carbonyl carbon. The cyanide ions are generated from HCN under aqueous conditions. First, the cyanide ion attacks the carbonyl carbon. This pushes the π electrons of the C=O bond onto the oxygen atom and forms an alkoxide ion intermediate. The alkoxide ion is...

aldehydes and ketones to alkenes: wittig reaction overview

aldehydes-and-ketones-to-alkenes-wittig-reaction-overview

How Wittig Reagents Build Alkenes

The Wittig reaction builds alkenes from carbonyl compounds such as aldehydes and ketones. It uses phosphorus ylides, also called Wittig reagents, to replace the carbonyl group with a carbon-carbon double bond. Phosphorus ylides are neutral molecules with a negatively charged carbon bonded directly to a positively charged phosphorus atom. Resonance helps stabilize this unusual structure. Georg Wittig pioneered the reaction and received the Nobel Prize in Chemistry for his work. Wittig reagents...

aldehydes and ketones to alkenes: wittig reaction mechanism

aldehydes-and-ketones-to-alkenes-wittig-reaction-mechanism

Wittig Reaction: Ylide Formation to Alkene

The Wittig reaction turns aldehydes or ketones into alkenes using a phosphorus ylide. It follows a nucleophilic addition–elimination pathway, so the carbonyl compound is first attacked and then the intermediate breaks apart. A phosphorus ylide acts as a strong nucleophile because of its carbanionic character. It attacks the electrophilic carbonyl group and forms a charge-separated dipolar intermediate called betaine. The negatively charged oxygen and positively charged phosphorus in betaine...

aldehydes and ketones with amines: imine and enamine formation overview

aldehydes-and-ketones-with-amines-imine-and-enamine-formation-overview

Aldehydes and Amines: Imines and Enamines

Aldehydes and ketones react with amines to form imines and enamines. These products are common in organic chemistry and depend on whether the amine is primary or secondary. Primary amines react with aldehydes and ketones to make imines. Imines have a C=N double bond and are also called Schiff bases, a name linked to the German chemist Hugo Schiff. Secondary amines react with aldehydes and ketones to form enamines. In enamines, a C=C double bond sits next to the nitrogen atom, which allows the...

aldehydes and ketones with amines: imine formation mechanism

aldehydes-and-ketones-with-amines-imine-formation-mechanism

pH Control in Imine Formation

Imine formation links a carbonyl compound with a primary amine. The reaction starts when the amine attacks the carbonyl carbon, and this first step leads to a carbinolamine, which is an intermediate molecule. After that, proton transfers occur before water is removed and the imine is formed. The reaction works best under mildly acidic conditions. A pH of 4.5 is ideal for imine formation. If the solution is too acidic, the reaction slows in the first step because the amine becomes protonated.

aldehydes and ketones with amines: enamine formation mechanism

aldehydes-and-ketones-with-amines-enamine-formation-mechanism

pH Effects on Enamine Formation in Amines

Enamine formation is a reaction between a carbonyl compound and a secondary amine. It proceeds through several steps that build a carbinolamine intermediate before the final enamine is made. The process depends on proton transfers, which help move the reaction forward. The mechanism starts when the nitrogen lone pair attacks the carbonyl carbon. This nucleophilic attack, or electron-pair donation, leads to carbinolamine formation. After that, several proton transfer steps occur. The hydroxyl...

aldehydes and ketones to alkanes: wolff&ndash;kishner reduction

aldehydes-and-ketones-to-alkanes-wolffkishner-reduction

Wolff–Kishner Reduction Reaction Pathway

Wolff–Kishner reduction converts aldehydes and ketones into alkanes. It replaces the carbonyl group with a methylene group. The reaction uses hydrazine and a base. The method was independently discovered by N. Kishner in 1911 and L. Wolff in 1912. It is carried out in high-boiling solvents such as ethylene glycol and diethylene glycol. These solvents are used because heat is needed to deprotonate the N–H proton in one of the reaction steps. The mechanism begins with formation of a hydrazone,...

oxidations of aldehydes and ketones to carboxylic acids

oxidations-of-aldehydes-and-ketones-to-carboxylic-acids

Aldehyde Tests and Oxidation to Carboxylic Acids

Aldehydes and ketones can be oxidized to form carboxylic acids. Aldehydes are much easier to oxidize because they have a hydrogen next to the carbonyl group. That aldehydic proton can be removed during oxidation. Strong oxidizing agents such as potassium permanganate and chromic acid can oxidize aldehydes. Mild oxidizing agents, including silver oxide, can also do this. Aldehydes may even react with oxygen in air. Because of this slow autoxidation, samples are often kept in airtight...

reactions of aldehydes and ketones: baeyer&ndash;villiger oxidation

reactions-of-aldehydes-and-ketones-baeyervilliger-oxidation

Baeyer-Villiger Oxidation and Product Formation

Baeyer-Villiger oxidation changes aldehydes and ketones into new oxygen-containing products. Aldehydes are converted to carboxylic acids, and ketones are converted to esters. This reaction is often carried out with acid and a peroxy acid, also called a peracid. Several oxidizing agents can be used for this reaction. Examples include m-chloroperoxybenzoic acid (mCPBA), perbenzoic acid (C6H5COOOH), peracetic acid (CH3COOOH), hydrogen peroxide (H2O2), and tert-butyl hydroperoxide (t-BuOOH). The...

keto&ndash;enol tautomerism: mechanism

Keto–Enol Tautomerism in Acid and Base

Keto–enol tautomerism is the reversible interconversion between keto and enol forms. These tautomers can switch between each other under acid-catalyzed or base-catalyzed conditions. The two pathways use the same basic steps, protonation and deprotonation, but in reverse order. In the base-catalyzed pathway, the reaction starts when the alpha hydrogen on the carbonyl compound is removed. This creates a carbanion, which is stabilized by delocalization of the negative charge across the carbonyl...

key terms and concepts

See how strong nucleophiles attack aldehydes and ketones directly, while weak nucleophiles need acid activation of the carbonyl group.

Carbonyl Attack by Strong and Weak Nucleophiles | JoVE K12

organic chemistry

JoVE Core Organic Chemistry explains basic concepts of stereochemistry, reactions, and mechanisms using concise and easy-to-understand animated video lessons. Additionally, the scientist-in-action videos demonstrate the application of related concepts in classical and original research experiments performed in today's laboratories worldwide.

Carbonyl Attack by Strong and Weak Nucleophiles

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