Name: why ring nitrogen changes amine basicity
Uploaded: 2023-04-30T10:39:04.000Z
Duration: 1 min 25 s
Channel: JoVE

The basicity of heterocyclic amines is influenced by both the resonance and the hybridization effects.
To understand the resonance effect, consider two aromatic heterocyclic amines&#8212;pyridine and pyrrole. The nonbonded electrons of the pyridine nitrogen reside in an sp2 hybrid orbital. As they do not contribute to the aromatic sextet, they are available for protonation.
In pyrrole, the nonbonding electrons are present in a p orbital and are part of the aromatic &#960; system. Here, protonation is unfavorable as aromaticity is lost in the conjugated acid.
As the pKa of the protonated pyrrole is less than pKa of the protonated pyridine, pyridine is more basic than pyrrole.
For the hybridization effect, consider the hybridization of the amine nitrogen. As the percent s character increases, the nonbonded electrons are held more tightly and are less available for protonation.
With less s character of the sp3-hybridized piperidine nitrogen, it is easily protonated with a higher pKa value of the conjugate acid. Thus, piperidine is more basic than pyridine.

basiciteit van heterocyclische aromatische aminen

Basicity of Heterocyclic Aromatic Amines

Heterocyclische aminen, waarbij het N-atoom deel uitmaakt van een alicyclisch systeem, zijn qua basiciteit vergelijkbaar met alkylaminen. Interessant genoeg heeft het heterocyclische amine met een stikstofatoom als onderdeel van een aromatische ring veel minder basiciteit dan zijn overeenkomstige alicyclische tegenhanger. Om deze reden, zoals weergegeven in Figuur 1, is piperidine (pKb = 2.8) aanzienlijk basischer dan pyridine (pKb = 8,8).


 <img alt="Figure1" src="/files/ftp_upload/12527/12527-PT_Figure_1.svg" style="text-align: center; height: 110px;" />

 Figure 1. De vergelijking van de basiciteit van piperidine en pyridine.


 Dit verschil in basiciteit kan worden toegeschreven aan de staat van hybridisatie van orbitalen die een alleenstaande elektronenpaar op het N-atoom bevatten, zoals weergegeven in figuur 2. In het geval van piperidine bevindt het alleenstaande paar zich in een sp3-gehybridiseerde orbitaal met lagere s karakter, waardoor het alleenstaande paar meer beschikbaar is voor het vertonen van basiciteit ten opzichte van zuur. Aan de andere kant bevindt het alleenstaande paar zich in piperidine in een sp2-gehybridiseerde orbitaal met een veel hoger s karakter. Hierdoor is het alleenstaande paar nauwer gebonden aan de arylring en minder beschikbaar voor het vertonen van basiciteit ten opzichte van zuur.


 <img alt="Figure2" src="/files/ftp_upload/12527/12527-PT_Figure_2.svg" style="text-align: center; height: 60px;" />

 Figure 2. Het effect van de gehybridiseerde orbitalen op de basiciteit.


 Pyrrool is veel minder basisch dan pyridine en heeft een pKb-waarde van 15. Het enige elektronenpaar op het N-atoom, weergegeven in Figuur 3, bevindt zich in een zuivere p-orbitaal en is perfect uitgelijnd met de p-orbitalen van C-atomen, die deelnemen aan de aromatische aard van de ring. Daarom wordt het alleenstaande elektronenpaar op het N-atoom van pyrrool gedelokaliseerd door resonantie door de hele ring. Vice versa is het alleenstaande paar op het N-atoom van pyridine dat zich in een sp2-gehybridiseerde orbitaal bevindt, loodrecht uitgelijnd op de andere sp2-orbitalen van C-atomen die deelnemen aan resonantie. Het alleenstaande elektronenpaar op het N-atoom van pyridine is dus veel beter beschikbaar dan dat in pyrrool, wat resulteert in een hogere basiciteit van pyridine.


 <img alt="Figure3" src="/files/ftp_upload/12527/12527-PT_Figure_3.svg" style="text-align: center; height: 90px;" />

 Figure 3. De Lewis-structuur van pyrrool.


 Imidazol bevat twee N-atomen in een vijfring en is een vitale heterocyclus die in veel eiwitten voorkomt. Dit heterocyclische amine met een pKb van 7 is een factor 100 basischer dan pyridine. Het N-atoom dat lijkt op dat in pyrrool is niet-basisch. Het andere N-atoom is basisch en onttrekt H aan het zuur, waardoor het geconjugeerde zuur ontstaat, dat wordt gestabiliseerd door de resonantie, zoals geïllustreerd in figuur 4. Deze resonantiestabilisatie van de geconjugeerde base resulteert in de verhoogde basiciteit van imidazool ten opzichte van pyridine.


 <img alt="Figure4" src="/files/ftp_upload/12527/12527-PT_Figure_4.svg" style="text-align: center; height: 125px;" />

 Figure 4. De resonantiestabilisatie in imidazoliumionen.


 De basiciteit van aminen biedt een waardevol praktisch hulpmiddel om aminen te scheiden van een mengsel dat andere neutrale verbindingen bevat. Dit wordt bereikt door het onzuivere mengsel op te lossen in ether en te schudden met water in een scheitrechter. Nadat de twee lagen gescheiden zijn, verwijdert het draineren van de waterlaag het zout en de meeste anorganische onzuiverheden. Wanneer verdund waterig zuur aan de organische laag wordt toegevoegd, worden aminen selectief geprotoneerd in het overeenkomstige zuur en lossen ze op in de waterige laag. Door de organische laag af te tappen, wordt de neutrale organische onzuiverheid verwijderd. Langzame basisch maken van de waterlaag regenereert opnieuw het vrije amine, dat geëxtraheerd zou kunnen worden met een vers volume ether. De daaropvolgende verdamping van ether levert een zuiver amine op.

Basiciteit van heterocyclische aromatische aminen

Heterocyclic amines, where the N atom is a part of an alicyclic system, are similar in basicity to alkylamines. Interestingly, the heterocyclic amine ...

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why ring nitrogen changes amine basicity

Heterocyclic amines can show very different basicity depending on where the nitrogen atom sits in the ring. When nitrogen is part of an alicyclic ring, the amine behaves much like an alkylamine. When nitrogen is part of an aromatic ring, the compound is usually much less basic than its alicyclic counterpart.

Piperidine and pyridine show this difference clearly. Piperidine is significantly more basic than pyridine, with pKb values of 2.8 and 8.8, respectively. The reason is the orbital that holds the lone pair on nitrogen. In piperidine, the lone pair is in an sp3-hybridized orbital with lower s character, so it is easier to use in reactions with acid. In pyridine, the lone pair is in an sp2-hybridized orbital with higher s character, so it is held more tightly and is less available.

Pyrrole is even less basic than pyridine. Its pKb value is 15. The lone pair on nitrogen is in a pure p orbital, and it lines up with the p orbitals of the carbon atoms in the ring. That lone pair helps the ring stay aromatic, so it is delocalized by resonance. In pyridine, by contrast, the lone pair is in an sp2 orbital that points away from the ring system, so it is much more available for basic behavior.

Imidazole has two nitrogen atoms in a five-membered ring and is found in many proteins. It is more basic than pyridine by a factor of 100, with a pKb of 7. The nitrogen that acts like pyrrole is not basic. The other nitrogen is basic and can accept H from acid. Its conjugate acid is stabilized by resonance, and that stabilization helps explain the higher basicity of imidazole.

The basicity of amines is also useful in the lab for separating amines from neutral compounds. A common method uses ether and water in a separatory funnel. The water layer is drained first to remove the salt and most inorganic impurities. Then dilute aqueous acid is added to the organic layer. The amines become protonated and move into the aqueous layer, while the neutral organic impurity stays behind. The aqueous layer is then basified slowly to regenerate the free amine, which can be extracted with fresh ether and recovered after the ether is evaporated.

Why Ring Nitrogen Changes Amine Basicity

amines: introduction

Amines: Types and Classifications

Amines are organic derivatives of ammonia. They form when one or more ammonia protons are replaced by alkyl or aryl groups. Chemists sort amines by the number of organyl groups attached to the nitrogen atom. Primary amines have one organyl group on nitrogen. Secondary amines have two, and tertiary amines have three. If a fourth organyl group is present, the nitrogen carries a formal positive charge. These compounds are called quaternary ammonium salts. Amines are also grouped as aliphatic or...

nomenclature of primary amines

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Primary amines are named by following a few clear organic chemistry rules. These rules help identify the amino group, written as –NH2, and show how it connects to the carbon chain. Common names for primary amines use the alkyl group name plus the suffix -amine. In IUPAC naming, the final -e of the parent alkane is changed to -amine, which gives an alkanamine name. The longest carbon chain attached to the amine nitrogen is chosen, and the carbon bonded to nitrogen gets the lowest locant. Any...

nomenclature of secondary and tertiary amines

nomenclature-of-secondary-and-tertiary-amines

Naming Secondary, Tertiary, and Quaternary Amines

Secondary and tertiary amines are ammonia derivatives with two or three hydrogen atoms replaced by alkyl groups. They may be symmetrical, with the same alkyl groups attached to nitrogen, or unsymmetrical, with more than one kind of alkyl group present. These compounds are often named as alkylamines in standard naming. For symmetrical secondary and tertiary amines, the prefixes di- and tri- are used. For unsymmetrical amines, each substituent is named and listed in alphabetical order. IUPAC...

nomenclature of aryl and heterocyclic amines

nomenclature-of-aryl-and-heterocyclic-amines

Naming Aniline and Ring Amine Derivatives

Naming aniline and ring amine derivatives follows clear rules for aromatic and heterocyclic amines. The simplest aromatic amine is phenylamine, which has an –NH2 group directly attached to an aromatic ring. The common name for this skeleton is aniline. Functionalized anilines often use the prefixes ortho-, meta-, and para- to show where a substituent is placed on the ring. Many of these compounds also have trivial, or common, names. For systematic naming, the ring is numbered from the carbon...

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Amines: Shape, Bonding, and Chirality

Amines have a nitrogen atom with a lone pair of electrons. That lone pair affects the shape of the molecule, the bond angles, and the bond lengths around nitrogen. In most amines, nitrogen is hybridized and attached to three substituents. The bond angle is about 108°, which is a little less than the 109.5° tetrahedral angle. The C–N–H bond angle is slightly larger at 112°, and the carbon-nitrogen bond length is 147 pm. This bond is longer than the carbon-oxygen bond in alcohols, which is 143...

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Amines show clear physical properties that depend on molecular size and structure. Low molecular weight amines are usually gases at room temperature, while higher molecular weight amines are often liquids or solids. Many low molecular weight amines also have a rotten fish-like smell, and diamines usually have a pungent odor. Amines are polar molecules, so they can take part in intermolecular hydrogen bonding. Primary and secondary amines have N–H bonds that allow these interactions. Because of...

basicity of aliphatic amines

How Aliphatic Amines Act as Bases

Aliphatic amines act as bases because the nitrogen atom can accept a proton from an acid. They can also behave as Lewis bases, since the nitrogen lone pair can form a covalent bond with an electrophile. These properties make amines useful examples of basic behavior in organic chemistry. Amine basicity is commonly described in two ways. One method uses the basicity constant, K b, for the reaction in which the amine removes a proton from water. A lower K b means a stronger base. By this measure,...

basicity of aromatic amines

Why Aromatic Amines Are Less Basic

Aromatic amines are less basic than aliphatic amines because the nitrogen lone pair can share electrons with the aryl ring through resonance. When the lone pair is delocalized, it is less available to accept a proton, so the amine shows weaker basicity. Substituents on the aryl ring can change this effect. Electron-donating groups increase electron density on the ring and raise the basicity of the amine. Electron-withdrawing groups have the opposite effect and can lower basicity sharply. A...

basicity of heterocyclic aromatic amines

Heterocyclic amines can show very different basicity depending on where the nitrogen atom sits in the ring. When nitrogen is part of an alicyclic ring, the amine behaves much like an alkylamine. When nitrogen is part of an aromatic ring, the compound is usually much less basic than its alicyclic counterpart. Piperidine and pyridine show this difference clearly. Piperidine is significantly more basic than pyridine, with pKb values of 2.8 and 8.8, respectively. The reason is the orbital that...

nmr spectroscopy of amines

Amines in NMR: Key Signal Patterns

Amines in NMR spectroscopy show clear signal patterns that help identify their structure. In proton NMR, primary amines and secondary amines give a broad N–H signal between δ 0.5 and 5 ppm. The exact position can change with sample concentration, hydrogen bonding, and the solvent used. The N–H protons in amines are labile, which means they exchange quickly in solution. Because of this fast proton exchange, they do not split with nearby protons. Their peak stays broad and does not reveal the...

mass spectrometry of amines

Amines in Mass Spectra

Amines in mass spectra show a clear pattern that helps identify them. Their parent ions often have odd molecular weights, which follows the nitrogen rule. That rule says a molecule with an odd number of nitrogen atoms gives a molecular ion with an odd molecular weight. Amines also break apart in a characteristic way during alpha cleavage. Alpha cleavage means the bond next to the nitrogen atom splits. This forms nitrogen-containing cations called iminium ions and alkyl radicals. The molecular...

preparation of amines: alkylation of ammonia and amines

preparation-of-amines-alkylation-of-ammonia-and-amines

Alkylation of Ammonia to Make Amines

To make only primary amines, chemists use specific reaction conditions such as excess ammonia. Ammonia is the most common substrate because it is cheap and readily available. Tertiary alkyl halides are not the best choice for alkylation because they are too hindered. Secondary alkyl halides can react, but they are also less preferred because they tend to undergo elimination reactions.

preparation of 1&deg; amines: azide synthesis

Azide Route to Primary Amines

Azide synthesis is a useful route to primary amines. It helps avoid the polyalkylation that can happen when ammonia is alkylated directly. In that direct reaction, unwanted polyalkylated amines and a quaternary ammonium salt can form. In the azide method, azide ions act as strong nucleophiles. A nucleophile is a species that donates an electron pair in a reaction. They react with unhindered alkyl halides to make alkyl azides. Alkyl azides do not take part in more nucleophilic substitution...

preparation of 1&deg; amines: gabriel synthesis

preparation-of-1-amines-gabriel-synthesis

Gabriel Synthesis for Primary Amines

Gabriel synthesis is a selective way to make primary amines. It avoids direct alkylation, which can create polyalkylated products. For that reason, it is a preferred method when the goal is to make only one alkylated amine product. The reaction starts with phthalimide, which holds nitrogen in a protected form. A strong base such as NaOH or KOH removes a hydrogen from phthalimide and forms an anion. This anion acts as a nucleophile and attacks an alkyl halide, giving N-alkylphthalimide. The...

preparation of amines: reduction of oximes and nitro compounds

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Routes to Amines from Oximes and Nitro Groups

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preparation of amines: reduction of amides and nitriles

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Making Amines from Nitriles and Amides

Nitriles and amides can both be turned into amines by reduction. Nitriles are reduced to primary amines with reducing agents such as lithium aluminum hydride or by catalytic hydrogenation. In this reaction, the amino group is added with one extra carbon in the chain. Nitriles are often made first from alkyl halides and sodium cyanide. This step follows an S N 2 mechanism, and primary alkyl halides are the best substrates for preparing nitriles. The nitrile can then be reduced to the primary...

preparation of amines: reductive amination of aldehydes and ketones

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Making Amines with Reductive Amination

Reductive amination is a way to make amines from carbonyl compounds and primary amines. A carbonyl compound is a molecule with a carbon-oxygen double bond. The reaction first forms an imine, and then the same mixture is reduced to give a secondary amine. Selective reducing agents make this step work. Sodium cyanoborohydride and sodium triacetoxyborohydride are commonly used because they reduce the imine without reacting too aggressively. Reductive amination with sodium cyanoborohydride is...

preparation of 1&deg; amines: hofmann and curtius rearrangement overview

preparation-of-1-amines-hofmann-and-curtius-rearrangement-overview

Carbon-Loss Routes to Primary Amines

Carbon-loss reactions can turn certain amides into primary amines. The Hofmann rearrangement uses an aqueous base and a halogen to remove the carbonyl group as carbon dioxide and form a primary amine. It often gives aryl and alkyl primary amines in high yield, and the products are free of secondary and tertiary amine contamination. The Curtius rearrangement follows a similar goal but starts from an acyl azide. When heated, the acyl azide converts into a primary amine and releases nitrogen gas...

preparation of 1&deg; amines: hofmann and curtius rearrangement mechanism

preparation-of-1-amines-hofmann-and-curtius-rearrangement-mechanism

Primary Amine Synthesis by Rearrangement

Hofmann and Curtius rearrangements are used to make primary amines from carboxylic acid derivatives. In the Hofmann rearrangement, a primary amide is treated with a base and then halogenated to form an N-haloamide. A second proton loss gives a stable anionic species that rearranges to an isocyanate after an alkyl group migrates from the carbonyl carbon to the nearby nitrogen. The isocyanate then reacts with water to form carbamic acid. Carbamic acid breaks down on its own to release carbon...

amines to amides: acylation of amines

Using Acylation to Modify Amines

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amines to alkenes: hofmann elimination

Hofmann Elimination and Alkene Formation

Hofmann elimination turns an amine into an alkene through an E2 elimination. The amine is first changed into a good leaving group. A quaternary ammonium salt is formed by treating the amine with an excess of alkyl halide, which gives a halide salt. Next, the halide salt is converted into a hydroxide salt. This hydroxide salt acts as a base during the elimination. With heat, the hydroxide removes a proton from the beta carbon. At the same time, an alkene forms and a neutral amine molecule...

amines to alkenes: cope elimination

Syn Elimination in Cope Reaction

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1&deg; amines to diazonium or aryldiazonium salts: diazotization with nano2 overview

1-amines-to-diazonium-or-aryldiazonium-salts-diazotization-with-nano2

Nitrous Acid Reactions with Amines

Nitrous acid reacts with amines in acidic conditions, and the products depend on the type of amine. It is a key nitrogen-containing acid, but it is weaker than nitric acid. Nitrous acid has a pKa of 3.37, so it ionizes in water to form nitrite ion and hydronium ion. Nitrous acid is unstable, so it is made in situ, or formed in the reaction mixture as needed. A sodium nitrite solution is combined with a cold aqueous acid such as hydrochloric acid or sulfuric acid. In acid, the –OH group of...

1&deg; amines to diazonium or aryldiazonium salts: diazotization with nano2 mechanism

Diazotizing Primary Amines with Nitrous Acid

Diazotizing primary amines with nitrous acid forms diazonium salts. The reaction begins with nitrous acid, a weak and unstable acid made in situ from sodium nitrite and cold, dilute hydrochloric acid. In acidic solution, nitrous acid is protonated and loses water to form the nitrosonium ion, which acts as the electrophile. Primary amines react with the nitrosonium ion to start diazotization. The amine serves as the nucleophile and attacks the electrophile. After deprotonation, an N-nitrosamine...

2&deg; amines to n-nitrosamines: reaction with nano2

2-amines-to-n-nitrosamines-reaction-with-nano2

Nitrosamine Formation from Secondary Amines

Secondary amines can form N-nitrosamines when they react with nitrous acid. Nitrous acid is weak and unstable, so it is made in the reaction mixture from sodium nitrite and a strong acid such as hydrochloric acid or sulfuric acid. The reaction is carried out in cold conditions. In acid, nitrous acid becomes protonated. It then loses water and forms the nitrosonium ion, a reactive electrophile. The secondary amine acts as a nucleophile and attacks this ion. That step gives an N-nitrosammonium...

diazonium group substitution with halogens and cyanide: sandmeyer and schiemann reactions

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Making Aryl Halides from Diazonium Salts

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diazonium group substitution: &ndash;oh and &ndash;h

Arenediazonium Salt Reactions: Phenols and H

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aryldiazonium salts to azo dyes: diazo coupling

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Diazo Coupling and Azo Dye Formation

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amines to sulfonamides: the hinsberg test

Amines and the Hinsberg Reagent Test

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key terms and concepts

Compare piperidine, pyridine, pyrrole, and imidazole to see how nitrogen placement changes basicity and how amines are separated in the lab.

Why Ring Nitrogen Changes Amine Basicity | JoVE K12

organic chemistry

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Why Ring Nitrogen Changes Amine Basicity

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