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

La basicidad de las aminas heterocíclicas está influenciada tanto por los efectos de resonancia como por los de hibridación.
Para comprender el efecto de resonancia, considere dos aminas heterocíclicas aromáticas: piridina y pirrol. Los electrones no enlazados del nitrógeno piridínico residen en un orbital híbrido sp2. Como no contribuyen al sexteto aromático, están disponibles para la protonación.
En el pirrol, los electrones no enlazantes están presentes en un orbital p y forman parte del sistema de π aromáticos. Aquí, la protonación es desfavorable ya que la aromaticidad se pierde en el ácido conjugado.
Como el pKa del pirrol protonado es menor que el pKa de la piridina protonada, la piridina es más básica que el pirrol.
Para el efecto de hibridación, considere la hibridación del nitrógeno amina. A medida que aumenta el carácter de porcentaje s, los electrones no enlazados se mantienen más firmemente y están menos disponibles para la protonación.
Con menos carácter s del nitrógeno piperidínico hibridado sp3, se protona fácilmente con un valor más alto de pKa del ácido conjugado. Por lo tanto, la piperidina es más básica que la piridina.

basicidad de las aminas aromáticas heterocíclicas

Basicity of Heterocyclic Aromatic Amines

Las aminas heterocíclicas, donde el átomo de N es parte de un sistema alicíclico, son similares en basicidad a las alquilaminas. Curiosamente, la amina heterocíclica que tiene un átomo de nitrógeno como parte de un anillo aromático tiene mucha menos basicidad que su correspondiente contraparte alicíclica. Por esta razón, como se presenta en la Figura 1, la piperidina (pK_b = 2,8) es significativamente más básica que la piridina (pK_b = 8,8).

<img alt="Figure1" src="/files/ftp_upload/12527/12527-PT_Figure_1.svg" style="text-align: center; height: 110px;">
Figura 1. Comparación de la basicidad de piperidina y piridina.

 Esta diferencia en basicidad puede atribuirse al estado de hibridación de orbitales que contienen un par solitario de electrones en el átomo de N, como se muestra en la Figura 2. En el caso de la piperidina, el par solitario reside en un orbital con hibridación sp^3 que tiene s más bajos. carácter, haciendo que el par solitario esté más disponible para exhibir basicidad hacia el ácido. Por otro lado, en la piperidina, el par solitario reside en un orbital con hibridación sp^2 que contiene un carácter s mucho mayor. En consecuencia, el par solitario está más estrechamente unido al anillo arilo y menos disponible para exhibir basicidad hacia el ácido.

<img alt="Figure2" src="/files/ftp_upload/12527/12527-PT_Figure_2.svg" style="text-align: center; height: 60px;">
Figura 2. El efecto de los orbitales híbridos sobre la basicidad.

 El pirrol es mucho menos básico que la piridina y tiene un valor de pK_b de 15. El único par de electrones del átomo de N que se muestra en la Figura 3 reside en un orbital p puro y está perfectamente alineado con los orbitales p de los átomos de C, que participan en la La aromaticidad del anillo. Por lo tanto, el único par de electrones del átomo de N del pirrol se deslocaliza por resonancia en todo el anillo. Por el contrario, el par solitario del átomo de N de la piridina que se encuentra en un orbital hibridado sp^2 está alineado perpendicular a los otros orbitales sp^2 de los átomos de C que participan en la resonancia. Entonces, el par solitario de electrones en el átomo de N de la piridina está mucho más disponible que el del pirrol, lo que resulta en una mayor basicidad de la piridina.

<img alt="Figure3" src="/files/ftp_upload/12527/12527-PT_Figure_3.svg" style="text-align: center; height: 90px;">
Figura 3. La estructura de Lewis del pirrol.

 El imidazol contiene dos átomos de N en un anillo de cinco miembros y es un heterociclo vital que se encuentra en muchas proteínas. Esta amina heterocíclica con un pK_b de 7 es más básica que la piridina por un factor de 100. El átomo de N que se parece al del pirrol no es básico. El otro átomo de N es básico y extrae H del ácido dando lugar a su ácido conjugado, que se estabiliza mediante la resonancia, como se ilustra en la Figura 4. Esta estabilización por resonancia de la base conjugada da como resultado una mayor basicidad del imidazol en relación con la piridina.

<img alt="Figure4" src="/files/ftp_upload/12527/12527-PT_Figure_4.svg" style="text-align: center; height: 125px;">
Figura 4. La estabilización por resonancia en iones imidazolio.

 La basicidad de las aminas proporciona una valiosa herramienta práctica para separar aminas de una mezcla que contiene otros compuestos neutros. Esto se logra disolviendo la mezcla impura en éter y agitándola con agua en un embudo de decantación. Después de que las dos capas se separan, el drenaje de la capa de agua elimina la sal y la mayoría de las impurezas inorgánicas. Cuando se añade ácido acuoso diluido a la capa orgánica, las aminas se protonan selectivamente en el ácido correspondiente y se disuelven en la capa acuosa. El drenaje de la capa orgánica elimina la impureza orgánica neutra. La lenta basificación de la capa acuosa regenera nuevamente la amina libre, que podría extraerse usando un nuevo volumen de éter. La posterior evaporación del éter produce una amina pura.

Basicidad de las aminas aromáticas heterocíclicas

Las aminas heterocíclicas, donde el átomo de N es parte de un sistema alicíclico, son similares en basicidad a las alquilaminas. Curiosamente, la amina heterocíclica ...

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Organic Chemistry

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Amines

Aminas

KEY TERMS AND CONCEPTS

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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

Naming Primary Amines in Organic Chemistry

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...

structure of amines

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...

physical properties of amines

Amines: Smell, Solubility, and Boiling Points

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

preparation-of-amines-reduction-of-oximes-and-nitro-compounds

Routes to Amines from Oximes and Nitro Groups

Oximes and nitro compounds can both be converted into primary amines. Oximes are reduced by catalytic hydrogenation, hydride reduction, or sodium metal reduction. A primary amine is an amine with one carbon group attached to nitrogen, so this step is an important way to build nitrogen-containing molecules. Nitro compounds follow a similar path to primary amines. Aliphatic and aromatic nitro compounds can be reduced by catalytic hydrogenation or by active metals such as Fe, Zn, and Sn in the...

preparation of amines: reduction of amides and nitriles

preparation-of-amines-reduction-of-amides-and-nitriles

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

preparation-of-amines-reductive-amination-of-aldehydes-and-ketones

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

Amines can be modified by acylation to form amides. In this reaction, a carboxylic acid derivative such as an acid chloride, ester, or anhydride provides the acyl group. The process uses two equivalents of amine, and each one has a different job. The first amine acts as a nucleophile. It attacks the carbonyl carbon and forms a tetrahedral intermediate. The leaving group then leaves, and the C=O bond is restored. The second amine acts as a Brønsted base, meaning it removes a proton from the...

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

The Cope elimination reaction converts tertiary amines into alkenes. It uses hydrogen peroxide and heat. The process starts with oxidation of the tertiary amine to form an amine oxide. The amine oxide then acts as a base during the elimination step. The reaction follows syn stereochemistry, which means the groups leave from the same side. It also proceeds through a cyclic transition state. The N,N-dimethyl hydroxylamine group is formed as the leaving group. The major product is usually the...

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

diazonium-group-substitution-with-halogens-cyanide-sandmeyer

Making Aryl Halides from Diazonium Salts

Arenediazonium salts can be used to make substituted aromatic compounds. In these reactions, the diazonium group is replaced by other functional groups such as halides, hydroxyl, and nitrile. The transcript focuses on how this chemistry is used to form aryl chlorides, bromides, fluorides, iodides, and nitriles. When arenediazonium salts react with copper(I) salts of chloride, bromide, or cyanide, they form the corresponding aryl chloride, aryl bromide, or aryl nitrile. These are called...

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

Arenediazonium Salt Reactions: Phenols and H

Arenediazonium salt reactions show how a diazonium group can be replaced by other functional groups. These reactions begin with diazotization, the formation of an arenediazonium salt from a primary arylamine. The process uses nitrous acid, which is made in situ from sodium nitrite and a strong acid under cold conditions. In acidic solution, nitrous acid breaks down to form nitrosonium ions. A primary arylamine then attacks the nitrosonium ion. This first step leads to an N-nitrosoaminium ion...

aryldiazonium salts to azo dyes: diazo coupling

aryldiazonium-salts-to-azo-dyes-diazo-coupling

Diazo Coupling and Azo Dye Formation

Diazo coupling is the reaction that forms azo dyes from aryldiazonium salts and highly activated aromatic compounds. The product contains an —N=N— azo linkage, and the nitrogen atoms from the diazonium salt remain in the product. Phenols and arylamines are common activated partners for this reaction. The coupling usually takes place at the para position on the aromatic ring. If the para position is already occupied, the reaction shifts to the ortho position instead. The mechanism is an...

amines to sulfonamides: the hinsberg test

Amines and the Hinsberg Reagent Test

The Hinsberg test identifies primary, secondary, and tertiary amines by their reaction with benzenesulfonyl chloride, also called the Hinsberg reagent. It is named after Oscar Hinsberg. The test uses excess aqueous base, and the mixture is then acidified to show different results for each amine type. A primary amine reacts with the Hinsberg reagent to form an N-substituted benzenesulfonamide. The sulfonyl group pulls electron density away and makes the N-H proton acidic. Because of this, base...

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

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Why Ring Nitrogen Changes Amine Basicity

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