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Acylation
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In chemistry, acylation is a broad class of chemical reactions in which an acyl group (R−C=O) is added to a substrate. The compound providing the acyl group is called the acylating agent. The substrate to be acylated and the product include the following:
A particularly common type of acylation is acetylation, the addition of the acetyl group. Closely related to acylation is formylation, which employ sources of "HCO+ in place of "RCO+".
Examples
[edit]Because they form a strong electrophile when treated with Lewis acids, acyl halides are commonly used as acylating agents. For example, Friedel–Crafts acylation uses acetyl chloride (CH3COCl) as the agent and aluminum chloride (AlCl3) as a catalyst to add an acetyl group to benzene:[2]
This reaction is an example of electrophilic aromatic substitution.
Acyl halides and acid anhydrides of carboxylic acids are also common acylating agents. In some cases, active esters exhibit comparable reactivity. All react with amines to form amides and with alcohols to form esters by nucleophilic acyl substitution.
Acylation can be used to prevent rearrangement reactions that would normally occur in alkylation. To do this an acylation reaction is performed, then the carbonyl is removed by Clemmensen reduction or a similar process.[3]
Acylation in biology
[edit]Protein acylation is the post-translational modification of proteins via the attachment of functional groups through acyl linkages. Protein acylation has been observed as a mechanism controlling biological signaling.[4] One prominent type is fatty acylation, the addition of fatty acids to particular amino acids (e.g. myristoylation, palmitoylation or palmitoleoylation).[5] Different types of fatty acids engage in global protein acylation.[6] Palmitoleoylation is an acylation type where the monounsaturated fatty acid palmitoleic acid is covalently attached to serine or threonine residues of proteins.[7][8] Palmitoleoylation appears to play a significant role in the trafficking, targeting, and function of Wnt proteins.[9][10]
See also
[edit]References
[edit]- ^ 裴, 坚 (2016). 基础有机化学 [Basic Organic Chemistry] (4th ed.). 北京大学出版社. p. 508. ISBN 978-7-301-27212-1.
- ^ Brown, William H.; Iverson, Brent L.; Anslyn, Eric V.; Foote, Christopher S. (2017). Organic Chemistry (8th ed.). Boston, MA: Cengage Learning. p. 1002. ISBN 978-1-305-58035-0. OCLC 974377227.
- ^ Vollhardt, Peter; Neil E. Schore (2014). Organic Chemistry: Structure and Function (7th ed.). New York, NY: W.H. Freeman and Company. pp. 714–715. ISBN 978-1-4641-2027-5.
- ^ Towler, D A; Gordon, J I; Adams, S P; Glaser, L (1988). "The Biology and Enzymology of Eukaryotic Protein Acylation". Annual Review of Biochemistry. 57 (1): 69–97. doi:10.1146/annurev.bi.57.070188.000441. PMID 3052287.
- ^ Resh, M. D. (1999). "Fatty acylation of proteins: New insights into membrane targeting of myristoylated and palmitoylated proteins". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1451 (1): 1–16. doi:10.1016/S0167-4889(99)00075-0. PMID 10446384.
- ^ Mohammadzadeh, Fatemeh; Hosseini, Vahid; Mehdizadeh, Amir; Dani, Christian; Darabi, Masoud (2019). "A method for the gross analysis of global protein acylation by gas–liquid chromatography". IUBMB Life. 71 (3): 340–346. doi:10.1002/iub.1975. ISSN 1521-6551. PMID 30501005.
- ^ Hannoush, Rami N. (October 2015). "Synthetic protein lipidation". Current Opinion in Chemical Biology. 28: 39–46. doi:10.1016/j.cbpa.2015.05.025. ISSN 1879-0402. PMID 26080277.
- ^ Pelegri, Francisco; Danilchik, Michael; Sutherland, Ann (2016-12-13). Vertebrate development : maternal to zygotic control. Cham, Switzerland. ISBN 9783319460956. OCLC 966313034.
{{cite book}}: CS1 maint: location missing publisher (link) - ^ Hosseini, Vahid; Dani, Christian; Geranmayeh, Mohammad Hossein; Mohammadzadeh, Fatemeh; Nazari Soltan Ahmad, Saeed; Darabi, Masoud (2018-10-20). "Wnt lipidation: Roles in trafficking, modulation, and function". Journal of Cellular Physiology. 234 (6): 8040–8054. doi:10.1002/jcp.27570. ISSN 1097-4652. PMID 30341908. S2CID 53009014.
- ^ Nile, Aaron H.; Hannoush, Rami N. (February 2016). "Fatty acylation of Wnt proteins". Nature Chemical Biology. 12 (2): 60–69. doi:10.1038/nchembio.2005. ISSN 1552-4469. PMID 26784846.
Acylation
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Fundamentals
Definition of Acylation
Acylation is a fundamental class of chemical reactions in organic chemistry wherein an acyl group, represented as $ \ce{R-C=O} $ (where R is typically an alkyl or aryl substituent), is introduced into an organic substrate through the use of an acylating agent. This process generally proceeds via the reaction of the acylating agent with a nucleophilic site on the substrate, resulting in the formation of a new carbon-acyl bond. Common acylating agents include acyl chlorides ($ \ce{RCOCl} \ce{(RCO)2O} $), and other activated derivatives of carboxylic acids.[2]/Carboxylic_Acids/Reactivity_of_Carboxylic_Acids/Acyl_Chlorides) In a typical schematic, an acyl chloride such as $ \ce{RCOCl} $ reacts with a nucleophile (Nu:) or suitable substrate to yield the acylated product $ \ce{RC(O)Nu} $ and a leaving group like chloride ion, thereby establishing the core transformation central to acylation. This distinguishes acylation from related substitution processes: unlike alkylation, which incorporates an alkyl group ($ \ce{R-} \ce{RSO2-} $) for sulfone or sulfonamide formation, acylation specifically leverages the reactivity of the carbonyl functionality for bond formation.[2]/Arenes/Reactivity_of_Arenes/Friedel-Crafts_Acylation) The concept of acylation has historical roots in late 19th-century organic chemistry, with the term first appearing in the late 19th century[5] amid studies of carboxylic acid derivatives; influential work by chemists like Victor Meyer on esterification and acid reactivity laid foundational groundwork for understanding these transformations. Acylation reactions span both intermolecular and intramolecular variants, enabling the synthesis of diverse carbonyl-containing compounds such as esters (from alcohols), amides (from amines), ketones (via carbon nucleophiles), and thioesters (from thiols), thereby serving as a versatile tool in synthetic organic chemistry.[6][2][7]The Acyl Group
The acyl group is a key functional moiety in organic chemistry, characterized by the general formula , where represents hydrogen, an alkyl chain, an aryl group, or another organic substituent. This group is derived from carboxylic acids () by the removal of the hydroxyl () portion of the carboxyl group, leaving behind the carbonyl () unit. In the context of inorganic chemistry, acyl groups can also arise from oxoacids more broadly, but in organic applications, the carboxylic acyl form predominates.[8] Nomenclature for acyl groups follows systematic IUPAC conventions, with those derived from aliphatic carboxylic acids termed alkanoyl groups—for instance, the acetyl group () from acetic acid (). Acyl groups from aromatic carboxylic acids are known as aroyl groups, such as the benzoyl group () obtained from benzoic acid (). These names are formed by replacing the -ic acid ending of the parent acid with -oyl, ensuring precise identification in chemical structures and reactions.[9] The electronic properties of the acyl group render it highly reactive, particularly at the carbonyl carbon, which exhibits electrophilic character due to the polarity of the bond. The oxygen atom's high electronegativity withdraws electron density from the carbon, creating a partial positive charge () that attracts nucleophiles. Resonance stabilization in acyl derivatives can modulate this electrophilicity, but the inherent -bond character of the carbonyl further enhances the carbon's susceptibility to nucleophilic attack.[10] Common acylating agents that deliver the acyl group in synthetic transformations include acyl halides (, where is chloride or bromide), which are highly reactive due to the excellent leaving group ability of the halide, and acid anhydrides ($ (RCO)_2O RCOOH$) can also serve as acylating agents when activated, for example, via conversion to mixed anhydrides or using coupling reagents, allowing milder conditions in amide bond formation.[11] Less common variations of the acyl group encompass thioacyl groups (), where sulfur replaces the carbonyl oxygen, leading to thiocarbonyl compounds with distinct reactivity profiles, such as in thioester synthesis. Iminoacyl groups (), featuring a unit instead of , appear in specialized contexts like metal coordination chemistry but are rarer in routine organic synthesis. These analogues highlight the acyl group's versatility through chalcogen or nitrogen substitution.[12]Reaction Types
Nucleophilic Acyl Substitution
Nucleophilic acyl substitution is a class of reactions in which a nucleophile, such as an alcohol, amine, or water, attacks the electrophilic carbonyl carbon of an acyl derivative, displacing a leaving group and resulting in the formation of new carbonyl compounds like esters, amides, or carboxylic acids.[13][14] This process is fundamental to the reactivity of carboxylic acid derivatives, where the acyl group serves as the reactive electrophilic unit.[15] Common substrates for these reactions include acyl chlorides, acid anhydrides, esters, and amides, with reactivity decreasing in the order acyl chlorides > anhydrides > esters > amides due to the stability and leaving group ability of the departing group—chloride being an excellent leaving group compared to alkoxide or amide ions.[16][17] For instance, acyl chlorides react rapidly with nucleophiles even under mild conditions, while amides require harsher conditions owing to the poor leaving group ability of the nitrogen-based group.[13] A prominent example is the Schotten-Baumann reaction, in which an acyl chloride reacts with an amine in the presence of an aqueous base like sodium hydroxide to form an amide, with the base neutralizing the HCl byproduct and preventing salt formation that could inhibit the nucleophilic attack.[18][19] Another variant involves esterification, such as the acid-catalyzed Fischer esterification, where a carboxylic acid reacts with an alcohol to form an ester, though this proceeds via protonation of the carbonyl to enhance electrophilicity rather than direct nucleophilic substitution on a derivative.[20][21] In terms of stereochemistry, nucleophilic acyl substitution typically occurs with retention of configuration at any existing chiral centers in the substrate, as the reaction proceeds through a tetrahedral intermediate at the achiral carbonyl carbon, which reforms the planar sp² geometry without creating a new stereocenter.[13] These reactions offer high yields in the synthesis of esters and amides, particularly in peptide chemistry where acyl chlorides or activated esters facilitate efficient amide bond formation between amino acids.[18][14]Electrophilic Acylation
Electrophilic acylation refers to a class of reactions in which an electrophilic acyl species, typically an acylium ion (RC≡O⁺), is generated and reacts with electron-rich substrates to form new carbon-carbon bonds.[22] This process contrasts with nucleophilic acyl substitutions by emphasizing the acyl group as the attacking electrophile rather than the target.[23] The acylium ion is formed from acylating agents such as acyl chlorides or anhydrides in the presence of a Lewis acid catalyst, enabling the electrophile to target nucleophilic centers like aromatic rings or activated alkenes./Arenes/Reactivity_of_Arenes/Friedel-Crafts_Acylation) A prominent example is the Friedel-Crafts acylation, where benzene reacts with acetyl chloride in the presence of aluminum chloride (AlCl₃) to produce acetophenone.[23] The reaction proceeds as follows:
This method efficiently introduces ketone functionality onto aromatic systems, serving as a cornerstone for synthesizing aryl ketones.[22]
The scope of electrophilic acylation is primarily limited to activated or moderately deactivated aromatic compounds, such as those bearing alkyl or alkoxy substituents, while strongly deactivated rings like nitrobenzene fail to react under standard conditions due to insufficient electron density./Arenes/Reactivity_of_Arenes/Friedel-Crafts_Acylation) It also applies to electron-rich alkenes, though less commonly in classical protocols.[24] Deactivated substrates may require harsher conditions or alternative catalysts to proceed.[25]
A key variation is the Vilsmeier-Haack formylation, which introduces an aldehyde group onto activated aromatics using dimethylformamide (DMF) and phosphoryl chloride (POCl₃) to generate an iminium electrophile equivalent to an acylium ion for R = H.[26] This reaction is particularly useful for heteroaromatic systems like indoles and pyrroles.[27]
Limitations include the prevention of polyacylation, as the resulting ketone deactivates the aromatic ring toward further electrophilic attack, ensuring monoselectivity.[28] In substituted benzenes, the acylation exhibits ortho-para directing effects influenced by existing substituents, aligning with general electrophilic aromatic substitution regiochemistry./Arenes/Reactivity_of_Arenes/Friedel-Crafts_Acylation)
Mechanisms
Nucleophilic Addition-Elimination Pathway
The nucleophilic addition-elimination pathway characterizes the mechanism of nucleophilic acyl substitution reactions, where a nucleophile replaces a leaving group on an acyl derivative through a two-step process. In the first step, the nucleophile attacks the electrophilic carbonyl carbon, forming a tetrahedral intermediate in which the carbon adopts a sp³ hybridization and bears four substituents, including a negatively charged oxygen. This addition disrupts the carbonyl π bond, with the electron pair from the nucleophile forming a new σ bond. The tetrahedral intermediate is often stabilized by resonance involving the oxygen lone pair, which can delocalize the negative charge, particularly when the nucleophile is electron-rich, such as an amine.[29][30][14] In the second step, the tetrahedral intermediate collapses via elimination, reforming the carbonyl π bond and expelling the leaving group, such as chloride from an acyl chloride. This elimination restores the planar sp² geometry of the carbonyl carbon and yields the substitution product. If the nucleophile is neutral, like an amine (R'NH₂), a proton transfer step may follow to deprotonate the intermediate or product, ensuring charge balance; for instance, in amide formation, the nitrogen-attached intermediate loses a proton to generate the neutral amide. A representative example is the reaction of an acyl chloride with a primary amine:
[29][31][30]
Several factors influence the rate of this pathway. The leaving group's ability is critical, with better leaving groups (e.g., Cl⁻ over OR⁻) facilitating faster elimination due to lower bond dissociation energy and higher stability of the departing anion. Nucleophile strength also plays a key role, as stronger nucleophiles (e.g., amines or alkoxides) accelerate the addition step by more effectively donating electrons to the carbonyl. Solvent effects are significant, with polar aprotic solvents (e.g., DMF or DMSO) enhancing rates by solvating cations without hydrogen-bonding the nucleophile, thereby increasing its nucleophilicity compared to protic solvents like water.[14][32][33]
Kinetic studies confirm the mechanism's bimolecular nature, with second-order rate laws (rate = k [acyl derivative] [nucleophile]) indicating that the addition step is typically rate-determining, as the concentration of both reactants affects the overall velocity. In some cases, tetrahedral intermediates have been isolated and characterized, providing direct evidence for their role; for example, lithium carbenoids added to Weinreb amides yield stable tetrahedral species observable by NMR and X-ray crystallography. These findings underscore the pathway's generality across acyl derivatives, with reactivity decreasing in the order acyl chlorides > anhydrides > esters > amides due to leaving group differences.[34][35][36]
Electrophilic Aromatic Substitution Pathway
The electrophilic aromatic substitution pathway in acylation involves the introduction of an acyl group onto an aromatic ring through the action of a strong electrophile, typically generated from an acyl chloride and a Lewis acid catalyst. This process, commonly exemplified by the Friedel-Crafts acylation, proceeds without disrupting the aromatic system's stability, yielding aryl ketones as products. Unlike other substitution reactions, the acylium ion serves as the key electrophile, ensuring clean reactivity without the rearrangements often seen in alkylations.[3] The mechanism begins with the coordination of a Lewis acid, such as AlCl₃, to the carbonyl oxygen of the acyl chloride, facilitating the departure of the chloride ion and generating the acylium ion (RC≡O⁺) paired with AlCl₄⁻. This acylium ion is a highly reactive electrophile due to its linear structure and sp hybridization at the carbon atom, which concentrates positive charge effectively. The aromatic ring's π electrons then attack the electrophilic carbon of the acylium ion, forming a sigma complex (also known as the arenium or Wheland intermediate), a resonance-stabilized carbocation where the positive charge is delocalized across the ring. Finally, deprotonation of the sigma complex by AlCl₄⁻ or another base restores aromaticity, releasing HCl and producing the acylated aromatic compound.[37][38] A representative equation for the ionization step in Friedel-Crafts acylation of benzene using acetyl chloride is:
This step highlights the role of AlCl₃ in polarizing the acyl chloride to form the stable acylium ion, which then undergoes electrophilic attack. The overall reaction is:
[3][39]
The acylium ion's stability arises from resonance between two structures: RC⁺=O ↔ RC≡O⁺, where the positive charge is shared between carbon and oxygen, rendering it less prone to side reactions compared to carbocation intermediates in other substitutions. The sigma complex intermediate features three resonance forms that distribute the positive charge to ortho and para positions relative to the acyl group's attachment point, explaining the kinetic preference for these sites in unsubstituted benzene. This delocalization minimizes the energy barrier for formation, with the intermediate's stability enhanced by the empty p-orbital on the sp²-hybridized ring carbon.[37][40]
Regioselectivity in electrophilic aromatic acylation is primarily governed by the electronic effects of existing substituents on the ring, which influence the stability of the sigma complex. Electron-donating groups, such as alkoxy (-OR) or alkyl (-R), direct the acylium ion to ortho and para positions by stabilizing the positive charge in the intermediate through resonance donation, often favoring para substitution due to steric hindrance at ortho sites. In contrast, electron-withdrawing groups like nitro (-NO₂) destabilize the sigma complex at ortho and para positions, directing substitution to the meta position, though acylation typically does not proceed efficiently on strongly deactivated rings. This directing behavior follows the same principles as other electrophilic substitutions but is amplified by the acylium ion's bulkiness, promoting kinetic control over thermodynamic products in most cases.[3][41]