Aldehydes and ketones. Chapter iii. protection of functional groups during synthesis Chemical properties of carbonyl compounds

In some syntheses, the molecule must be subjected to such harsh chemical influences that the functional groups that need to be preserved in the molecule are destroyed. This occurs, for example, in the following synthesis:

The dehydrohalogenation reaction is carried out under the influence of bases, but under these conditions aldol condensation can occur. To prevent this undesirable process, it is necessary to “protect” the base-sensitive aldehyde group by converting it into an acetal. Generally speaking, a particular functional group can be "protected" or "blocked" if it is converted into a derivative that is stable under the subsequent reaction conditions. The original group can later be regenerated by selectively removing the "protection". This approach, when applied to the dehydrohalogenation reaction mentioned above, is illustrated by the following synthesis:

A similar method was used to synthesize propargyl aldehyde from acrolein via a diethyl acetal intermediate:

In some cases, it may seem necessary to protect a specific functional group during the synthesis process. But in fact, you just need to change the order of the individual stages of synthesis.

Let's consider the synthesis of 4-ketobutyric acid from 4-bromo-butene-2 ​​with the introduction of a protecting group:

However, the need for protection disappears if the formation of groups is carried out in such an order that the most active is formed at the last stage:

Below are some of the reagents most widely used for the protection of various functional groups.

ALDEHYDES[abbr. from novolat. al(cohol)dehyd(rogenatum) - alcohol devoid of hydrogen], org. conn., containing aldehyde SNO group. According to IUPAC nomenclature the name. A. is produced by adding to the name. the corresponding hydrocarbon suffix "al" or to the name. hydrocarbon containing one less C atom, suffix "carb" aldehyde"; in the first case, carbon aldehydic groups are numbered 1, in the second - aldehydic the group is not included in the chain numbering. In multifunctional connections aldehydic the group is denoted by the prefix "formyl", e.g. conn. OSNCH 2 CH (CHO)CH 2 CHO called. 1,2,3-propanetricarb aldehyde or 3-formylpentandial; some A. have trivial names (see table).

PROPERTIES ALDEHYDES

In the IR spectra A. characteristic. absorption bands v C=o lie in the region 1740-1720 cm -1 (aliphatic A.), 1715-1695 cm -1 (aromatic), 1705-1685 cm -1 unsaturated); V C_H -B region 2880-2650 cm -1. Chem. shift aldehydic proton in the NMR spectra (1 H) - in the region of 9.4-9.7 ppm. (aliphatic A.) and 9.6-10.1 ppm. (aromatic). The characteristic doublet in the NMR spectra (13 C), due to the 13 CHO group, is in the region of 190-205 ppm. (by 5-10 ppm in a stronger field than the 13 CO shifts of the corresponding ketones). Electronic spectra contain bands with 290 nm for RCHO (R = CH 3, C 2 H 5, C 3 H 7), 345 nm for acrolein and 327 nm for creton A. (in all cases 15-25); mass spectra (RCHO) peaks corresponding to (HCO) + , (RCO) + and R + ions. If A. have H atoms in position, then for linear connections. characteristic peaks at those 44, and for branched ones - at those 44 + 12i, where P - 1, 2, 3...

A. - one of the most reactive classes org. connections. Lower A. easily polymerize. According to the degree of oxidation, A. occupy an intermediate range. the position between alcohols and carbon compounds, which largely determines their properties. A. easily oxidized by O 2 air to already during storage (intermediate product - peroxyacid):

They are reduced under the influence of H 2 (cat.-Pt or Ni), as well as by donors of hydride ions, for example. LiAlH 4 and NaBH 4, into primary alcohols. When restored, aromatic. A. metals or electrochemically produce lyaryl-substituted glycols. Disproportionate with the formation of alcohol and compounds: 2C 6 H 5 CHO + H 2 O -> C 6 H 5 CH 2 OH + C 6 H 5 COOH (Cannizzaro district) or ester: 2RCHO -> RCOOCH 2 R (Tishchenko district). Reduced with alcohols in the presence. alcoholate A1 (Meerwein-Ponndorf-Verley district): RCHO + (CH 3) 2 CHONRCH 2 OH + (CH 3) 2 = O. Aromatic. A. enter benzoin condensation.

Due to the polarization of the bonds, A. is able to add nucleophiles at the carbonyl group: water, alcohols, amines, etc. Usually A. means. more active in reactions with nucleophiles than ketones. max. easily responsive forms aldehyde, which is primarily found in the water solution. in hydrated form. In an alcohol solution, A. forms sequentially hemiacetals and acetals: RCHO + R"OH -> RCH(OR")OH RCH(OR") 2, upon interaction with hydroxylamine-oximes RCH=NOH, with hydrazine-hydra -zones RCH=NNH 2 and azines, with primary amines-Schiff bases (azomethines) RCH=NR"; with secondary amines A. RCH 2 CHO give enamines RCH=CHNR 2. From CH 2 O and NH 3 hexamethylenetetramine (urotropine) is produced in industry. The formation of acetals and enamines is used in synthesis as a method of protection aldehydic groups; solution A. with NaHSO 3, leading to crystalline. adducts, - for the isolation and purification of A.

Extremely important in the organization. synthesis aldol condensation to form hydroxy aldehydes. The latter easily split off water, becoming unlimited aldehydes(creton condensation):

In similar areas, aromatic. A. with carbonic anhydrides (Perkin's solution), as well as aliphatic. and aromatic A. with esters of malonic acid (Knoevenagel solution), respectively, unsaturated acids or their esters are formed, for example:

Condensation of amino acids with esters of succinic acid leads to alkylidenesuccinic acids (Stobbe district), and with amino acids - to azlactones (Erlenmeyer-Plöchl district). Nucleof. addition to the carbonyl group of A. is the basis of the synthesis of: alcohols - interaction. A. with Grignard reagents or other metallurgical compounds. connection, as well as with acetylene (Reppe solution): 2CH 2 O + HCCH -> NOCH 2 CCCH 2 OH; aminocarbonyl compounds - mutual. A. or ketones with CH 2 O and amines (Mannich solution): CH 3 COCH 3 + CH 2 O + (C 2 H 5) 2 MH * HC1 -> CH 3 COCH 2 CH 2 M (C 2 H 5 ) 2 * HC1 + H 2 O; olefins - by condensation of A. with alkylidene phosphoranes (Wittig solution): RCH 2 O + (C 6 H 5) 3 -CH 2 -> RCH=CH 2 + (C 6 H 5) 3 PO; glycide ethers - A. solution with halogencarbon esters (Darzan solution):

The carbonyl group of A. is also capable of participating in the reactions of Henri, Kizhner - Wolf, Leuckart, Strecker and others. A. (chief sample CH 2 O) reacts as an electroph. reagents with olefins, forming 1,3-dioxanes and 1,3-glycols (Prince’s solution), for example:

Electroph. substitution in aromatic nucleus under the influence of A. leads to arylcarbinols. The reaction of CH 2 O with phenols underlies the production of phenol-formal. resin

When homolytic the addition of A. to olefins, initiated by peroxides or O 2, ketones are formed, with photochemical. A. solutions with olefins - oxacyclobutanes (oxetanes), for example:

A. decarbonylate (cat.-Rh) to form hydrocarbons.

A. includes the most important mono- and oligosaccharides - glucose, lactose, etc. A. is contained in essential oils, eg. citral - in lemongrass (up to 80%) and coriander oils, citronellal - in citronella (~ 30%) and eucalyptus oils, benzene aldehyde- in bitter almond oil; Vanilla fruits contain 1.5-3% vanillin.

Dehydrogenation of alcohols over Ag, Cu or monochrome catalysts - most. general industrial A. production method (basically forms aldehyde and A. composition C 5 and above). Acet aldehyde produce ch. arr. ethylene oxidation, as well as catalytic. hydration of acetylene (Kucherov's district), acrolein oxidation of propylene, propionic and oil A. - hydroformylation, respectively. ethylene and propylene. A. is also synthesized in the industry as catalytic. restoration of carbonaceous compounds (mainly higher samples) with formic acid, hydrolysis of dihalogen-substituted hydrocarbons.

Preparative methods for obtaining A.: oxidation of alcohols with chromates or ketones in the presence. alcoholates A1 (Oppenauer district); ozonolysis of olefins; restoration of decomposition carbon derivatives, for example. acid chlorides-H 2 in the presence. Pd (Rosenmund district), metal nitriles-hydrides with the following. hydrolysis of the resulting aldimines, etc.; interaction Grignard reagents with orthoformic ether; rearrangement of allyl vinyl ethers (Claisen rearrangement); oxidation of 1,2-glycols with iodine or (CH 3 COO) 4 Pb, as well as the solutions of Duff, Nef, Reimer-Tiemann, Sommlet, Gutterman and Gutterman-Koch syntheses.

For qualities. definitions A. AgNO 3 solution is usually used in excess water solution NH 3 (formation of a silver mirror) or Fehling's reagent-alkaline solution containing CuSO 4 and tartaric salt (release of a red precipitate Cu 2 O). These reagents do not react with ketones.

A. is used for the production of alcohols (butyl, 2-ethylhexanol, pentaerythritol, etc.), carbonic acids and their derivatives (for example, acetic, peracetic, acetic anhydride, vinyl acetate, acetopropylacetate), polymers, antioxidants, pyridine bases, etc. A., containing 8-12 C atoms, fragrant substances. max. the volume of world production of aluminum (several million tons/year) falls on aldehydes C 1 -C 4.

A. irritate the mucous membranes of the eyes and upper respiratory tract, have a harmful effect on nervous system. With an increase in the number of carbon atoms in the molecule, the irritant effect weakens. Unsaturated A. have a stronger irritant effect than saturated ones.

see also Acrolein, Anise aldehyde, Acet aldehyde, Benz aldehyde, Cinnamon aldehyde. Oil aldehyde, Propionic aldehyde, Salicylic aldehyde, Form aldehyde and etc.

Lit.: Roberts D.D., Caserio M.K., Fundamentals of Organic Chemistry, trans. from English, vol. 2, M., 1978; Buhler K., Pearson D., Organic syntheses, trans. from English, part 2, M., 1973, p. 51-91; Brettl R., in the book: General organic chemistry, trans. from English, vol. 2, M., 1982, p. 488-569; Kirk-Othmer encyclopedia. 3 ed., v. I, N.Y.-, 1978, p. 790-98. M.G. Vinogradov.

The special course “Strategy of Organic Synthesis” is intended for students specializing in the Department of Organic Chemistry of the Faculty of Chemistry of Moscow State University. The course is a continuation of the special course “Methods of Organic Chemistry” and introduces students to the basic modern approaches to planning multi-stage syntheses. The course is based on retrosynthetic analysis. The material is systematized by types of retrons. The main focus of the course is on solving problems and considering syntheses of complex organic compounds described in the literature - mainly natural objects (steroids, prostaglandins, alkaloids, etc.).

I. Protective groups in synthesis.

1. Protection of C-H bonds in alkynes, its application in the syntheses of di- and polyynes (Glaser, Kadio-Khodkiewicz). Syntheses based on 3-bromopropiolic acid.
2. Protection of the alcohol HO group. Protecting groups: benzyl, p-methoxybenzyl, trityl, di(p-methoxy)trityl, trimethylsilyl, tert-butyldimethylsilyl, tetrahydropyranyl, 4-methoxy-5, 6-dihydropyranyl, 3-benzoylpropionyl.
3. Protection of the HO group in glycols: isopropylidene, benzylidene, ethylidene protecting groups. Cyclic carbonates.
4. Protection of the HO group in phenols: methyl, tert-butyl, tetrahydropyranyl, phenacetyl, trimethylsilyl ethers of phenols. Methylenedioxy protecting group for dihydric phenols.
5. Protection of the carbonyl group in aldehydes and ketones: cyclic acetals and thioacetals. Selective protection of one of the unequal carbonyl groups in the molecule.
6. Protection of the carboxyl group: benzyl and p-methoxybenzyl ethers.
7. Protection of the amino group. Protecting groups: acetyl, phthaloyl, succinoyl, benzyloxycarbonyl, tert-butyloxycarbonyl (BOK). The use of benzenesulfonyl chloride and benzaldehyde to protect the amino group and its modification.
8. Protection of the thiol group (benzyl, p-methoxybenzyl).
9. The concept of photoremovable protective groups using the example of 1-(2-nitrophenyl)e tandiol-1, 2.
10. Conditions for the introduction and removal of protective groups, their resistance to the action of various reagents (acids, bases, oxidizing agents, reducing agents, etc.). Strategy for the use of protecting groups: principles of orthogonal stability and modulated lability.

II. Basic concepts of retrosynthetic analysis.

1. Target molecule (TM), transform, synthon, retron. Types of transforms: dissection (D), articulation (R), introduction of a functional group (FGA), replacement of one functional group with another (FGI), rearrangement (Rt). Retrons are partial and complete. Correspondence between synthons and reactants.
2. Retrosynthetic analysis as a heuristic approach to finding a route for the synthesis of a given compound. Two variants of the problem: searching for a synthesis route when the starting substance is given and when only the target compound (TM) is known. The concept of a formalized approach to the choice of division (D) based on the different seniority of bonds in the molecule (M. Smith).
Computer programs that allow you to plan synthesis: SYNGEN, LHASA, MARSEIL / SOS, the principle of their operation. Synthesis tree using the example of retrosynthetic analysis of valeranone.
Fighting the “arithmetic demon”; synthesis is linear and convergent.
3. Reduction of molecular complexity as the main strategic line of retrosynthetic analysis. The principle of “small bites”. Tactical techniques that help in planning synthesis: recognition of available starting compounds in parts of the molecule, taking into account symmetry, auxiliary keys.
4. The main stages of retrosynthetic analysis: transformation of functional groups into oxygen-containing ones (FGI); determination of the types of retrons contained in the molecule; choice of primary dissection; carrying out the necessary dissections in accordance with the type of retron; application of FGA tactics.
5. Types of strategies in retrosynthetic analysis. Strategies based on transformations, retrons, functional groups; topological and stereochemical strategies.

III. Retrons involving the dissection of two carbon-heteroatom bonds (X, Y-retrons).

1. Bifunctional retrons based on two carbon-heteroatom bonds: 1, 1- and 1, 2-retrons, their reduction to acetals, epoxides and carbonyl compounds. Synthesis of thiols from S - alkylthiuronium salts.
2. Division of 1, 3- X, Y - retron based on addition to α, β -unsaturated carbonyl compounds and on the basis of malonic ester.

IV. Retrons involving the dissection of carbon-carbon and carbon-heteroatom bonds.
Bifunctional retrons with one carbon-heteroatom bond.

1. Dissection of 1, 1-retron based on alcohols: reactions of aldehydes, ketones and esters with organomagnesium and organolithium compounds.
Analysis of ketones: nitriles, acid chlorides and salts of carboxylic acids as reagents, corresponding to the R(CO) + synthon.
Cyanide ion as a reagent corresponding to the HOOC - synthon. Dissection of α - amino - and α - hydroxy acids based on 1, 1-C, X - retron. Synthesis of α - amino acids from aldehydes (Strecker).
2. Reduction of 1, 2-retron to epoxides. Analysis of carbonyl compounds based on 1, 2-retron. Two cases of unambiguous halogenation of unsymmetrical ketones. FGA: introduction of an activating group (COOEt or CH=O) at the a-position of a ketone to eliminate ambiguity in the alkylation of unsymmetrical ketones. Malonic ester as a reagent corresponding to the EtOOC-CH 2 - synthon.
3. Michael’s transform as the main tactic for analyzing 1, 3-retron.

V. Retron Diels-Alder.

1. The Diels-Alder reaction as one of the “powerful reactions” (cycloaddition) to create a six-membered ring. Diene and dienophile. o-Quinodimethanes as dienes, their preparation.
Types of Diels-Alder reaction: carbo reaction, hetero reaction, 1, 4-cycloelimination. Retro reaction.
Catalysis in the Diels-Alder reaction.
2. Stereochemistry of the reaction, endo-rule. Regioselectivity of cycloaddition in the case of unsymmetrical dienes and dienophiles. Regioselectivity of the hetero-reaction. Enantioselective version of the Diels-Alder reaction.
3. Auxiliary keys to detect the Diels-Alder retron: the relative arrangement of substituents in the six-membered ring, their stereo ratio.
4. a - Chloroacrylonitrile as a synthetic equivalent of ketene in the Diels-Alder reaction. a - Nitroalkenes as reagents for the synthesis of cyclohexylamines.

VI. Bifunctional retrons, involving the dissection of one carbon-carbon bond (1, n-retrons).
Dissection of the C-C bond based on bifunctional compounds: 1, 2-, 1, 3-, 1, 4-, 1, 5- and 1, 6-retrons.

1. Syntons arising from the division of 1, 2-bifunctional retron: “logical” (natural) and “illogical”. Alternation of donor and acceptor atoms in an aliphatic chain (D. Seebach).
Umpolung on the example of benzoin condensation, lithium salts of dithiane, and a-lithiated ethers of enols. Acetylene ion as an equivalent of acyl anion.
Reduction of a - functionalized carbonyl compounds to acetylenes; a - amino -, a - hydroxy acids and 1, 2-diols - to cyanohydrins. Reduction of a-functionalized alcohols to alkenes. Reduction of acetylenes to 1, 2-retron (oxidation of dihydrazones and deoxygenation of a-dicarbonyl compounds).
Analysis of 1, 2-retron based on reductive coupling of ketones: pinacone condensation and condensation under the influence of Ti(3+) compounds (McMurry, Mukayama).
2. 1, 3-Retron based on dicarbonyl and b-hydroxycarbonyl compounds. Claisen condensation, aldol-crotonic condensation, Mannich and Reformatsky reactions as tactics that allow the dissection of 1, 3-retron. Syntheses based on g-butyrolactone. Condensations of unsymmetrical ketones that occur unambiguously (the predominant formation of one of the products due to dehydration or the formation of a stabilized anion). Synthesis of 3- and 4-substituted cyclic conjugated enones from 4-substituted anisoles (Birch) and 1, 3-cyclohexanedione.
3. Reduction of 1, 4-retron to 1, 4-dicarbonyl compounds. Application of a - halocarbonyl compounds and nitroalkanes (synthesis of ketones according to Nef and McMurry). Synthesis of chloromethyl ketones from acid chlorides and diazomethane (Clibbens-Nierenstein) and bromomethyl ketones from diazoketones.
Use of transform junction (R) in the analysis of 1, 4-bifunctional compounds: junction with the formation of a double C = C bond. 1, 4-Functionalization based on halogen derivatives of the allylic and propargyl type.
Stetter transform (addition of aldehydes to α, β-unsaturated carbonyl compounds) as one of the tactics for the analysis of 1, 4-retron based on Umpolung.
4. The Michael reaction as the main route for the dissection of 1, 5-retron based on 1, 5-dicarbonyl compounds. Stereo control in Michael's reaction. Robinson's reduction of retron to 1,5-dicarbonyl compounds. Synthesis of cyclic b-diketones.
5. Analysis of 1, 6-retron. Articulation leading to the Diels-Alder retron as a main tactic for the analysis of 1, 6-bifunctional compounds. Articulation in combination with the Bayer-Villiger transform.
6. Syntheses based on sigmatropic rearrangements. Rearrangements of allyl ethers of enols (Claisen-Cope) and phenols (Claisen). Synthesis of eugenol. Rearrangements of 1,5-dienes (Cope), allyl vinylcarbinols (Cope oxy-rearrangement) and allylic alcohol esters (Carroll).
7. Syntheses based on rearrangements of diazoketones (Arndt-Eistert, Wolf), a-haloketones (Favorsky), pinacoline. Rearrangement of epoxides into aldehydes.

VII. Approaches to creating cyclic structures.

Kinetic and thermodynamic factors promoting cyclization reactions. Baldwin's rules governing cyclization processes. Breakdown of cycles by strategic connections.
1. Dissection of three-membered alicycles based on diazoalkanes, sulfur ylides and the Simmons-Smith reaction. Intramolecular annulation with the formation of a three-membered ring.
2. Dissection of four-membered alicycles based on the cyclization of a, a "- dihaloesters of dicarboxylic acids and acyloin condensation.
Photochemical and thermal - cycloaddition. Regioselectivity of these reactions, nucleophilic and electrophilic ends of the double bond.
Creation of four-membered alicycles based on epoxides (spiro-annelation with sulfur ylides followed by rearrangement of the epoxide).
3. Reduction of five-membered alicycles to 1, 4-, 1, 5- and 1, 6-dicarbonyl compounds. Syntheses based on the rearrangement of dienones into cyclopentenones (Nazarov).
4. Analysis of 6-membered alicycles based on Robinson annulation, Diels-Alder reaction and reduction of aromatic compounds (including Birch).
Application of allilylidene-triphenylphosphoranes for the creation of 6-membered alicycles.
5. Formation of 5- and 6-membered saturated heterocycles by a combination of Michael addition and Claisen condensation. 1, 3-Dipolar cycloaddition of diazomethane and nitrones as a method for creating 5-membered heterocycles with two heteroatoms. Synthesis of nitrones based on amine N-oxides (Cope).
6. Synthesis of polycyclic structures using the example of juvabion, bullvalene and steroid precursors. Convergent schemes for creating cycles using examples of the synthesis of ferruginol, a-bisabolene and trisporic acid.

VIII. Examples of synthesis of natural and related compounds.

Ascorbic acid(vitamin C), biotin, b- trance-bergamotene, helminthosporal, (+)- herboxidiene, coccinellin, leukotriene A 1, lucidulin, methylenomycin A, multistriatin, pentalenene, pentalenolactone, prostaglandins F2 a and E2, sirenine, (±) sparteine, (+)- sparteine, testosterone, tetracycline , E, E-farnesol, semi-synthetic penicillins, cedren, cedrol, estrone.

Recommended reading.
1. K. Buehler, D. Pearson, Organic syntheses, parts 1 and 2, M., Mir, 1973.
2. R. K. Mackie, D. M. Smith, R. A. Aitken, Guidebook to Organic Synthesis, 3rd Ed., Prentice Hall, Harlow, England, 1999.
3. H. O. House, Modern Synthetic Reactions, W. A. ​​Benjamin, New York, 1965; 2nd Ed., Benjamin, Menlo Park, CA, 1972.
4. Michael B. Smith, Organic Synthesis / McGraw-Hill, Inc., N. -Y., 1994; 2nd Ed., McGraw-Hill, New York, 2002.
5. Protecting groups in organic chemistry, ed. J. Makomi, M., Mir, 1976.
6. T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2 nd Ed., Wiley, New York, 1991; P. G. M. Wuts, T. W. Green, Protective Groups in Organic Synthesis, 3rd Ed., Wiley, New-York, 1999.
7. S. Warren, Organic Synthesis: The Disconnection Approach / Wiley, Chichester, 1983.
8. S. Warren, Workbook for Organic Synthesis: The Disconnection Approach / Wiley, Chichester, 1982.
9. E. J. Corey, X. Cheng, The Logic of Chemical Synthesis / Wiley, N. -Y., 1989.
10. T. - L. Ho, Tactics of Organic Synthesis / Wiley, N. -Y., 1994.
11. I. Fleming, Frontier Orbitals and Organic Chemical Reactions, Wiley, London, 1976.

The program has been compiled
Assoc. Dyadchenko V. P.

Aldehydes and ketones are distinguished by the presence of a carbonyl group >C=Oh.

The carbonyl group is bond polarized S-O:

Aldehydes and ketones can be considered as derivatives alkanes, who have one of methyl (-CH 3) or methylene groups ( -SN 2 - ) is replaced by a carbonyl group:

Ketones have two alkyl radicals as substituents on the carbonyl group, while aldehydes have one substituent b- alkyl group, the other is hydrogen. This difference leads to significant differences in chemical properties ( cm. below).

Nomenclature

NomenclatureIUPAC

When naming aldehydes and ketones according to the IUPAC nomenclature rules, the longest carbon chain containing the carbonyl group is selected. The numbering of carbon atoms in this chain is carried out from the end where the carbonyl group is closer, and when forming the name to the name of the hydrocarbon corresponding to the number of carbon atoms in the main chain (1-methane, 2-ethane, 3-propane, 4-butane, 5 - pentane, etc.) the ending is added -A l (for aldehydes) or -He for ketones.

The position of the carbonyl group in ketones is indicated by a dash if multiple isomers are possible. The position of the carbonyl group of aldehydes is not indicated by a number, since in all cases it appears under the first number:

Rational nomenclature

Ketones are often named after the radicals connected through the carbonyl group, with the addition of the word ketone. For example, hexanone-3 or methylethyl ketone , acetone or dimethyl keto n.

Aldehydes can be named as derivatives ethanal or acetaldehyde:

Other name e - trimethylethanal.

Chemical properties carbonyl compounds

All reactions of carbonyl compounds can be divided into groups:

Reactions on the carbonyl group (addition)

Reactions by carbon skeleton

Oxidation reactions

Recovery reactions

Addition reactions at the carbonyl group (addition of nucleophilic reagents)

1. water connection

Emerging heme diols are unstable and the equilibrium in this reaction is strongly shifted to the left. The exception is aldehydes and ketones with electron-withdrawing groups, for example, chloral or hexafluoroacetone, which in the aquatic environment exist in the form heme diols:

2. addition of bisulfite

The addition occurs through the more nucleophilic sulfur atom rather than the oxygen atom, although it has a negative charge. Derivatives are formed alkanesulfonic acids(salts alkaneoxysulfonic acids).

Emerging adducts insoluble in saturated sodium bisulfite solution or alcohols and precipitates in the form of crystals. This way you can separate carbonyl compounds from a mixture with alcohols. The carbonyl compound is released in free form from adduct when treated with acid.

When reacting with ketones, bisulfites add only to methyl ketones CH 3 -CO-R.

3. addition of cyanide

The reaction is catalyzed by potassium cyanide or sodium cyanide. Emerging oxynitriles(or cyanohydrins) can be hydrolyzed before oxycarbonic acids:

4. addition of alcohols

Upon addition of the first alcohol molecule, hemiacetals. The reaction is catalyzed by acids or bases:

The addition of a second alcohol molecule results in the formation acetals. Education acetals catalyzed only in acidic medium:

Acetalsstable in neutral and alkaline environments, therefore they can be used for temporary protection of aldehyde groups. Acetals wide common in nature.

5. connection of reagents Grignard

Interaction of organometallic compounds type R-Mg-X(reagents Grignard), where X = halogen, with carbonyl groups (nucleophilic addition at a multiple bond WITH=O):

Interaction formaldehyde, aldehydes, ketones And - leads to primary, secondary and tertiary alcohols, respectively.

Tertiary alcohols are obtained from ketones. Yes, from methyl ethyl ketone(butanone-2) produces 2-methylbutanol-2. Aldehydes in a similar reaction give secondary alcohols. From propionic aldehyde ( propanal) butanol-2 is obtained:

Primary alcohols are formed from formaldehyde. When reactants interact Grignard With acid halides carboxylic acids and esters form tertiary alcohols, which have two identical alkyl substituents. This consumes two moles of reagent Grignard:

6. Addition of ammonia and amines

Primary amines combine with aldehydes and ketones to formimins (reasons Schiffa :

A similar reaction of secondary amines with carbonyl compounds gives enamines :

Hydrazine and its derivatives can also react with carbonyl compounds to form hydrazones:

Hydroxylamines combine with aldehydes and ketones to form aldoximes And ketoximes:

7. Aldol-crotonic condensation

Condensation can occur in both acidic and alkaline environments.

Acid catalyzed condensation

They enter into condensation enol And protonated carbonyl group of the second molecule of the compound:

Base catalyzed condensation

Education enolate ion, generating carbanion, proceeds according to the scheme:

Further carbanion attaches to the carbonyl group of the second molecule, and proceeds C-alkylation, Unlike thermodynamically disadvantageous ABOUT- alkylation:

Emerging aldehyde alcohol (aldol) easily loses water in the presence of catalytic amounts of bases or acids, as well as with slight heating, with the formation of a,b - unsaturated carbonyl compound, this completes the condensation reaction (R,X = alkyl or H):

Thus, in the reaction aldoln O- croton condensation (including self-condensation) both aldehydes and ketones can enter, having alpha carbons hydrogen atoms. In the case of ketones, the equilibrium position is unfavorable for the formation of products; however, by carrying out the reaction under special conditions (for example, excluding contact of the product with the main catalyst), significant yields can be achieved. Cross-reactions between aldehydes and ketones have no laboratory application because they form difficult to separate a mixture of four products and unreacted starting compounds. More often, for synthetic purposes, a reaction is carried out between two carbonyl compounds, one of which is a source of carbanions ( methylene component ), and the other serves carbonyl component (without alpha carbon hydrogen atoms). Typically, formaldehyde, aromatic aldehydes, esters of carbonic, oxalic and formic acids are used as the carbonyl component. The methylene component is also used CH acids and even derivatives of acetylene hydrocarbons with a terminal triple bond.

8. Cannizzaro's reaction

Aldehydes that do not have alpha carbon Hydrogen atoms, when heated, with strong bases enter into an oxidation-reduction reaction, when one of the molecules is reduced to alcohol due to the oxidation of the second molecule to a carboxylic acid. Such reactions are called Cannizzaro's reactions, and proceed according to the scheme:

Intramolecular oxidation-reduction reactions are also known:

With a peculiar type of intramolecular oxidation-reduction is Benzyl regrouping :

Reactions on the carbon skeleton of aldehydes and ketones

Reactions affecting the carbon skeleton include:

Keto-enol tautomerism of aldehydes and ketones;

Halogenation (haloform reaction and replacement of a-carbon hydrogen atoms)

1. Keto-enol tautomerism

Carbonyl compounds can coexist in two forms - ketone and enol:

The transformation of aldehydes and ketones into enols (unsaturated alcohols) occurs both spontaneously and with catalysis by acids and bases. Enol forms, although present in aldehydes and ketones in insignificant concentrations, play a significant role in their reactivity. A number of important reactions of aldehydes and ketones occur through the formation of enols. Let us consider the mechanisms of the transition of ketone forms to enol forms, which occur under the catalytic action of acids and bases.

Enolization acid catalyzed

The formation of enol can be catalyzed by an acid according to the scheme below (R" = alkyl or H):

The reaction begins with the protonation of the oxygen atom of the carbonyl group and ends with the removal of a proton from alpha carbon atom. Thus, formally the proton plays the role of a catalyst.

Enolization , catalyzed basis

The formation of enolate ion proceeds according to the following scheme:

The acidity of the alpha carbon hydrogen atoms plays an important role in the formation of enols catalyzed by bases. Their increased acidity associated with the close proximity to the carbonyl group and its negative inductive effect, which pulls away electrons S-N connections and thus facilitating the removal of a proton. In other words, proton abstraction is facilitated because the resulting carbanion is stabilized by delocalization of the negative charge onto the carbonyl group.

Halogens are added to the resulting enols via a multiple C = C bond. Only unlike alkenes, where such addition is completed by complete binding of the halogen, in aldehydes and ketones only one halogen atom is added (on the carbon adjacent to the carbonyl group). The second halogen atom (on the carbonyl group) is not added, and the reaction ends with the removal of a proton and regeneration of the carbonyl group:

In an acidic environment the reaction stops there. The second hydrogen atom is not replaced by a halogen. But in an alkaline environment, a rapid reaction of substitution of the second, and an even faster reaction of substitution of the third carbon atom with a halogen occurs (an increase in the number of halogen atoms at carbon sharply increases the acidity of its hydrogens):

Ultimately, all three hydrogen atoms are replaced by halogens, followed by elimination of the group CX 3 as an anion, followed by immediate proton exchange:

As a result, trihalomethane, called haloform (iodoform CHJ 3, bromoform CHBr 3, chloroform CHCl 3) and carboxylic acid anion. And the process itself is called a haloform reaction. Any methyl ketones are susceptible to the haloform reaction. Haloforms precipitate as a colored precipitate (yellow iodoform), have a specific odor and can serve as a qualitative reaction to the presence of methyl ketones. Alcohols also give a haloform reaction, the oxidation of which can form methyl ketones (for example, isopropanol). Oxidation is carried out by an excess amount of halogen.

Oxidation of aldehydes and ketones

Aldehydes are easily oxidized to the corresponding acids:

Ketones are difficult to oxidize under harsh conditions. Oxidation is accompanied by the cleavage of the C-C bond adjacent to the carbonyl group. The result is a set of oxidation products - carboxylic acids with different lengths carbon chain:

Methods receiving

1. Oxidation primary alcohols produce aldehydes, and secondary alcohols produce ketones:

Oxidation can be carried out using “dry” and “wet” methods. The first is to pass alcohol vapor through a heated to 300-350 WITH copper oxide CuO. The “wet” method is the oxidation of alcohols with an acidified solution of potassium or sodium bichromate:

When oxidizing by the “wet” method, the resulting aldehyde should be distilled off from the reaction sphere, otherwise it is easily oxidized further to carboxylic acid:

2. Aldehydes and ketones are obtained with hydrolysis heme-dihaloalkanes

First, two halogen atoms are replaced by hydroxyl groups. But unstable heme diols quickly rearrange into carbonyl compounds with the elimination of a water molecule:

3. Ozonolysis alkenes

leads to the formation of mixtures of aldehydes and ketones, depending on the structure of the starting material alkene:

At the first stage of ozonation, ozonide is obtained, the decomposition of which with water produces carbonyl compounds and hydrogen peroxide. To prevent peroxide from provoking further oxidation of aldehydes, zinc dust is added to the water during the decomposition of ozonides. Ozonation of alkenes is aimed not so much at the synthesis of aldehydes and ketones, but at determining the location of the multiple bond:

4. Addition of water to alkynes

The addition of water to a triple bond in the presence of mercury salts leads to acetaldehyde in the case of acetylene, and to ketones in the case of substituted acetylenes. Waterjoins according to Markovnikov's rule:

5.1. general characteristics

Related classes of aldehydes and ketones contain a carbonyl functional group and are classified as carbonyl compounds. They also have a common name oxo compounds, since the =O group is called an oxo group.

Aldehydes are compounds in which the carbonyl group is bonded to an organic radical and a hydrogen atom; ketones are carbonyl compounds with two organic radicals.

The -CH=O group that is part of aldehydes is called aldehydic, respectively, the group in ketones - ketone, or keto group.

Depending on the nature of organic radicals, aldehydes and ketones may belong to aliphatic or aromatic row; there are ketones mixed(Table 5.1).

Unlike alcohols, the molecules of aldehydes and ketones do not contain mobile hydrogen atoms associated with oxygen atoms. In this regard, aldehydes and ketones are not associated due to the formation of hydrogen bonds, but are prone to form hydrogen bonds with water molecules and therefore dissolve well in it (especially the first members of the homologous series).

Table 5.1.Aldehydes and ketones

5.2. Reaction centers of aldehydes and ketones

sp 2 -The hybridized carbon atom of the carbonyl group forms three σ bonds lying in the same plane and a π bond with the oxygen atom due to the unhybridized p orbital. Due to the difference in electronegativity of carbon and oxygen atoms, the π bond between them is highly polarized (Fig. 5.1). As a result, a partial positive charge δ+ appears on the carbon atom of the carbonyl group, and a partial negative charge δ- appears on the oxygen atom. Since the carbon atom is electron deficient, it provides a site for nucleophilic attack.

Distribution of electron density in molecules of aldehydes and ketones, taking into account the transfer of electronic influence by electron-

Rice. 5.1.Electronic structure of the carbonyl group

the deficient carbon atom of the carbonyl group along σ-bonds is presented in Scheme 5.1.

Scheme 5.1.Reaction centers in the molecule of aldehydes and ketones

There are several reaction centers in the molecules of aldehydes and ketones:

The electrophilic center - the carbon atom of the carbonyl group - determines the possibility of nucleophilic attack;

The main center - the oxygen atom - makes it possible to attack with a proton;

A CH acid center whose hydrogen atom has weak proton mobility and can, in particular, be attacked by a strong base.

In general, aldehydes and ketones are highly reactive.

5.3. Nucleophilic addition

For aldehydes and ketones, nucleophilic addition reactions are most typical A N.

General description of the mechanism of nucleophilic addition A N

The ease of nucleophilic attack on the carbon atom of the carbonyl group of an aldehyde or ketone depends on the magnitude of the partial

positive charge on the carbon atom, its spatial accessibility and acid-base properties of the environment.

Taking into account the electronic effects of groups associated with the carbonyl carbon atom, the value of the partial positive charge δ+ on it in aldehydes and ketones decreases in the following order:

The spatial accessibility of the carbonyl carbon atom decreases when hydrogen is replaced by bulkier organic radicals, so aldehydes are more reactive than ketones.

General scheme of nucleophilic addition reactions A N to a carbonyl group involves a nucleophilic attack on the carbonyl carbon atom, followed by the addition of an electrophile to the oxygen atom.

In an acidic environment, the activity of the carbonyl group generally increases because protonation of the oxygen atom creates a positive charge on the carbon atom. Acid catalysis is usually used when the attacking nucleophile has low activity.

According to the above mechanism, a number of important reactions of aldehydes and ketones are carried out.

Many reactions characteristic of aldehydes and ketones occur under body conditions; these reactions are presented in subsequent sections of the textbook. This chapter will consider the most important reactions of aldehydes and ketones, which are summarized in Scheme 5.2.

Addition of alcohols. Alcohols, when interacting with aldehydes, easily form hemiacetals. Hemiacetals are usually not isolated due to their instability. When there is an excess of alcohol in an acidic environment, hemiacetals transform into acetals.

The use of an acid catalyst in the conversion of hemiacetal to acetal is clear from the reaction mechanism given below. The central place in it is occupied by the formation of a carbocation (I), stabilized due to the participation of a lone pair of electrons of a neighboring oxygen atom (+M-effect of the C 2 H 5 O group).

The formation reactions of hemiacetals and acetals are reversible, so acetals and hemiacetals are easily hydrolyzed by excess water in an acidic environment. Hemiacetals are stable in an alkaline environment, since the alkoxydione is a more difficult leaving group than the hydroxide ion.

The formation of acetals is often used as a temporary protection for the aldehyde group.

Connecting water. Addition of water to a carbonyl group - hydration- reversible reaction. The degree of hydration of an aldehyde or ketone in an aqueous solution depends on the structure of the substrate.

The hydration product, as a rule, cannot be isolated in free form by distillation, since it decomposes into its original components. Formaldehyde in an aqueous solution is more than 99.9% hydrated, acetaldehyde is approximately half, acetone is practically not hydrated.

Formaldehyde (formaldehyde) has the ability to coagulate proteins. Its 40% water solution, called formaldehyde, used in medicine as disinfectant and a preservative for anatomical preparations.

Trichloroacetic aldehyde (chloral) is completely hydrated. The electron-withdrawing trichloromethyl group stabilizes chloral hydrate so much that this crystalline substance splits off water only during distillation in the presence of dehydrating substances - sulfuric acid, etc.

At the core pharmacological effect chloral hydrate CC1 h CH(OH)2 lies the specific effect on the body of the aldehyde group, which determines the disinfecting properties. Halogen atoms enhance its effect, and hydration of the carbonyl group reduces the toxicity of the substance as a whole.

Addition of amines and their derivatives. Amines and other nitrogen-containing compounds general formula N.H. 2 X (X = R, NHR) react with aldehydes and ketones in two stages. First, nucleophilic addition products are formed, which then, due to instability, eliminate water. In this regard, this process is generally classified as a reaction attachment-elimination.

In the case of primary amines, substituted imines(they are also called Schiff's bases).

Imines are intermediate products of many enzymatic processes. The production of imines goes through the stage of formation of amino alcohols, which are relatively stable, for example, when formaldehyde reacts with α-amino acids (see 12.1.4).

Imines are intermediate products in the production of amines from aldehydes and ketones by reductive amination. This general method consists of reducing a mixture of a carbonyl compound with ammonia (or amine). The process proceeds according to the addition-elimination scheme with the formation of an imine, which is then reduced to an amine.

When aldehydes and ketones react with hydrazine derivatives, they produce hydrazones. This reaction can be used to isolate aldehydes and ketones from mixtures and identify them chromatographically.

Schiff bases and other similar compounds are easily hydrolyzed by aqueous solutions of mineral acids to form the starting products.

In most cases, reactions of aldehydes and ketones with nitrogenous bases require acid catalysis, which accelerates the dehydration of the addition product. However, if the acidity of the medium is increased too much, the reaction will slow down as a result of the conversion of the nitrogenous base into the non-reactive conjugate acid XNH 3+.

Polymerization reactions. These reactions are characteristic mainly of aldehydes. When heated with mineral acids, aldehyde polymers decompose into their original products.

The formation of polymers can be considered as the result of a nucleophilic attack by the oxygen atom of one aldehyde molecule on the carbonyl carbon atom of another molecule. So, when formaldehyde stands, the polymer of formaldehyde - paraform - precipitates in the form of a white precipitate.

5.4. Condensation reactions

The presence of a CH acid center in an aldehyde or ketone molecule results in the α-hydrogen atoms of these carbonyl compounds having some proton mobility. Under the influence of bases, such protons can be eliminated to form the corresponding carbanions. Carbanions play the role of nucleophiles towards the carbonyl substrate. This makes it possible to carry out reactions in which one molecule, as a nucleophile, attaches to the carbonyl group of another molecule of a neutral carbonyl compound. Such processes belong to condensation reactions.

Condensation is a reaction that leads to the formation of a new carbon-carbon bond, and a new, more complex molecule is formed from two or more relatively simple molecules.

Thus, in an alkaline environment, two molecules of acetaldehyde form hydroxyaldehyde with twice the number of carbon atoms.

The reaction product containing hydroxyl and aldehyde groups is called aldolem(from words ald egid and alcohol ol), and the reaction itself was called aldol condensation, or aldol addition.

The mechanism of aldol condensation. When a base acts in a carbonyl compound, a proton is removed from the α-position and a carbonyl group is formed (I), in which the negative charge is delocalized with the participation of the carbonyl group.

The anion (I) is a strong nucleophile (shown in color in the next step of the mechanism) that adds to the second (non-ionized) molecule of the carbonyl compound. As a result of such interaction, a new S-S connection and the intermediate alkoxide ion (II) is formed. In an aqueous environment, this anion is stabilized by removing a proton from a water molecule and turns into the final product - an aldol.

The aldol addition reaction is shown using the example of propanal (the molecule that attaches to the C=O group of another molecule is highlighted in color); A similar reaction is shown using acetone as an example.

The condensation product, the aldol, is capable of eliminating water to form an α,β-unsaturated carbonyl compound. This usually occurs at elevated temperatures. In this case, the reaction as a whole is called Croton condensation.

Condensation reactions can also occur in a mixed version, using different carbonyl compounds, and one of them may not contain a CH acid center, such as formaldehyde and benzaldehyde in the following reactions:

Aldol condensation is a reversible reaction; the reverse process is called aldol cleavage(or retroaldol reaction). Both reactions occur in many biochemical processes.

5.5. Reduction and oxidation

Recoveryaldehydes and ketones are carried out using complex metal hydrides LiAlH 4, NaBH 4. The reaction involves a nucleophilic attack on the carbonyl carbon atom by a hydride ion.

Subsequent hydrolysis of the resulting alcoholate produces a primary or secondary alcohol.

OxidationThe transformation of aldehydes into carboxylic acids is carried out under the influence of most oxidizing agents, including atmospheric oxygen. Ketones do not oxidize under mild conditions.

Silver oxide in the form of an ammonia complex 2 OH (Tollens' reagent) oxidizes aldehydes into carboxylic acids, releasing metallic silver. This is where the name comes from - reaction "silver mirror"

Aldehydes are also easily oxidized by copper(II) hydroxide in an alkaline medium.

Both of these reactions are often used qualitatively to detect the aldehyde group, although they are nonspecific with respect to aldehydes: for example, polyhydric phenols, aminophenols, aromatic amines, hydroxyketones and other easily oxidized compounds are subject to oxidation by these reagents.