Tetrahedral carbonyl addition compound
Encyclopedia
Tetrahedral intermediate is a reaction intermediate
in which the bond arrangement around an initially double-bonded carbon atom has been transformed from trigonal to tetrahedral. Tetrahedral intermediates result from nucleophilic addition
to a carbonyl
group. The stability of tetrahedral intermediate depends on the ability of the groups
attached to the new tetrahedral carbon atom to leave with the negative charge. Tetrahedral intermediates are very significant in organic syntheses and biological systems as a key intermediate in esterification
, transesterification
, ester hydrolysis, formation and hydrolysis of amides and peptides, hydride reductions, and other chemical reactions.
in 1887. In the reaction of benzyl benzoate
with sodium methoxide
, and methyl benzoate
with sodium benzyloxide, he observed a white precipitate which under acidic conditions yields benzyl benzoate, methyl benzoate, methanol, and benzyl alcohol. He named the likely common intermediate “aditionelle Verbidung.”
Victor Grignard
assumed the existence of unstable tetrahedral intermediate in 1901, while investigating the reaction of esters with organomagnesium reagents.
The first evidence for tetrahedral intermediates in the substitution reactions of carboxylic derivatives was provided by Myron L. Bender
in 1951. He labeled carboxylic acid derivatives with oxygen isotope O18 and reacted these derivatives with water to make labeled carboxylic acids. At the end of the reaction he found that the remaining starting material had a decreased proportion of labeled oxygen, which is consistent with the existence of the tetrahedral intermediate.
1) polycyclic structures (e.g.tetrodotoxin)
2) compounds with a strong electron-withdrawing group attached to the acyl carbon (e.g.N,N-dimethyltrifluoroacetamide)
3) compounds with donor groups that are poorly conjugated with the potential carbonyl group (e.g.cyclol)
4) compounds with sulfur atoms bonded to the anomeric centre (e.g.S-acylated-1,8-Naphtalenedithiol)
These compounds were used to study the kinetics of tetrahedral intermediate decomposition into its respective carbonyl species, and to measure the IR, UV, and NMR spectra of the tetrahedral adduct.
Some insight into the structure of tetrahedral intermediate can be obtained from the crystal structure of N-brosylmitomycin A, crystallized in 1967. The tetrahedral carbon C17 forms a 136.54pm bond with O3, which is shorter than C8-O3 bond (142.31pm). In contrast, C17-N2 bond (149.06pm) is longer than N1-C1 bond (148.75pm) and N1-C11 bond (147.85pm) due to donation of O3 lone pair into σ* orbital of C17-N2. This model however is forced into tetracyclic sceleton, and tetrahedral O3 is methylated which makes it a poor model overall.
The more recent x-ray crystal structure of 1-aza-3,5,7-trimethyladamantan-2-one is a good model for cationic tetrahedral intermediate. The C1-N1 bond is rather long [155.2(4)pm], and C1-O1(2) bonds are shortened [138.2(4)pm]. The protonated nitrogen atom N1 is a great amine leaving group.
Reaction intermediate
A reaction intermediate or an intermediate is a molecular entity that is formed from the reactants and reacts further to give the directly observed products of a chemical reaction. Most chemical reactions are stepwise, that is they take more than one elementary step to complete...
in which the bond arrangement around an initially double-bonded carbon atom has been transformed from trigonal to tetrahedral. Tetrahedral intermediates result from nucleophilic addition
Nucleophilic addition
In organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new covalent bonds by the addition of a nucleophile....
to a carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
group. The stability of tetrahedral intermediate depends on the ability of the groups
Leaving group
In chemistry, a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl−, Br−, and I−, and sulfonate esters, such as para-toluenesulfonate...
attached to the new tetrahedral carbon atom to leave with the negative charge. Tetrahedral intermediates are very significant in organic syntheses and biological systems as a key intermediate in esterification
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
, transesterification
Transesterification
In organic chemistry, transesterification is the process of exchanging the organic group R″ of an ester with the organic group R′ of an alcohol. These reactions are often catalyzed by the addition of an acid or base catalyst...
, ester hydrolysis, formation and hydrolysis of amides and peptides, hydride reductions, and other chemical reactions.
History
One of the earliest accounts of the tetrahedral intermediate came from Rainer Ludwig ClaisenRainer Ludwig Claisen
Rainer Ludwig Claisen was a famous German chemist best known for his work with condensations of carbonyls and sigmatropic rearrangements. He was born in Cologne as the son of a jurist and studied chemistry at the university of Bonn , where he became a member of K.St.V. Arminia...
in 1887. In the reaction of benzyl benzoate
Benzyl benzoate
Benzyl benzoate is the ester of benzyl alcohol and benzoic acid, with the formula C6H5CH2O2CC6H5. This easily prepared compound has a variety of uses.-Synthesis:This colorless liquid is formally the condensation product of benzoic acid and benzyl alcohol...
with sodium methoxide
Sodium methoxide
Sodium methoxide is a chemical compound, with formula CH3ONa. This colourless solid, which is formed by the deprotonation of methanol, is a widely used reagent in industry and the laboratory...
, and methyl benzoate
Methyl benzoate
Methyl benzoate is an ester with the chemical formula C6H5COOCH3. It is formed by the condensation of methanol and benzoic acid, in presence of a strong acid such as hydrochloric acid. It is a colorless liquid that is poorly soluble in water, but miscible with organic solvents.-Reactions:Methyl...
with sodium benzyloxide, he observed a white precipitate which under acidic conditions yields benzyl benzoate, methyl benzoate, methanol, and benzyl alcohol. He named the likely common intermediate “aditionelle Verbidung.”
Victor Grignard
Victor Grignard
François Auguste Victor Grignard was a Nobel Prize-winning French chemist.Grignard was the son of a sail maker. After studying mathematics at Lyon he transferred to chemistry and discovered the synthetic reaction bearing his name in 1900...
assumed the existence of unstable tetrahedral intermediate in 1901, while investigating the reaction of esters with organomagnesium reagents.
The first evidence for tetrahedral intermediates in the substitution reactions of carboxylic derivatives was provided by Myron L. Bender
Myron L. Bender
Myron Lee Bender was born in St. Louis, Missouri. He obtained his B.S. and his Ph.D. from Purdue University. The latter was under the direction of Henry B. Hass. After postdoctoral research under Paul D. Barlett , and Frank H. Westheimer , he spent one year as a faculty member at the...
in 1951. He labeled carboxylic acid derivatives with oxygen isotope O18 and reacted these derivatives with water to make labeled carboxylic acids. At the end of the reaction he found that the remaining starting material had a decreased proportion of labeled oxygen, which is consistent with the existence of the tetrahedral intermediate.
Reaction Mechanism
The nucleophilic attack on the carbonyl group proceeds via Bürgi-Dunitz trajectory. The angle between the line of nucleophilic attack and the C-O bond is greater than 90˚. This due to a better orbital overlap between the HOMO of the nucleophile and the π* LUMO of the C-O double bond.Early Investigations
Early studies of tetrahedral intermediates focused on compounds with four specific structural features:1) polycyclic structures (e.g.tetrodotoxin)
2) compounds with a strong electron-withdrawing group attached to the acyl carbon (e.g.N,N-dimethyltrifluoroacetamide)
3) compounds with donor groups that are poorly conjugated with the potential carbonyl group (e.g.cyclol)
4) compounds with sulfur atoms bonded to the anomeric centre (e.g.S-acylated-1,8-Naphtalenedithiol)
These compounds were used to study the kinetics of tetrahedral intermediate decomposition into its respective carbonyl species, and to measure the IR, UV, and NMR spectra of the tetrahedral adduct.
X-Ray Crystal Structure Determination
The first x-ray crystal structures of tetrahedral intermediates were obtained from the porcine trypsin crystallized with soybean tripsin inhibitor in 1974, and the bovine trypsin crystallized with bovine pancreatic trypsin inhibitor in 1973. In both cases the tetrahedral intermediate is stabilized in the active sites of enzymes, which have evolved to stabilize the transition state of peptide hydrolysis.Some insight into the structure of tetrahedral intermediate can be obtained from the crystal structure of N-brosylmitomycin A, crystallized in 1967. The tetrahedral carbon C17 forms a 136.54pm bond with O3, which is shorter than C8-O3 bond (142.31pm). In contrast, C17-N2 bond (149.06pm) is longer than N1-C1 bond (148.75pm) and N1-C11 bond (147.85pm) due to donation of O3 lone pair into σ* orbital of C17-N2. This model however is forced into tetracyclic sceleton, and tetrahedral O3 is methylated which makes it a poor model overall.
The more recent x-ray crystal structure of 1-aza-3,5,7-trimethyladamantan-2-one is a good model for cationic tetrahedral intermediate. The C1-N1 bond is rather long [155.2(4)pm], and C1-O1(2) bonds are shortened [138.2(4)pm]. The protonated nitrogen atom N1 is a great amine leaving group.