Oxocarbenium
Encyclopedia
An oxacarbenium ion is a canonical form of a carbocation
, real or hypothetical, which places a formal positive charge on an oxygen atom. They are common transition states for the hydrolysis of glycosidic bond
s, and are a commonly used strategy for chemical glycosylation
. These ions have since been proposed as transition states of a wide range of chemical transformations, and have been utilized in the total synthesis of several natural products. In addition, they commonly appear in mechanisms of enzyme-catalyzed biosynthesis and hydrolysis of carbohydrates in nature.
, the oxocarbenium ion is more polar, and more reactive with nucleophile
s. A common example of this is the activation of a ketone by the addition of a Lewis Acid
to the oxygen. An average dipole moment
for a general ketone R2CO is δ = 0.51. With the addition of an acidic hydrogen to the oxygen atom to produce [R2COH]+, the diople moment increases to δ = 0.61, making the oxocarbenium ion more susceptible to nucleophilic addition
than the ketone.
, which activates the ketone, making is a more effective electrophile. The Lewis acid can be a wide range of molecules, from a simple hydrogen atom to metal complexes. The remainder of this article will focus on alkly oxocarbenium ions, however, where the atom added to the oxygen is a carbon. One way that this sort of ion will form is the elimination
of an leaving group
. In carbohydrate chemistry, this leaving group is often an ether
or ester
. An alternative to elimination is direct deprotonation of the molecule to form the ion, however, this can be difficult and require strong bases to achieve.
involved in the reactions of five-membered rings was proposed by Woerpel in 1999. By looking at the C-glycosylation
of ribose
, they determined that the stereochemistry present at C3 was driving the stereochemistry of the allyl addition. This led them to the development of the envelope transition state model to explain these effects. A nucleophile favors addition from the "inside" of the envelope, or from the top of the figure on the right. The "inside" addition produces a results in a staggered conformation, rather than the eclipsed conformation that results from the "outside" addition. By determining the lowest energy conformation based on the substituents of the ring, one can assume an "inside" addition can correct the stereochemical outcome.
, with three carbons and the oxygen in a plane with the two other carbon atome puckered out of the plane, with one above and one below (see the figure to the right). Based on the substituients present on the ring, the lowest energy conformation is determined, keeping in mind steric and steroelectronic effects (see the section below for a discussion of stereoelectronic effects in oxocarbenium rings). Once this conformation is established, one can consider the nucleophilic addition. The addition will proceed through the low energy chair transition state, rather than the relatively high energy twist-boat. An example of this type of reaction can be seen below. The example also highlights how the stereoelectronic effect exerted by an electronegative substituent flips the lowest energy conformation and leads to opposite selectivity.
ring that does not containin an oxygen atom, an any large substituent prefers to be in an equatorial position, in order to minimize steric effects
. It has been observed in rings containing oxocarbenium ions that electronegative substituents prefer the axial
or pseudo-axial positions. When the electronegative atom is in the axial position, its electron density can be donated through space to the positively-charged oxygen atom in the ring. This electronic interaction stabilizes the axial conformation. Hydroxyl
groups, ethers and halogens are examples of substituents that exhibit this phenomenon. Stereoelectronic effects must be taken into consideration when determining the lowest energy conformation in the analysis for nucleophilic addition
to an oxocarbenium ion.
reactions. They are commonly employed as dienophiles in the Diels-Alder Reaction
. An electron withdrawing ketone is often added to the dienophile to increase the rate of the reaction, and these ketones are often converted to vinyl oxocarbenium ions during the reaction It is not clear that an oxocarbenium ion necessarily will form, but Roush and co-workers demonstrated the oxocarbenium intermediate in the cyclization shown below. Two products were observed in this reaction, which could only form if the oxocarbenium ring is present as an intermediate.. [4+3], [2+2], [3+2] and [5+2] cycloadditions with oxocarbenium intermediates have also been reported
addition reactions.. The oxocarbenium ion is used as an electrophile
in the reaction. When the methyl group increases in size, the diastereoselevtivity increases.
Another example is seen in the key step of the synthesis of (-)-Neopeltolide, which uses another six-membered oxocarbenium ring reduction for a diastereoselective hydride addition.
s. Since sugars are present in the structure of nucleic acids, with a ribose
sugar
present in RNA
and a deoxyribose
present in the structure of DNA
, their chemistry plays an important role in wide range of cellular functions of nucleic acids. In addition to their functions in nucleotides, sugars are also used for structural components of organisms, as energy storage molecules, cell signaling molecules, protein modification and play key roles in the immune system
, fertilization, preventing pathogenesis
, blood clotting, and development
.. The abundance of sugar chemistry in biological processes leads many reaction mechanisms to proceed through oxocarbenium ions. Several important biological reactions that utilize oxocarbenium ions are outlined in this section.
. An intermediate for this transformation can be seen below.
in animals, as well as in the breakdown of cellulose
by organisms that feed on plants. In general, aspartic or glutamic acid residues in the active site of the enzyme catalyze the hydrolysis of the glycosidic bond. The mechanism of these enzymes involves an oxocarbenium ion intermediate, a general example of which is shown below.
Carbocation
A carbocation is an ion with a positively-charged carbon atom. The charged carbon atom in a carbocation is a "sextet", i.e. it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability . Therefore carbocations are often reactive,...
, real or hypothetical, which places a formal positive charge on an oxygen atom. They are common transition states for the hydrolysis of glycosidic bond
Glycosidic bond
In chemistry, a glycosidic bond is a type of covalent bond that joins a carbohydrate molecule to another group, which may or may not be another carbohydrate....
s, and are a commonly used strategy for chemical glycosylation
Chemical glycosylation
A chemical glycosylation reaction involves the coupling of a sugar to a glycosyl acceptor forming a glycoside. If the acceptor is another sugar, the product is an oligosaccharide. The reaction involves coupling a glycosyl donor to a glycosyl acceptor via activation utilizing a suitable activator...
. These ions have since been proposed as transition states of a wide range of chemical transformations, and have been utilized in the total synthesis of several natural products. In addition, they commonly appear in mechanisms of enzyme-catalyzed biosynthesis and hydrolysis of carbohydrates in nature.
Structure
The general structure of an oxocarbenium ion contains an oxygen-carbon double-bond, with the oxygen atom attached to an additional group. The molecule has a formal positive charge, which is placed on the oxygen atom. Compared to a ketoneKetone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
, the oxocarbenium ion is more polar, and more reactive with nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
s. A common example of this is the activation of a ketone by the addition of a Lewis Acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...
to the oxygen. An average dipole moment
Dipole moment
Dipole moment can be defined as the product of magnitude of charge & distance of separation between the charges.Dipole moment may refer to:*Electric dipole moment, the measure of the electrical polarity of a system of charges...
for a general ketone R2CO is δ = 0.51. With the addition of an acidic hydrogen to the oxygen atom to produce [R2COH]+, the diople moment increases to δ = 0.61, making the oxocarbenium ion more susceptible to 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....
than the ketone.
Formation
Formation of oxocarbenium ions can proceed through several different pathways. Most commonly, the oxygen of a ketone will bind to a Lewis AcidLewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...
, which activates the ketone, making is a more effective electrophile. The Lewis acid can be a wide range of molecules, from a simple hydrogen atom to metal complexes. The remainder of this article will focus on alkly oxocarbenium ions, however, where the atom added to the oxygen is a carbon. One way that this sort of ion will form is the elimination
Elimination
- Science and medicine :*Elimination reaction, an organic reaction in which two functional groups split to form an organic product*Elimination, clearance of a drug or other foreign agent from the body...
of an leaving group
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...
. In carbohydrate chemistry, this leaving group is often an ether
Ether
Ethers are a class of organic compounds that contain an ether group — an oxygen atom connected to two alkyl or aryl groups — of general formula R–O–R'. A typical example is the solvent and anesthetic diethyl ether, commonly referred to simply as "ether"...
or ester
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...
. An alternative to elimination is direct deprotonation of the molecule to form the ion, however, this can be difficult and require strong bases to achieve.
5-Membered Rings
A model for predicting the stereochemistryStereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
involved in the reactions of five-membered rings was proposed by Woerpel in 1999. By looking at the C-glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
of ribose
Ribose
Ribose is an organic compound with the formula C5H10O5; specifically, a monosaccharide with linear form H––4–H, which has all the hydroxyl groups on the same side in the Fischer projection....
, they determined that the stereochemistry present at C3 was driving the stereochemistry of the allyl addition. This led them to the development of the envelope transition state model to explain these effects. A nucleophile favors addition from the "inside" of the envelope, or from the top of the figure on the right. The "inside" addition produces a results in a staggered conformation, rather than the eclipsed conformation that results from the "outside" addition. By determining the lowest energy conformation based on the substituents of the ring, one can assume an "inside" addition can correct the stereochemical outcome.
6-Membered Rings
The transition state model for a six-membered oxocarbenium ring was proposed earlier in 1992 by Woods et al. The general strategy for determining the stereochemistry of a nucleophilic addition to a six-membered ring follows a similar procedure to the case of the five-membered ring. The assumption that one makes for this analysis is that the ring is in the same conformation as cyclohexeneCyclohexene
Cyclohexene is a hydrocarbon with the formula C6H10. This cycloalkene is a colorless liquid with a sharp smell. It is an intermediate in various industrial processes...
, with three carbons and the oxygen in a plane with the two other carbon atome puckered out of the plane, with one above and one below (see the figure to the right). Based on the substituients present on the ring, the lowest energy conformation is determined, keeping in mind steric and steroelectronic effects (see the section below for a discussion of stereoelectronic effects in oxocarbenium rings). Once this conformation is established, one can consider the nucleophilic addition. The addition will proceed through the low energy chair transition state, rather than the relatively high energy twist-boat. An example of this type of reaction can be seen below. The example also highlights how the stereoelectronic effect exerted by an electronegative substituent flips the lowest energy conformation and leads to opposite selectivity.
Stereoelectronic Effects
In an alkeneAlkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...
ring that does not containin an oxygen atom, an any large substituent prefers to be in an equatorial position, in order to minimize steric effects
Steric effects
Steric effects arise from the fact that each atom within a molecule occupies a certain amount of space. If atoms are brought too close together, there is an associated cost in energy due to overlapping electron clouds , and this may affect the molecule's preferred shape and reactivity.-Steric...
. It has been observed in rings containing oxocarbenium ions that electronegative substituents prefer the axial
Axial
Axial may mean:* Along the same line as an axis of rotation in geometry* A type of modal frame in music* One of several anatomical directions in an animal body* Axial age, the period from 800 to 200 BC in China, India and the western world...
or pseudo-axial positions. When the electronegative atom is in the axial position, its electron density can be donated through space to the positively-charged oxygen atom in the ring. This electronic interaction stabilizes the axial conformation. Hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
groups, ethers and halogens are examples of substituents that exhibit this phenomenon. Stereoelectronic effects must be taken into consideration when determining the lowest energy conformation in the analysis for 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 an oxocarbenium ion.
Cycloadditions
In organic synthesis, vinyl oxocarbenium ions (structure on right) can be utilized in a wide range of cycloadditionCycloaddition
A cycloaddition is a pericyclic chemical reaction, in which "two or more unsaturated molecules combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity." The resulting reaction is a cyclization reaction.Cycloadditions are usually described by the...
reactions. They are commonly employed as dienophiles in the Diels-Alder Reaction
Diels-Alder reaction
The Diels–Alder reaction is an organic chemical reaction between a conjugated diene and a substituted alkene, commonly termed the dienophile, to form a substituted cyclohexene system. The reaction can proceed even if some of the atoms in the newly formed ring are not carbon...
. An electron withdrawing ketone is often added to the dienophile to increase the rate of the reaction, and these ketones are often converted to vinyl oxocarbenium ions during the reaction It is not clear that an oxocarbenium ion necessarily will form, but Roush and co-workers demonstrated the oxocarbenium intermediate in the cyclization shown below. Two products were observed in this reaction, which could only form if the oxocarbenium ring is present as an intermediate.. [4+3], [2+2], [3+2] and [5+2] cycloadditions with oxocarbenium intermediates have also been reported
Aldol Reaction
Chiral oxocarbenium ions have been exploited to carry out highly diastereoselective and enantioselective acetate aldoladdition reactions.. The oxocarbenium ion is used as an electrophile
Electrophile
In general electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile...
in the reaction. When the methyl group increases in size, the diastereoselevtivity increases.
Examples from Total Synthesis
Oxocarbenium ions have been utilized in total synthesis on several occasions. A major subunit of (+)-Clavosolide was synthesized with a reduction of a six-membered oxocarbenium ring. All the large substituents were found in an equatorial position, and the transformation went through the chair transition state, as predicted.Another example is seen in the key step of the synthesis of (-)-Neopeltolide, which uses another six-membered oxocarbenium ring reduction for a diastereoselective hydride addition.
Applications to Biology
In biological systems, oxocarbenium ions are mostly seen during reactions of carbohydrateCarbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
s. Since sugars are present in the structure of nucleic acids, with a ribose
Ribose
Ribose is an organic compound with the formula C5H10O5; specifically, a monosaccharide with linear form H––4–H, which has all the hydroxyl groups on the same side in the Fischer projection....
sugar
Sugar
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...
present in RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
and a deoxyribose
Deoxyribose
Deoxyribose, more, precisely 2-deoxyribose, is a monosaccharide with idealized formula H---3-H. Its name indicates that it is a deoxy sugar, meaning that it is derived from the sugar ribose by loss of an oxygen atom...
present in the structure of DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, their chemistry plays an important role in wide range of cellular functions of nucleic acids. In addition to their functions in nucleotides, sugars are also used for structural components of organisms, as energy storage molecules, cell signaling molecules, protein modification and play key roles in the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, fertilization, preventing pathogenesis
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
, blood clotting, and development
Developmental biology
Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...
.. The abundance of sugar chemistry in biological processes leads many reaction mechanisms to proceed through oxocarbenium ions. Several important biological reactions that utilize oxocarbenium ions are outlined in this section.
Nucleotide Biosynthesis
Nucleotides can undergo enzyme-catalyzed intramolecular cyclization in order to produce several important biological molecules. These cyclizations typically proceed through an oxocarbenium intermediate. An example of this reaction can be seen in the cyclization cyclic ADP ribose, which is an important molecule for intracellular calcium signalingCalcium signaling
Calcium is a common signaling mechanism, as once it enters the cytoplasm it exerts allosteric regulatory effects on many enzymes and proteins...
. An intermediate for this transformation can be seen below.
Glycosidases
A glycosidase is an enzyme that catalyzes the breakdown of a glycosidic linkage to produce two smaller sugars. This process has important implications in the utilization of stored energy, like glycogenGlycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
in animals, as well as in the breakdown of cellulose
Cellulose
Cellulose is an organic compound with the formula , a polysaccharide consisting of a linear chain of several hundred to over ten thousand β linked D-glucose units....
by organisms that feed on plants. In general, aspartic or glutamic acid residues in the active site of the enzyme catalyze the hydrolysis of the glycosidic bond. The mechanism of these enzymes involves an oxocarbenium ion intermediate, a general example of which is shown below.
See also
- CarbocationCarbocationA carbocation is an ion with a positively-charged carbon atom. The charged carbon atom in a carbocation is a "sextet", i.e. it has only six electrons in its outer valence shell instead of the eight valence electrons that ensures maximum stability . Therefore carbocations are often reactive,...
- Chemical glycosylationChemical glycosylationA chemical glycosylation reaction involves the coupling of a sugar to a glycosyl acceptor forming a glycoside. If the acceptor is another sugar, the product is an oligosaccharide. The reaction involves coupling a glycosyl donor to a glycosyl acceptor via activation utilizing a suitable activator...
- Glycosyl donorGlycosyl donorA glycosyl donor is a carbohydrate mono- or oligosaccharide that will react with a suitable glycosyl acceptor to form a new glycosidic bond. By convention, the donor is the member of this pair that contains the resulting anomeric carbon of the new glycosidic bond...
- Glycosidase
- Oxocarbon anionOxocarbon anionIn chemistry, an oxocarbon anion is a negative ion consisting solely of carbon and oxygen atoms, and therefore having the general formula CxOyn− for some integers x, y, and n....