Alkylation

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Alkylation 

 

Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion or a carbene (or their equivalents). An alkyl group is a piece of a molecule with the general formula C_nH_2n+1, where n is the integer depicting the number of carbons linked together. For example, a methyl group (n = 1, CH₃) is a fragment of a methane molecule (CH₄). Alkylating agents use selective alkylation by adding the desired aliphatic carbon chain to the previously chosen starting molecule. This is one of many known chemical syntheses. Alkyl groups can also be removed in a process known as dealkylation. Alkylating agents are often classified according to their nucleophilic or electrophilic character.

In oil refining contexts, alkylation refers to a particular alkylation of isobutane with olefins. For upgrading of petroleum, alkylation produces a premium blending stock for gasoline.

In medicine, alkylation of DNA is used in chemotherapy to damage the DNA of cancer cells. Alkylation is accomplished with the class of drugs called alkylating antineoplastic agents.

Typical route for alkylation of benzene with ethylene and ZSM-5 as a heterogeneous catalyst

Nucleophilic alkylating agents

Nucleophilic alkylating agents deliver the equivalent of an alkyl anion (carbanion). The formal "alkyl anion" attacks an electrophile, forming a new covalent bond between the alkyl group and the electrophile. The counterion, which is a cation such as lithium, can be removed and washed away in the work-up. Examples include the use of organometallic compounds such as Grignard (organomagnesium), organolithium, organocopper, and organosodium reagents. These compounds typically can add to an electron-deficient carbon atom such as at a carbonyl group. Nucleophilic alkylating agents can displace halide substituents on a carbon atom through the SN2 mechanism. With a catalyst, they also alkylate alkyl and aryl halides, as exemplified by Suzuki couplings. 

The Kumada coupling employs both a nucleophilic alkylation step subsequent to the oxidative addition of the aryl halide (L = Ligand, Ar = Aryl).

 

The SN2 mechanism is not available for aryl substituents, where the trajectory to attack the carbon atom would be inside the ring. Thus only reactions catalyzed by organometallic catalysts are possible.

Electrophilic alkylating agents

C-alkylation

C-alkylation is a process for the formation of carbon-carbon bonds. For alkylation at carbon, the electrophilicity of alkyl halides is enhanced by the presence of a Lewis acid such as aluminium trichloride. Lewis acids are particularly suited for C-alkylation. C-alkylation can also be effected by alkenes in the presence of acids.

N-and P-alkylation

N- and P-alkylation are important processes for the formation of carbon-nitrogen and carbon-phosphorus bonds. 

Amines are readily alkylated. The rate of alkylation follows the order tertiary amine < secondary amine < primary amine. Typical alkylating agents are alkyl halides. Industry often relies on green chemistry methods involving alkylation of amines with alcohols, the byproduct being water. Hydroamination is another green method for N-alkylation.

In the Menshutkin reaction, a tertiary amine is converted into a quaternary ammonium salt by reaction with an alkyl halide. Similar reactions occur when tertiary phosphines are treated with alkyl halides, the products being phosphonium salts.

S-alkylation

Thiols are readily alkylated to give thioethers. The reaction is typically conducted in the presence of a base or using the conjugate base of the thiol. Thioethers undergo alkylation to give sulfonium ions.

O-alkylation

Alcohols alkylate to give ethers:

ROH + R'X → ROR'

When the alkylating agent is an alkyl halide, the conversion is called the Williamson ether synthesis. Alcohols are also good alkylating agents in the presence of suitable acid catalysts. For example, most methyl amines are prepared by alkylation of ammonia with methanol. The alkylation of phenols is particularly straightforward since it is subject to fewer competing reactions.

${\displaystyle \mathrm {Ph{-}O^{-}\ +\ Me_{2}{-}SO_{4}\ \longrightarrow \ Ph{-}O{-}Me\ +\ Me{-}SO_{4}^{-}} }$

More complex alkylation of a alcohols and phenols involve ethoxylation. Ethylene oxide is the alkylating group in this reaction.

Oxidative addition to metals

In the process called oxidative addition, low-valent metals often react with alkylating agents to give metal alkyls. This reaction is one step in the Cativa process for the synthesis of acetic acid from methyl iodide. Many cross coupling reactions proceed via oxidative addition as well.

Electrophilic alkylating agents

Electrophilic alkylating agents deliver the equivalent of an alkyl cation. Alkyl halides are typical alkylating agents. Trimethyloxonium tetrafluoroborate and triethyloxonium tetrafluoroborate are particularly strong electrophiles due to their overt positive charge and an inert leaving group (dimethyl or diethyl ether). Dimethyl sulfate is intermediate in electrophilicity. 

Triethyloxonium tetrafluoroborate is one of the most electrophilic alkylating agents.

Hazards

Electrophilic, soluble alkylating agents are often toxic and carcinogenic, due to their tendency to alkylate DNA. This mechanism of toxicity is relevant to the function of anti-cancer drugs in the form of alkylating antineoplastic agents. Some chemical weapons such as mustard gas function as alkylating agents. Alkylated DNA either does not coil or uncoil properly, or cannot be processed by information-decoding enzymes.

Catalysts

Friedel-Crafts alkylation of benzene is often catalyzed by aluminium trichloride.

 

Electrophilic alkylations use Lewis acids and Brønsted acids, sometimes both. Classically, Lewis acids, e.g., aluminium trichloride, are employed when the alkyl halide are used. Brønsted acids are used when alkylating with olefins. Typical catalysts are zeolites, i.e. solid acid catalysts, and sulfuric acid. Silicotungstic acid is used to manufacture ethyl acetate by the alkylation of acetic acid by ethylene:

C₂H₄ + CH₃CO₂H → CH₃CO₂C₂H₅

In biology

Methylation is the most common type of alkylation. Methylation in nature is often effected by vitamin B12- and radical-SAM-based enzymes.

The SN2-like methyl transfer reaction in DNA methylation. Only the SAM cofactor and cytosine base are shown for simplicity.

In methanogenesis, coenzyme M is methylated by tetrahydromethanopterin.

Commodity chemicals

Several commodity chemicals are produced by alkylation. Included are several fundamental benzene-based feedstocks such as ethylbenzene (precursor to styrene), cumene (precursor to phenol and acetone), linear alkylbenzene sulfonates (for detergents).

Sodium dodecylbenzene, obtained by alkylation of benzene with dodecene, is a precursor to linear alkylbenzene sulfonate detergents.

Oil refining

Typical acid-catalyzed route to 2,4-dimethylpentane.

 

In a conventional oil refinery, isobutane is alkylated with low-molecular-weight alkenes (primarily a mixture of propene and butene) in the presence of a Brønsted acid catalyst, which can include solid acids (zeolites). The catalyst protonates the alkenes (propene, butene) to produce carbocations, which alkylate isobutane. The product, called "alkylate", is composed of a mixture of high-octane, branched-chain paraffinic hydrocarbons (mostly isoheptane and isooctane). Alkylate is a premium gasoline blending stock because it has exceptional antiknock properties and is clean burning. Alkylate is also a key component of avgas. By combining fluid catalytic cracking, polymerization, and alkylation refineries can obtain a gasoline yield of 70 percent. The widespread use of sulfuric acid and hydrofluoric acid in refineries poses significant environmental risks.

Epoxide

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Epoxide 

 

 

 A generic epoxide.

An epoxide is a cyclic ether with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for many applications. In general, low molecular weight epoxides are colourless and nonpolar, and often volatile.

Nomenclature

A compound containing the epoxide functional group can be called an epoxy, epoxide, oxirane, and ethoxyline. Simple epoxides are often referred to as oxides. Thus, the epoxide of ethylene (C₂H₄) is ethylene oxide (C₂H₄O). Many compounds have trivial names; for instance, ethylene oxide is called "oxirane". Some names emphasize the presence of the epoxide functional group, as in the compound 1,2-epoxyheptane, which can also be called 1,2-heptene oxide.

A polymer formed from epoxide precursors is called an epoxy, but such materials do not contain epoxide groups (or contain only a few residual epoxy groups that remain unreacted in the formation of the resin).

Synthesis

The dominant epoxides industrially are ethylene oxide and propylene oxide, which are produced respectively on the scales of approximately 15 and 3 million tonnes/year.

Heterogeneously catalyzed oxidation of alkenes

The epoxidation of ethylene involves its reaction of oxygen according to the following stoichiometry:

7 H₂C=CH₂ + 6 O₂ → 6 C₂H₄O + 2 CO₂ + 2 H₂O

The direct reaction of oxygen with alkenes is useful only for this epoxide. Modified heterogeneous silver catalysts are typically employed. Other alkenes fail to react usefully, even propylene, though TS-1 supported Au catalysts can perform propylene epoxidation selectively.

Olefin oxidation using organic peroxides and metal catalysts

Aside from ethylene oxide, most epoxides are generated by treating alkenes with peroxide-containing reagents, which donate a single oxygen atom. Safety considerations weigh on these reactions because organic peroxides are prone to spontaneous decomposition or even combustion.

Metal complexes are useful catalysts for epoxidations involving hydrogen peroxide and alkyl hydroperoxides. Peroxycarboxylic acids, which are more electrophilic, convert alkenes to epoxides without the intervention of metal catalysts. In specialized applications, other peroxide-containing reagents are employed, such as dimethyldioxirane. Depending on the mechanism of the reaction and the geometry of the alkene starting material, cis and/or trans epoxide diastereomers may be formed. In addition, if there are other stereocenters present in the starting material, they can influence the stereochemistry of the epoxidation. Metal-catalyzed epoxidations were first explored using tert-butyl hydroperoxide (TBHP). Association of TBHP with the metal (M) generates the active metal peroxy complex containing the MOOR group, which then transfers an O center to the alkene.

Simplified mechanism for metal-catalyzed epoxidation of alkenes with peroxide (ROOH) reagents.

Organic peroxides are used for the production of propylene oxide from propylene. Catalysts are required as well. Both t-butyl hydroperoxide and ethylbenzene hydroperoxide can be used as oxygen sources.

Olefin peroxidation using peroxycarboxylic acids

More typically for laboratory operations, the Prilezhaev reaction is employed. This approach involves the oxidation of the alkene with a peroxyacid such as m-CPBA. Illustrative is the epoxidation of styrene with perbenzoic acid to styrene oxide:

The reaction proceeds via what is commonly known as the "Butterfly Mechanism". The peroxide is viewed as an electrophile, and the alkene a nucleophile. The reaction is considered to be concerted (the numbers in the mechanism below are for simplification). The butterfly mechanism allows ideal positioning of the O-O sigma star orbital for C-C Pi electrons to attack. Because two bonds are broken and formed to the epoxide oxygen, this is formally an example of a coarctate transition state.

Hydroperoxides are also employed in catalytic enantioselective epoxidations, such as the Sharpless epoxidation and the Jacobsen epoxidation. Together with the Shi epoxidation, these reactions are useful for the enantioselective synthesis of chiral epoxides. Oxaziridine reagents may also be used to generate epoxides from alkenes.

Homogeneously catalysed asymmetric epoxidations

Arene oxides are intermediates in the oxidation of arenes by cytochrome P450. For prochiral arenes (naphthalene, toluene, benzoates, benzopyrene), the epoxides are often obtained in high enantioselectivity.

Chiral epoxides can often be derived enantioselectively from prochiral alkenes. Many metal complexes give active catalysts, but the most important involve titanium, vanadium, and molybdenum.

The Sharpless epoxidation.

The Sharpless epoxidation reaction is one of the premier enantioselective chemical reactions. It is used to prepare 2,3-epoxyalcohols from primary and secondary allylic alcohols.

Epichlorohydrin, is prepared by the chlorohydrin method. It is a precursor in the production of epoxy resins.

Intramolecular S_N2 substitution

This method involves dehydrohalogenation. It is a variant of the Williamson ether synthesis. In this case, an alkoxide ion intramolecularly displaces chloride. The precursor compounds are called halohydrins and can be generated through halohydration of an alkene.  Starting with propylene chlorohydrin, most of the world's supply of propylene oxide arises via this route.

An intramolecular epoxide formation reaction is one of the key steps in the Darzens reaction. 

In the Johnson–Corey–Chaykovsky reaction epoxides are generated from carbonyl groups and sulfonium ylides. In this reaction, a sulfonium is the leaving group instead of chloride.

Nucleophilic epoxidation

Electron-deficient olefins, such as enones and acryl derivatives can be epoxidized using nucleophilic oxygen compounds such as peroxides. The reaction is a two-step mechanism. First the oxygen performs a nucleophilic conjugate addition to give a stabilized carbanion. This carbanion then attacks the same oxygen atom, displacing a leaving group from it, to close the epoxide ring.

Biosynthesis

Epoxides are uncommon in nature. They arise usually via oxygenation of alkenes by the action of cytochrome P450. (but see also the short-lived Epoxyeicosatrienoic acids which act as signalling molecules. and similar Epoxydocosapentaenoic acids, and Epoxyeicosatetraenoic acids.)

Reactions

Ring-opening reactions dominate the reactivity of epoxides.

Hydrolysis and addition of nucleophiles

Two pathways for the hydrolysis of an epoxide.

Alcohols, water, amines, thiols and many other reagents add to epoxides. This reaction is the basis of two commercial applications, the formation of epoxy glues and the production of glycols. Under acidic conditions, nucleophilic addition is affected by steric effects, as normally seen for S_N2 reactions, as well as the stability of emerging carbocation (as normally seen for S_N1 reactions). Hydrolysis of an epoxide in presence of an acid catalyst generates the glycol.

Polymerization and oligomerization

Polymerization of epoxides gives polyethers. For example ethylene oxide polymerizes to give polyethylene glycol, also known as polyethylene oxide. The reaction of an alcohol or a phenol with ethylene oxide, ethoxylation, is widely used to produce surfactants:

ROH + n C₂H₄O → R(OC₂H₄)_nOH

With anhydrides, epoxides give polyesters.

Deoxygenation

Epoxides can be deoxygenated using oxophilic reagents. This reaction can proceed with loss or retention of configuration. The combination of tungsten hexachloride and n-butyllithium gives the alkene.

Other reactions

• Reduction of an epoxide with lithium aluminium hydride or aluminium hydride produces the corresponding alcohol. This reduction process results from the nucleophilic addition of hydride (H⁻).
• Reductive cleavage of epoxides gives β-lithioalkoxides.
• Reduction with tungsten hexachloride and n-butyllithium generates the alkene
• Epoxides undergo ring expansion reactions, illustrated by the insertion of carbon dioxide to give cyclic carbonates.
• When treated with thiourea, epoxides convert to the episulfide, which are called thiiranes.

Uses

Illustrative epoxides

• 

  Bisphenol A diglycidyl ether is a component in common household "epoxy".
  
• 

  The chemical structure of the epoxide glycidol, a common chemical intermediate.
  
• 

  Epothilones are naturally occurring epoxides.
  
• 

  3,4-Epoxycyclohexylmethyl-3’,4’-epoxycyclohexane carboxylate, precursor to coatings.
  
• 

  Epoxidized linolein, a major component of epoxidized soybean oil (ESBO), a commercially important plasticizer.
  
• 

  Benzene oxide exists in equilibrium with the oxepin isomer.
  

Ethylene oxide is widely used to generate detergents and surfactants by ethoxylation. Its hydrolysis affords ethylene glycol. It is also used for sterilisation of medical instruments and materials.

The reaction of epoxides with amines is the basis for the formation of epoxy glues and structural materials. A typical amine-hardener is triethylenetetramine (TETA).

Safety

Epoxides are alkylating agents, making many of them highly toxic.

Vitamin K

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Vitamin_K

 

Vitamin K
Drug class
Vitamin K structures. MK-4 and MK-7 are both subtypes of K2.
Class identifiers
Use	Vitamin K deficiency, Warfarin overdose
ATC code	B02BA
Biological target	Gamma-glutamyl carboxylase
Clinical data
Drugs.com	Medical Encyclopedia
External links
MeSH	D014812

Vitamin K is a group of structurally similar, fat-soluble vitamins found in foods and in dietary supplements. The human body requires vitamin K for complete synthesis of certain proteins that are needed for blood coagulation (K from koagulation, Danish for "coagulation") or for controlling binding of calcium in bones and other tissues. The vitamin K–related modification of the proteins allows them to bind calcium ions, which they cannot do otherwise. Without vitamin K, blood coagulation is seriously impaired, and uncontrolled bleeding occurs. Preliminary clinical research indicates that deficiency of vitamin K may weaken bones, potentially leading to osteoporosis, and may promote calcification of arteries and other soft tissues.

Chemically, the vitamin K family comprises 2-methyl-1,4-naphthoquinone (3-) derivatives. Vitamin K includes two natural vitamers: vitamin K₁ and vitamin K₂. Vitamin K₂, in turn, consists of a number of related chemical subtypes, with differing lengths of carbon side chains made of isoprenoid groups of atoms.

Vitamin K₁, also known as phylloquinone, is made by plants, and is found in highest amounts in green leafy vegetables because it is directly involved in photosynthesis. It may be thought of as the plant form of vitamin K. It is active as a vitamin in animals and performs the classic functions of vitamin K, including its activity in the production of blood-clotting proteins. Animals may also convert it to vitamin K₂.

Bacteria in the gut flora can also convert K₁ into vitamin K₂ (menaquinone). In addition, bacteria typically lengthen the isoprenoid side chain of vitamin K₂ to produce a range of vitamin K₂ forms, most notably the MK-7 to MK-11 homologues of vitamin K₂. All forms of K₂ other than MK-4 can only be produced by bacteria, which use these during anaerobic respiration. The MK-7 and other bacterially derived forms of vitamin K₂ exhibit vitamin K activity in animals, but MK-7's extra utility over MK-4, if any, is unclear and is a matter of investigation.

Because a synthetic form of vitamin K, vitamin K₃ (menadione), may be toxic by interfering with the function of glutathione, it is no longer used to treat vitamin K deficiency.

Medical uses

Warfarin overdose and coumarin poisoning

Vitamin K is one of the treatments for bleeding events caused by overdose of the anticoagulant drug warfarin (Coumadin®). It can be administered by mouth, intravenously, or subcutaneously. Vitamin K is also used in situations when a patient's INR is greater than 10 and there is no active bleeding.

Vitamin K is also part of the suggested treatment regime for poisoning by rodenticide (coumarin poisoning).^[6] Vitamin K treatment may only be necessary in people who deliberately have consumed large amounts of rodenticide or have consumed an unknown amount of rodenticide. Patients are given oral vitamin K₁ to prevent the negative effects of rodenticide poisoning, and this dosing must sometimes be continued for up to nine months in cases of poisoning by "superwarfarin" rodenticides such as brodifacoum. Oral Vitamin K₁ is preferred over other vitamin K₁ routes of administration because it has less side effects.

Vitamin K deficiency bleeding in newborns

Vitamin K is given as an injection to newborns to prevent vitamin K deficiency bleeding. The blood clotting factors of newborn babies are roughly 30–60% that of adult values; this may be due to the reduced synthesis of precursor proteins and the sterility of their guts. Human milk contains 1–4 μg/L of vitamin K₁, while formula-derived milk can contain up to 100 μg/L in supplemented formulas. Vitamin K₂ concentrations in human milk appear to be much lower than those of vitamin K₁. Occurrence of vitamin K deficiency bleeding in the first week of the infant's life is estimated at 0.25–1.7%, with a prevalence of 2–10 cases per 100,000 births. Premature babies have even lower levels of the vitamin, so they are at a higher risk from this deficiency.

Bleeding in infants due to vitamin K deficiency can be severe, leading to hospitalization, blood transfusions, brain damage, and death. Supplementation can prevent most cases of vitamin K deficiency bleeding in the newborn. Intramuscular injection, typically given shortly after birth, is more effective in preventing late vitamin K deficiency bleeding than oral administration.

Osteoporosis

There is no good evidence that vitamin K supplementation benefits the bone health of postmenopausal women.

Cardiovascular health

Adequate intake of vitamin K is associated with the inhibition of arterial calcification and stiffening, but there have been few interventional studies and no good evidence that vitamin K supplementation is of any benefit in the primary prevention of cardiovascular disease.

One 10-year population study, the Rotterdam Study, did show a clear and significant inverse relationship between the highest intake levels of menaquinone (mainly MK-4 from eggs and meat, and MK-8 and MK-9 from cheese) and cardiovascular disease and all-cause mortality in older men and women.

Cancer

Vitamin K has been promoted in supplement form with claims it can slow tumor growth; however, no good medical evidence supports such claims.

Side effects

Although allergic reaction from supplementation is possible, no known toxicity is associated with high doses of the phylloquinone (vitamin K₁) or menaquinone (vitamin K₂) forms of vitamin K, so no tolerable upper intake level (UL) has been set. Specifically vitamin K₁ has been associated with severe adverse reactions such as bronchospasm and cardiac arrest when given intravenously as opposed to orally.

Blood clotting (coagulation) studies in humans using 45 mg per day of vitamin K₂ (as MK-4) and even up to 135 mg per day (45 mg three times daily) of K₂ (as MK-4), showed no increase in blood clot risk. Even doses in rats as high as 250 mg/kg body weight did not alter the tendency for blood-clot formation to occur.

Unlike the safe natural forms of vitamin K₁ and vitamin K₂ and their various isomers, a synthetic form of vitamin K, vitamin K₃ (menadione), is demonstrably toxic at high levels. The U.S. FDA has banned this form from over-the-counter sale in the United States because large doses have been shown to cause allergic reactions, hemolytic anemia, and cytotoxicity in liver cells.

Interactions

Phylloquinone (K₁) or menaquinone (K₂) are capable of reversing the anticoagulant activity of the anticoagulant warfarin (tradename Coumadin). Warfarin works by blocking recycling of vitamin K, so that the body and tissues have lower levels of active vitamin K, and thus a deficiency of vitamin K.

Supplemental vitamin K (for which oral dosing is often more active than injectable dosing in human adults) reverses the vitamin K deficiency caused by warfarin, and therefore reduces the intended anticoagulant action of warfarin and related drugs. Sometimes small amounts of vitamin K are given orally to patients taking warfarin so that the action of the drug is more predictable. The proper anticoagulant action of the drug is a function of vitamin K intake and drug dose, and due to differing absorption must be individualized for each patient. The action of warfarin and vitamin K both require two to five days after dosing to have maximum effect, and neither warfarin nor vitamin K shows much effect in the first 24 hours after they are given.

The newer anticoagulants apixaban, dabigatran and rivaroxaban have different mechanisms of action that do not interact with vitamin K, and may be taken with supplemental vitamin K.

Chemistry

Vitamin K₂ (menaquinone). In menaquinone, the side chain is composed of a varying number of isoprenoid residues. The most common number of these residues is four, since animal enzymes normally produce menaquinone-4 from plant phylloquinone.

The structure of phylloquinone, Vitamin K₁, is marked by the presence of a phytyl group. The structures of menaquinones are marked by the polyisoprenyl side chain present in the molecule that can contain four to 13 isoprenyl units.

A sample of phytomenadione for injection, also called phylloquinone

The three synthetic forms of vitamin K are vitamins K₃ (menadione), K₄, and K₅, which are used in many areas, including the pet food industry (vitamin K₃) and to inhibit fungal growth (vitamin K₅).

Conversion of vitamin K₁ to vitamin K₂

Vitamin K₁ (phylloquinone) – both forms of the vitamin contain a functional naphthoquinone ring and an aliphatic side chain. Phylloquinone has a phytyl side chain.

The MK-4 form of vitamin K₂ is produced by conversion of vitamin K₁ in the testes, pancreas, and arterial walls. While major questions still surround the biochemical pathway for this transformation, the conversion is not dependent on gut bacteria, as it occurs in germ-free rats and in parenterally administered K₁ in rats. In fact, tissues that accumulate high amounts of MK-4 have a remarkable capacity to convert up to 90% of the available K₁ into MK-4. There is evidence that the conversion proceeds by removal of the phytyl tail of K₁ to produce menadione as an intermediate, which is then condensed with an activated geranylgeranyl moiety (see also prenylation) to produce vitamin K₂ in the MK-4 (menatetrenone) form.

Vitamin K₂

Vitamin K₂ (menaquinone) includes several subtypes. The two most studied ones are menaquinone-4 (menatetrenone, MK-4) and menaquinone-7 (MK-7).

Physiology

Vitamin K₁ (phylloquinone), the precursor of most vitamin K in nature, is an important chemical in green plants, where it functions as an electron acceptor in photosystem I during photosynthesis. For this reason, vitamin K₁ is found in large quantities in the photosynthetic tissues of plants (green leaves, and dark green leafy vegetables such as romaine lettuce, kale, and spinach), but it occurs in far smaller quantities in other plant tissues (roots, fruits, etc.). Iceberg lettuce contains relatively little. The function of phylloquinone in plants appears to have no resemblance to its later metabolic and biochemical function (as "vitamin K") in animals, where it performs a completely different biochemical reaction.

Vitamin K (in animals) is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate (Gla) residues. The modified residues are often (but not always) situated within specific protein domains called Gla domains. Gla residues are usually involved in binding calcium, and are essential for the biological activity of all known Gla proteins.

At this time, 17 human proteins with Gla domains have been discovered, and they play key roles in the regulation of three physiological processes:

• Blood coagulation: prothrombin (factor II), factors VII, IX, and X, and proteins C, S, and Z.
• Bone metabolism: osteocalcin, also called bone Gla protein (BGP), matrix Gla protein (MGP), periostin, and the recently discovered Gla-rich protein (GRP).
• Vascular biology: growth arrest-specific protein 6 (Gas6).
• Unknown function: proline-rich γ-carboxyglutamyl proteins (PRGPs) 1 and 2, and transmembrane γ-carboxy glutamyl proteins (TMGs) 3 and 4.

When Vitamin K₁ enters the body through foods in a person's diet, it is absorbed through the jejunum and ileum in the small intestine, and like other lipid-soluble vitamins (A, D, and E), vitamin K is stored in the fatty tissue of the human body.

Absorption and dietary need

Previous theory held that dietary deficiency is extremely rare unless the small intestine was heavily damaged, resulting in malabsorption of the molecule. Another at-risk group for deficiency were those subject to decreased production of K₂ by normal intestinal microbiota, as seen in broad-spectrum antibiotic use. Taking broad-spectrum antibiotics can reduce vitamin K production in the gut by nearly 74% in people compared with those not taking these antibiotics. Diets low in vitamin K also decrease the body's vitamin K concentration. Those with chronic kidney disease are at risk for vitamin K deficiency, as well as vitamin D deficiency, and particularly those with the apoE4 genotype. Additionally, the elderly have a reduction in vitamin K₂.

Dietary recommendations

The U.S. Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for vitamin K in 1998. The IOM does not distinguish between K₁ and K₂ – both are counted as vitamin K. At that time, sufficient information was not available to establish EARs and RDAs for vitamin K. In instances such as these, the board sets Adequate Intakes (AIs), with the understanding that at some later date, AIs will be replaced by more exact information. The current AIs for adult women and men ages 19 and up are 90 and 120 μg/day, respectively. AI for pregnancy is 90 μg/day. AI for lactation is 90 μg/day. For infants up to 12 months, the AI is 2.0–2.5 μg/day; for children ages 1–18 years the AI increases with age from 30 to 75 μg/day. As for safety, the IOM sets tolerable upper intake levels (known as ULs) for vitamins and minerals when evidence is sufficient. Vitamin K has no UL, as human data for adverse effects from high doses are inadequate. Collectively, the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes.

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in United States. For women and men over age 18 the AI is set at 70 μg/day. AI for pregnancy is 70 μg/day, ad for lactation 70 μg/day. For children ages 1–17 years, the AIs increase with age from 12 to 65 μg/day. These AIs are lower than the U.S. RDAs. The EFSA also reviewed the safety question and reached the same conclusion as in United States – that there was not sufficient evidence to set a UL for vitamin K.

For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percentage of Daily Value (%DV). For vitamin K labeling purposes, 100% of the Daily Value was 80 μg, but as of May 27, 2016, it was revised upwards to 120 μg, to bring it into agreement with the AI. A table of the old and new adult Daily Values is provided at Reference Daily Intake. The original deadline to be in compliance was July 28, 2018, but on September 29, 2017, the FDA released a proposed rule that extended the deadline to January 1, 2020 for large companies and January 1, 2021 for small companies.

Food sources

Vitamin K₁

Food	Serving size	Vitamin K1 (μg)		Food	Serving size	Vitamin K1 (μg)
Kale, cooked	1 cup	531		Parsley, raw	​1⁄4 cup	246
Spinach, cooked	​1⁄2 cup, 77g	444		Spinach, raw	1 cup	145
Collards, cooked	​1⁄2 cup	418		Collards, raw	1 cup	184
Swiss chard, cooked	​1⁄2 cup	287		Swiss chard, raw	1 cup	299
Mustard greens, cooked	​1⁄2 cup	210		Mustard greens, raw	1 cup	279
Turnip greens, cooked	​1⁄2 cup	265		Turnip greens, raw	1 cup	138
Broccoli, cooked	1 cup	220		Broccoli, raw	1 cup	89
Brussels sprouts, cooked	1 cup	219		Endive, raw	1 cup	116
Cabbage, cooked	​1⁄2 cup	82		Green leaf lettuce	1 cup	71
Dandelion, green leaves	100 gram	778.4 μg or 741% of daily dose.
Asparagus	4 spears	48
Romaine lettuce, raw	1 cup	57
Table from "Important information to know when you are taking: Warfarin (Coumadin) and Vitamin K", Clinical Center, National Institutes of Health Drug Nutrient Interaction Task Force.

Vitamin K₁ is found chiefly in leafy green vegetables such as spinach, swiss chard, lettuce and Brassica vegetables (such as cabbage, kale, cauliflower, broccoli, and brussels sprouts) and often the absorption is greater when accompanied by fats such as butter or oils. Some fruits, such as avocados, kiwifruit and grapes, also contain vitamin K. Some vegetable oils, notably soybean oil, contain vitamin K, but at levels that would require relatively large calorie consumption to meet the recommended amounts.

The tight binding of vitamin K₁ to thylakoid membranes in chloroplasts makes it less bioavailable. For example, cooked spinach has a 5% bioavailability of phylloquinone, however, fat added to it increases bioavailability to 13% due to the increased solubility of vitamin K in fat.

Vitamin K₂

Vitamin K₂ can be found in eggs, dairy, and meat, as well as fermented foods such as cheese and yogurt.

Deficiency

Average diets are usually not lacking in vitamin K, and primary deficiency is rare in healthy adults. Newborn infants are at an increased risk of deficiency. Other populations with an increased prevalence of vitamin K deficiency include those who suffer from liver damage or disease (e.g. alcoholics), cystic fibrosis, or inflammatory bowel diseases, or have recently had abdominal surgeries. Secondary vitamin K deficiency can occur in people with bulimia, those on stringent diets, and those taking anticoagulants. Other drugs associated with vitamin K deficiency include salicylates, barbiturates, and cefamandole, although the mechanisms are still unknown. Vitamin K deficiency has been defined as a vitamin K-responsive hypoprothrombinemia which increase prothrombin time and thus can result in coagulopathy, a bleeding disorder. Symptoms of K₁ deficiency include anemia, bruising, nosebleeds and bleeding of the gums in both sexes, and heavy menstrual bleeding in women. 

Osteoporosis and coronary heart disease are strongly associated with lower levels of K₂ (menaquinone). Vitamin K₂ (as menaquinones MK-4 through MK-10) intake level is inversely related to severe aortic calcification and all-cause mortality.

Biochemistry

Function in animals

Mechanism of action of vitamin K₁.

 

Vitamin K hydroquinone

 

Vitamin K epoxide

In both cases R represents the isoprenoid side chain

The function of vitamin K₂ in the animal cell is to add a carboxylic acid functional group to a glutamate (Glu) amino acid residue in a protein, to form a gamma-carboxyglutamate (Gla) residue. This is a somewhat uncommon posttranslational modification of the protein, which is then known as a "Gla protein". The presence of two −COOH (carboxylic acid) groups on the same carbon in the gamma-carboxyglutamate residue allows it to chelate calcium ions. The binding of calcium ions in this way very often triggers the function or binding of Gla-protein enzymes, such as the so-called vitamin K-dependent clotting factors discussed below.

Within the cell, vitamin K undergoes electron reduction to a reduced form called vitamin K hydroquinone, catalyzed by the enzyme vitamin K epoxide reductase (VKOR). Another enzyme then oxidizes vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called gamma-glutamyl carboxylase or the vitamin K-dependent carboxylase. The carboxylation reaction only proceeds if the carboxylase enzyme is able to oxidize vitamin K hydroquinone to vitamin K epoxide at the same time. The carboxylation and epoxidation reactions are said to be coupled. Vitamin K epoxide is then reconverted to vitamin K by VKOR. The reduction and subsequent reoxidation of vitamin K coupled with carboxylation of Glu is called the vitamin K cycle. Humans are rarely deficient in vitamin K₁ because, in part, vitamin K₁ is continuously recycled in cells.

Warfarin and other 4-hydroxycoumarins block the action of VKOR. This results in decreased concentrations of vitamin K and vitamin K hydroquinone in tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient. This results in the production of clotting factors with inadequate Gla. Without Gla on the amino termini of these factors, they no longer bind stably to the blood vessel endothelium and cannot activate clotting to allow formation of a clot during tissue injury. As it is impossible to predict what dose of warfarin will give the desired degree of clotting suppression, warfarin treatment must be carefully monitored to avoid overdose.

Gamma-carboxyglutamate proteins

The following human Gla-containing proteins ("Gla proteins") have been characterized to the level of primary structure: blood coagulation factors II (prothrombin), VII, IX, and X, anticoagulant protein C and protein S, and the factor X-targeting protein Z. The bone Gla protein osteocalcin, the calcification-inhibiting matrix Gla protein (MGP), the cell growth regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs), the function of which is at present unknown. Gas6 can function as a growth factor to activate the Axl receptor tyrosine kinase and stimulate cell proliferation or prevent apoptosis in some cells. In all cases in which their function was known, the presence of the Gla residues in these proteins turned out to be essential for functional activity.

Gla proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish. The venom of a number of Australian snakes acts by activating the human blood-clotting system. In some cases, activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting.

Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail Conus geographus. These snails produce a venom containing hundreds of neuroactive peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain two to five Gla residues.

Methods of assessment

Vitamin K status can be assessed by:

• The prothrombin time (PT) test measures the time required for blood to clot. A blood sample is mixed with citric acid and put in a fibrometer; delayed clot formation indicates a deficiency. This test is insensitive to mild deficiency, as the values do not change until the concentration of prothrombin in the blood has declined by at least 50%.
• Undercarboxylated prothrombin (PIVKA-II); in a study of 53 newborns, found "PT (prothrombin time) is a less sensitive marker than PIVKA II", and as indicated above, PT is unable to detect subclinical deficiencies that can be detected with PIVKA-II testing.
• Plasma phylloquinone was found to be positively correlated with phylloquinone intake in elderly British women, but not men, but an article by Schurgers et al. reported no correlation between responses in a food frequency questionnaire and plasma phylloquinone.
• Urinary γ-carboxyglutamic acid responds to changes in dietary vitamin K intake. Several days are required before any change can be observed. In a study by Booth et al., increases of phylloquinone intakes from 100 μg to between 377 and 417 μg for five days did not induce a significant change. Response may be age-specific.
• Undercarboxylated osteocalcin (UcOc) levels have been inversely correlated with stores of vitamin K and bone strength in developing rat tibiae. Another study following 78 post-menopausal Korean women found a supplement regimen of vitamins K and D, and calcium, but not a regimen of vitamin D and calcium, was inversely correlated with reduced UcOc levels.

Function in bacteria

Many bacteria, such as Escherichia coli found in the large intestine, can synthesize vitamin K₂ (menaquinone-7 or MK-7, up to MK-11), but not vitamin K₁ (phylloquinone). In these bacteria, menaquinone transfers two electrons between two different small molecules, during oxygen-independent metabolic energy production processes (anaerobic respiration). For example, a small molecule with an excess of electrons (also called an electron donor) such as lactate, formate, or NADH, with the help of an enzyme, passes two electrons to menaquinone. The menaquinone, with the help of another enzyme, then transfers these two electrons to a suitable oxidant, such fumarate or nitrate (also called an electron acceptor). Adding two electrons to fumarate or nitrate converts the molecule to succinate or nitrite plus water, respectively.

Some of these reactions generate a cellular energy source, ATP, in a manner similar to eukaryotic cell aerobic respiration, except the final electron acceptor is not molecular oxygen, but fumarate or nitrate. In aerobic respiration, the final oxidant is molecular oxygen (O₂), which accepts four electrons from an electron donor such as NADH to be converted to water. E. coli, as facultative anaerobes, can carry out both aerobic respiration and menaquinone-mediated anaerobic respiration.

History

In 1929, Danish scientist Henrik Dam investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet. He initially replicated experiments reported by scientists at the Ontario Agricultural College (OAC). McFarlane, Graham and Richardson, working on the chick feed program at OAC, had used chloroform to remove all fat from chick chow. They noticed that chicks fed only fat-depleted chow developed hemorrhages and started bleeding from tag sites. Dam found that these defects could not be restored by adding purified cholesterol to the diet. It appeared that – together with the cholesterol – a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin. Edward Adelbert Doisy of Saint Louis University did much of the research that led to the discovery of the structure and chemical nature of vitamin K. Dam and Doisy shared the 1943 Nobel Prize for medicine for their work on vitamin K (K₁ and K₂) published in 1939. Several laboratories synthesized the compound(s) in 1939.

For several decades, the vitamin K-deficient chick model was the only method of quantifying vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food. The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content. Three groups of physicians independently found this: Biochemical Institute, University of Copenhagen (Dam and Johannes Glavind), University of Iowa Department of Pathology (Emory Warner, Kenneth Brinkhous, and Harry Pratt Smith), and the Mayo Clinic (Hugh Butt, Albert Snell, and Arnold Osterberg).

The first published report of successful treatment with vitamin K of life-threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 by Smith, Warner, and Brinkhous.

The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al., Nelsestuen et al., and Magnusson et. al.) isolated the vitamin K-dependent coagulation factor prothrombin (factor II) from cows that received a high dose of a vitamin K antagonist, warfarin. It was shown that, while warfarin-treated cows had a form of prothrombin that contained 10 glutamate (Glu) amino acid residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues that were chemically identified as γ-carboxyglutamate (Gla). The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla.