Vitamin B12

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Vitamin B₁₂
(data for cyanocobalamin)

Clinical data
Synonyms	vitamin B12, vitamin B-12
AHFS/Drugs.com	Monograph
Routes of administration	by mouth, sublingual, IV, IM, intranasal
ATC code	B03BA01 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: OTC
Pharmacokinetic data
Bioavailability	Readily absorbed in distal half of the ileum
Protein binding	Very high to specific transcobalamins plasma proteins Binding of hydroxocobalamin is slightly higher than cyanocobalamin.
Metabolism	liver
Elimination half-life	Approximately 6 days (400 days in the liver)
Excretion	kidney
Identifiers
CAS Number	68-19-9
PubChem CID	5479203
DrugBank	DB00115
ChemSpider	10469504
KEGG	D00166
ChEMBL	ChEMBL2110563
Chemical and physical data
Formula	C63H88CoN14O14P
Molar mass	1355.388 g·mol−1

Vitamin B₁₂, also called cobalamin, is a water-soluble vitamin that is involved in the metabolism of every cell of the human body: it is a cofactor in DNA synthesis, and in both fatty acid and amino acid metabolism. It is particularly important in the normal functioning of the nervous system via its role in the synthesis of myelin, and in the maturation of developing red blood cells in the bone marrow.

Vitamin B₁₂ is one of eight B vitamins; it is the largest and most structurally complex vitamin. It consists of a class of chemically related compounds (vitamers), all of which show physiological activity. It contains the biochemically rare element cobalt (chemical symbol Co) positioned in the center of a corrin ring. The only organisms to produce vitamin B₁₂ are certain bacteria, and archaea. Some of these bacteria are found in the soil around the grasses that ruminants eat; they are taken into the animal, proliferate, form part of their gut flora, and continue to produce vitamin B₁₂.

Because there are no reliable vegetable sources of the vitamin, vegans must use a supplement or fortified foods for B₁₂ intake or risk serious health consequences. Otherwise, most omnivorous people in developed countries obtain enough vitamin B₁₂ from consuming animal products including meat, milk, eggs, and fish. Staple foods, especially those that form part of a vegan diet, are often fortified by having the vitamin added to them. Vitamin B₁₂ supplements are available in single agent or multivitamin tablets; and pharmaceutical preparations may be given by intramuscular injection.

The most common cause of vitamin B₁₂ deficiency in developed countries is impaired absorption due to a loss of gastric intrinsic factor, which must be bound to food-source B₁₂ in order for absorption to occur. Another group affected are those on long term antacid therapy, using proton pump inhibitors, H2 blockers or other antacids. This condition may be characterised by limb neuropathy or a blood disorder called pernicious anemia, a type of megaloblastic anemia. Folate levels in the individual may affect the course of pathological changes and symptomatology. Deficiency is more likely after age 60, and increases in incidence with advancing age. Dietary deficiency is very rare in developed countries due to access to dietary meat and fortified foods, but children in some regions of developing countries are at particular risk due to increased requirements during growth coupled with lack of access to dietary B₁₂; adults in these regions are also at risk. Other causes of vitamin B₁₂ deficiency are much less frequent.

Chemistry

Methylcobalamin (shown) is a form of vitamin B₁₂. Physically it resembles the other forms of vitamin B₁₂, occurring as dark red crystals that freely form cherry-colored transparent solutions in water.

 

B₁₂ is the most chemically complex of all the vitamins. The structure of B₁₂ is based on a corrin ring, which is similar to the porphyrin ring found in heme. The central metal ion is cobalt. Four of the six coordination sites are provided by the corrin ring, and a fifth by a dimethylbenzimidazole group. The sixth coordination site, the reactive center, is variable, being a cyano group (–CN), a hydroxyl group (–OH), a methyl group (–CH₃) or a 5′-deoxyadenosyl group (here the C5′ atom of the deoxyribose forms the covalent bond with cobalt respectively, to yield the four vitamers (forms) of B₁₂. Historically, the covalent C-Co bond is one of the first examples of carbon-metal bonds to be discovered in biology. The hydrogenases and, by necessity, enzymes associated with cobalt utilization, involve metal-carbon bonds.

Vitamin B₁₂ is a generic descriptor name referring to a collection of cobalt and corrin ring molecules which are defined by their particular vitamin function in the body. All of the substrate cobalt-corrin molecules from which B₁₂ is made must be synthesized by bacteria. After this synthesis is complete, the human body has the ability (except in rare cases) to convert any form of B₁₂ to an active form, by means of enzymatically removing certain prosthetic chemical groups from the cobalt atom and replacing them with others.

Vitamers

The four vitamers of B₁₂ are all deeply red-colored crystals and water solutions, due to the color of the cobalt-corrin complex.

• Cyanocobalamin is one form of B₁₂ because it can be metabolized in the body to an active coenzyme form. The cyanocobalamin form of B₁₂ does not occur in nature normally, but is a byproduct of the fact that other forms of B₁₂ are avid binders of cyanide (–CN) which they pick up in the process of activated charcoal purification of the vitamin after it is made by bacteria in the commercial process. Since the cyanocobalamin form of B₁₂ is easy to crystallize and is not sensitive to air-oxidation, it is typically used as a form of B₁₂ for food additives and in many common multivitamins. Pure cyanocobalamin possesses the deep pink color associated with most octahedral cobalt(II) complexes and the crystals are well formed and easily grown up to millimeter size.
• Hydroxocobalamin is another vitamer of B₁₂ commonly encountered in pharmacology, but is not normally present in the human body. Hydroxocobalamin is sometimes denoted B_12a. This is the form of B₁₂ produced by bacteria, and which is converted to cyanocobalmin in the commercial charcoal filtration step of production. Hydroxocobalamin has an avid affinity for cyanide ions and has been used as an antidote to cyanide poisoning. It is supplied typically in water solution for injection. Hydroxocobalamin is thought to be converted to the active enzymic forms of B₁₂ more easily than cyanocobalamin, and since it is little more expensive than cyanocobalamin, and has longer retention times in the body, has been used for vitamin replacement in situations where added reassurance of activity is desired. Intramuscular administration of hydroxocobalamin is also the preferred treatment for pediatric patients with intrinsic cobalamin metabolic diseases, for vitamin B₁₂ deficient patients with tobacco amblyopia (which is thought to perhaps have a component of cyanide poisoning from cyanide in cigarette smoke); and for treatment of patients with pernicious anemia who have optic neuropathy.
• Adenosylcobalamin (adoB₁₂) and methylcobalamin (MeB₁₂) are the two enzymatically active cofactor forms of B₁₂ that naturally occur in the body. Most of the body's reserves are stored as adoB₁₂ in the liver. These are converted to the other methylcobalamin form as needed.

Dietary recommendations

The U.S. Institute of Medicine (renamed National Academy of Medicine in 2015) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for vitamin B₁₂ in 1998. The EAR for vitamin B₁₂ for women and men ages 14 and up is 2.0 μg/day; the RDA is 2.4 μg/day. RDAs are higher than EARs so as to identify amounts that will cover people with higher than average requirements. RDA for pregnancy equals 2.6 μg/day. RDA for lactation equals 2.8 μg/day. For infants up to 12 months the Adequate Intake (AI) is 0.4–0.5 μg/day. (AIs are established when there is insufficient information to determine EARs and RDAs.) For children ages 1–13 years the RDA increases with age from 0.9 to 1.8 μg/day. Because 10 to 30 percent of older people may be unable to effectively absorb vitamin B₁₂ naturally occurring in foods, it is advisable for those older than 50 years to meet their RDA mainly by consuming foods fortified with vitamin B₁₂ or a supplement containing vitamin B₁₂. As for safety, Tolerable Upper Intake Levels (known as ULs) are set for vitamins and minerals when evidence is sufficient. In the case of vitamin B₁₂ there is no UL, as there is no human data for adverse effects from high doses. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).

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 defined the same as in United States. For women and men over age 18 the Adequate Intake (AI) is set at 4.0 μg/day. AI for pregnancy is 4.5 μg/day, for lactation 5.0 μg/day. For children aged 1–17 years the AIs increase with age from 1.5 to 3.5 μg/day. These AIs are higher 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 B₁₂.

For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For vitamin B₁₂ labeling purposes 100% of the Daily Value was 6.0 μg, but as of May 27, 2016 was revised downward to 2.4 μg. 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.

Sources

Most omnivorous people in developed countries obtain enough vitamin B₁₂ from consuming animal products including, meat, fish, eggs, and milk, but there are no vegan sources other than B₁₂-fortified foods or B₁₂ supplements.

Bacteria and archaea

B₁₂ is only produced in nature by certain bacteria, and archaea. It is synthesized by some bacteria in the gut flora in humans and other animals, but humans cannot absorb this as it is made in the colon, downstream from the small intestine, where the absorption of most nutrients occurs. Ruminants, such as cows and sheep, absorb B₁₂ produced by bacteria in their guts. For gut bacteria of ruminants to produce B₁₂ the animal must consume sufficient amounts of cobalt. These grazing animals acquire the bacteria that produce vitamin B₁₂, and the vitamin itself. 

Feces are a rich source of vitamin B₁₂, and are eaten by many animals, including dogs and cats. Lagomorpha species, including rabbits and hares, form fecal pellets in their cecum called cecotropes, which consist of chewed plant material that has been metabolized by cecal bacteria; cecotropes contain digestible carbohydrates and B vitamins synthesized by the resident bacteria. These animals ingest cecotropes which have been expelled in their feces.

Animals

Animals store vitamin B₁₂ in liver and muscle and some pass the vitamin into their eggs and milk; meat, liver, eggs and milk are therefore sources of the vitamin for other animals as well as humans. For humans, the bioavailability from eggs is less than 9%, compared to 40% to 60% from fish, fowl and meat. Insects are a source of B₁₂ for animals (including other insects and humans).

Food sources with a high concentration of vitamin B₁₂—50 to 99 µg B₁₂ per 100 grams of food—include clams; liver and other organ meats from lamb, veal, beef, and turkey; mackerel; and crab meat.

Plants and algae

Natural sources of B₁₂ include dried and fermented plant foods, such as tempeh, nori and laver, a seaweed. Many other types of algae are rich in vitamin B₁₂, with some species, such as Porphyra yezoensis, containing as much cobalamin as liver.

Fortified foods

The UK Vegan Society, the Vegetarian Resource Group, and the Physicians Committee for Responsible Medicine, among others, recommend that every vegan who is not consuming adequate B₁₂ from fortified foods take supplements.

Foods for which B₁₂-fortified versions are widely available include breakfast cereals, soy products, energy bars, and nutritional yeast.

Supplements

A blister pack of 500 µg methylcobalamin tablets

 

Vitamin B₁₂ is included in multivitamin pills; and in some countries grain-based foods such as bread and pasta are fortified with B₁₂. In the U.S. non-prescription products can be purchased providing up to 5,000 µg per serving, and it is a common ingredient in energy drinks and energy shots, usually at many times the recommended dietary allowance of B₁₂. The vitamin can also be a prescription product via injection or other means. Tablets have sufficiently large quantities of the vitamin such that 1% to 5% of the free crystalline B₁₂ is absorbed along the entire intestine by passive diffusion.

Sublingual methylcobalamin, which contains no cyanide, is available in 5-mg tablets. The metabolic fate and biological distribution of methylcobalamin are expected to be similar to that of other sources of vitamin B₁₂ in the diet., but the amount of cyanide in cyanocobalamin even in the largest available dose—20 µg of cyanide in a 1,000-µg cyanocobalamin tablet—is less than the daily consumption of cyanide from food, and so cyanocobalamin is not considered a health risk.

Parenteral administration

Injection and patches are sometimes used if digestive absorption is impaired, but this course of action may not be necessary with high-potency oral supplements (such as 0.5–1 mg or more). Even pernicious anemia can be treated entirely by the oral route.

If the person has inborn errors in the methyltransfer pathway (cobalamin C disease, combined methylmalonic aciduria and homocystinuria), treatment with intravenous, intramuscular hydroxocobalamin or transdermal B₁₂ is needed.

Pseudovitamin-B₁₂

Pseudovitamin-B₁₂ refers to B₁₂-like analogues that are biologically inactive in humans and yet found to be present alongside B₁₂ in humans, many food sources (including animals), and possibly supplements and fortified foods. Most cyanobacteria, including Spirulina, and some algae, such as dried Asakusa-nori (Porphyra tenera), have been found to contain mostly pseudovitamin-B₁₂ instead of biologically active B₁₂. In one common form of pseudo-B₁₂ available to Salmonella enterica serovar Typhimurium, the α-axial ligand is changed from dimethylbenzimidazole to adenine.

Biochemistry

Metabolism of folic acid. The role of Vitamin B₁₂ is seen at bottom-left.

Coenzyme function

Vitamin B₁₂ functions as a coenzyme, meaning that its presence is required for enzyme-catalyzed reactions. Three types of enzymes:

1. Isomerases

   Rearrangements in which a hydrogen atom is directly transferred between two adjacent atoms with concomitant exchange of the second substituent, X, which may be a carbon atom with substituents, an oxygen atom of an alcohol, or an amine. These use the adoB₁₂ (adenosylcobalamin) form of the vitamin.

2. Methyltransferases

   Methyl (–CH₃) group transfers between two molecules. These use MeB₁₂ (methylcobalamin) form of the vitamin.

3. Dehalogenases

   Reactions in which a halogen atom is removed from an organic molecule. Enzymes in this class have not been identified in humans.

In humans, two major coenzyme B₁₂-dependent enzyme families corresponding to the first two reaction types, are known. These are typified by the following two enzymes:

1. MUT is an isomerase which uses the AdoB₁₂ form and reaction type 1 to catalyze a carbon skeleton rearrangement (the X group is -COSCoA). MUT's reaction converts MMl-CoA to Su-CoA, an important step in the extraction of energy from proteins and fats. This functionality is lost in vitamin B₁₂ deficiency, and can be measured clinically as an increased methylmalonic acid (MMA) level. Unfortunately, an elevated MMA is a sensitive but not specific test, and not all who have it actually have B₁₂ deficiency. For example, MMA is elevated in 90–98% of patients with B₁₂ deficiency; 20–25% of patients over the age of 70 have elevated levels of MMA, yet 25–33% of them do not have B₁₂ deficiency. For this reason, assessment of MMA levels is not routinely recommended in the elderly. There is no "gold standard" test for B₁₂ deficiency because as a B₁₂ deficiency occurs, serum values may be maintained while tissue B₁₂ stores become depleted. Therefore, serum B₁₂ values above the cut-off point of deficiency do not necessarily indicate adequate B₁₂ status. The MUT function is necessary for proper myelin synthesis and is not affected by folate supplementation.
2. MTR, also known as methionine synthase, is a methyltransferase enzyme, which uses the MeB₁₂ and reaction type 2 to transfer a methyl group from 5-methyltetrahydrofolate to homocysteine, thereby generating tetrahydrofolate (THF) and methionine.^[52] This functionality is lost in vitamin B₁₂ deficiency, resulting in an increased homocysteine level and the trapping of folate as 5-methyl-tetrahydrofolate, from which THF (the active form of folate) cannot be recovered. THF plays an important role in DNA synthesis so reduced availability of THF results in ineffective production of cells with rapid turnover, in particular red blood cells, and also intestinal wall cells which are responsible for absorption. THF may be regenerated via MTR or may be obtained from fresh folate in the diet. Thus all of the DNA synthetic effects of B₁₂ deficiency, including the megaloblastic anemia of pernicious anemia, resolve if sufficient dietary folate is present. Thus the best-known "function" of B₁₂ (that which is involved with DNA synthesis, cell-division, and anemia) is actually a facultative function which is mediated by B₁₂-conservation of an active form of folate which is needed for efficient DNA production. Other cobalamin-requiring methyltransferase enzymes are also known in bacteria, such as Me-H₄-MPT, coenzyme M methyltransferase.

Enzyme function

If folate is present in quantity, then of the two absolutely vitamin B₁₂-dependent enzyme-family reactions in humans, the MUT-family reactions show the most direct and characteristic secondary effects, focusing on the nervous system (see below). This is because the MTR (methyltransferase-type) reactions are involved in regenerating folate, and thus are less evident when folate is in good supply. 

Since the late 1990s, folic acid has begun to be added to fortify flour in many countries, so folate deficiency is now more rare. At the same time, since DNA synthetic-sensitive tests for anemia and erythrocyte size are routinely done in even simple medical test clinics (so that these folate-mediated biochemical effects are more often directly detected), the MTR-dependent effects of B₁₂ deficiency are becoming apparent not as anemia due to DNA-synthetic problems (as they were classically), but now mainly as a simple and less obvious elevation of homocysteine in the blood and urine (homocysteinuria). This condition may result in long-term damage to arteries and in clotting (stroke and heart attack), but this effect is difficult to separate from other common processes associated with atherosclerosis and aging. 

The specific myelin damage resulting from B₁₂ deficiency, even in the presence of adequate folate and methionine, is more specifically and clearly a vitamin deficiency problem. It has been connected to B₁₂ most directly by reactions related to MUT, which is absolutely required to convert methylmalonyl coenzyme A into succinyl coenzyme A. Failure of this second reaction to occur results in elevated levels of MMA, a myelin destabilizer. Excessive MMA will prevent normal fatty acid synthesis, or it will be incorporated into fatty acids itself rather than normal malonic acid. If this abnormal fatty acid subsequently is incorporated into myelin, the resulting myelin will be too fragile, and demyelination will occur. Although the precise mechanism or mechanisms are not known with certainty, the result is subacute combined degeneration of spinal cord. Whatever the cause, it is known that B₁₂ deficiency causes neuropathies, even if folic acid is present in good supply, and therefore anemia is not present. 

Vitamin B₁₂-dependent MTR reactions may also have neurological effects, through an indirect mechanism. Adequate methionine (which, like folate, must otherwise be obtained in the diet, if it is not regenerated from homocysteine by a B₁₂ dependent reaction) is needed to make S-adenosyl methionine (SAMe), which is in turn necessary for methylation of myelin sheath phospholipids. Although production of SAMe is not B₁₂ dependent, help in recycling for provision of one adequate substrate for it (the essential amino acid methionine) is assisted by B₁₂. In addition, SAMe is involved in the manufacture of certain neurotransmitters, catecholamines and in brain metabolism. These neurotransmitters are important for maintaining mood, possibly explaining why depression is associated with B₁₂ deficiency. Methylation of the myelin sheath phospholipids may also depend on adequate folate, which in turn is dependent on MTR recycling, unless ingested in relatively high amounts.

Physiology

Absorption

Methyl-B₁₂ is absorbed by two processes. The first is an intestinal mechanism using intrinsic factor through which 1–2 micrograms can be absorbed every few hours. The second is a diffusion process by which approximately 1% of the remainder is absorbed. The human physiology of vitamin B₁₂ is complex, and therefore is prone to mishaps leading to vitamin B₁₂ deficiency. Protein-bound vitamin B₁₂ must be released from the proteins by the action of digestive proteases in both the stomach and small intestine. Gastric acid releases the vitamin from food particles; therefore antacid and acid-blocking medications (especially proton-pump inhibitors) may inhibit absorption of B₁₂. 

B₁₂ taken in a low-solubility, non-chewable supplement pill form may bypass the mouth and stomach and not mix with gastric acids, but acids are not necessary for the absorption of free B₁₂ not bound to protein; acid is necessary only to recover naturally-occurring vitamin B₁₂ from foods. 

R-protein (also known as haptocorrin and cobalophilin) is a B₁₂ binding protein that is produced in the salivary glands. It must wait to bind food-B₁₂ until B₁₂ has been freed from proteins in food by pepsin in the stomach. B₁₂ then binds to the R-protein to avoid degradation of it in the acidic environment of the stomach.

This pattern of B₁₂ transfer to a special binding protein secreted in a previous digestive step, is repeated once more before absorption. The next binding protein for B₁₂ is intrinsic factor (IF), a protein synthesized by gastric parietal cells that is secreted in response to histamine, gastrin and pentagastrin, as well as the presence of food. In the duodenum, proteases digest R-proteins and release their bound B₁₂, which then binds to IF, to form a complex (IF/B₁₂). B₁₂ must be attached to IF for it to be efficiently absorbed, as receptors on the enterocytes in the terminal ileum of the small bowel only recognize the B₁₂-IF complex; in addition, intrinsic factor protects the vitamin from catabolism by intestinal bacteria. 

Absorption of food vitamin B₁₂ thus requires an intact and functioning stomach, exocrine pancreas, intrinsic factor, and small bowel. Problems with any one of these organs makes a vitamin B₁₂ deficiency possible. Individuals who lack intrinsic factor have a decreased ability to absorb B₁₂. In pernicious anemia, there is a lack of IF due to autoimmune atrophic gastritis, in which antibodies form against parietal cells. Antibodies may alternately form against and bind to IF, inhibiting it from carrying out its B₁₂ protective function. Due to the complexity of B₁₂ absorption, geriatric patients, many of whom are hypoacidic due to reduced parietal cell function, have an increased risk of B₁₂ deficiency. This results in 80–100% excretion of oral doses in the feces versus 30–60% excretion in feces as seen in individuals with adequate IF.

Once the IF/B₁₂ complex is recognized by specialized ileal receptors, it is transported into the portal circulation. The vitamin is then transferred to transcobalamin II (TC-II/B₁₂), which serves as the plasma transporter. Hereditary defects in production of the transcobalamins and their receptors may produce functional deficiencies in B₁₂ and infantile megaloblastic anemia, and abnormal B₁₂ related biochemistry, even in some cases with normal blood B₁₂ levels. For the vitamin to serve inside cells, the TC-II/B₁₂ complex must bind to a cell receptor, and be endocytosed. The transcobalamin-II is degraded within a lysosome, and free B₁₂ is finally released into the cytoplasm, where it may be transformed into the proper coenzyme, by certain cellular enzymes (see above). 

Investigations into the intestinal absorption of B₁₂ point out that the upper limit of absorption per single oral dose, under normal conditions, is about 1.5 µg: "Studies in normal persons indicated that about 1.5 µg is assimilated when a single dose varying from 5 to 50 µg is administered by mouth. In a similar study Swendseid et al. stated that the average maximum absorption was 1.6 µg [...]" The bulk diffusion process of B₁₂ absorption noted in the first paragraph above, may overwhelm the complex R-factor and IGF-factor dependent absorption, when oral doses of B₁₂ are very large (a thousand or more µg per dose) as commonly happens in dedicated-pill oral B₁₂ supplementation. It is this last fact which allows pernicious anemia and certain other defects in B₁₂ absorption to be treated with oral megadoses of B₁₂, even without any correction of the underlying absorption defects. See the section on supplements above.

Storage and excretion

The total amount of vitamin B₁₂ stored in body is about 2–5 mg in adults. Around 50% of this is stored in the liver. Approximately 0.1% of this is lost per day by secretions into the gut, as not all these secretions are reabsorbed. Bile is the main form of B₁₂ excretion; most of the B₁₂ secreted in the bile is recycled via enterohepatic circulation. Excess B₁₂ beyond the blood's binding capacity is typically excreted in urine. Owing to the extremely efficient enterohepatic circulation of B₁₂, the liver can store 3 to 5 years’ worth of vitamin B₁₂; therefore, nutritional deficiency of this vitamin is rare. How fast B₁₂ levels change depends on the balance between how much B₁₂ is obtained from the diet, how much is secreted and how much is absorbed. B₁₂ deficiency may arise in a year if initial stores are low and genetic factors unfavourable, or may not appear for decades. In infants, B₁₂ deficiency can appear much more quickly.

Deficiency

Vitamin B₁₂ deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system. At levels only slightly lower than normal, a range of symptoms such as fatigue, lethargy, difficulty walking (staggering balance problems) depression, poor memory, breathlessness, headaches, and pale skin, among others, may be experienced, especially in elderly people (over age 60) who produce less stomach acid as they age, thereby increasing their probability of B₁₂ deficiencies. Vitamin B₁₂ deficiency can also cause symptoms of mania and psychosis.

Vitamin B₁₂ deficiency is most commonly caused by low intakes, but can also result from malabsorption, certain intestinal disorders, low presence of binding proteins, and use of certain medications. Vitamin B₁₂ is rare from plant sources, so vegetarians are more likely to suffer from vitamin B₁₂ deficiency. Infants are at a higher risk of vitamin B₁₂ deficiency if they were born to vegetarian mothers. The elderly who have diets with limited meat or animal products are vulnerable populations as well. Vitamin B₁₂ deficiency may occur in between 40% to 80% of the vegetarian population who are not also consuming a vitamin B₁₂ supplement. In Hong Kong and India, vitamin B₁₂ deficiency has been found in roughly 80% of the vegan population as well. Vegans can avoid this by eating B12 fortified foods like cereals, plant-based milks, and nutritional yeast as a regular part of their diet. In addition to worries concerning those following a vegetarian or vegan diet, research has found that approximately 39 percent of the general population may have possible B12 deficiencies or difficulty with the absorption of this nutrient. Taking a B12 supplement could be beneficial to most people.

B₁₂ is a co-substrate of various cell reactions involved in methylation synthesis of nucleic acid and neurotransmitters. Synthesis of the trimonoamine neurotransmitters can enhance the effects of a traditional antidepressant. The intracellular concentrations of vitamin B₁₂ can be inferred through the total plasma concentration of homocysteine, which can be converted to methionine through an enzymatic reaction that uses 5-methyltetrahydrofolate as the methyl donor group. Consequently, the plasma concentration of homocysteine falls as the intracellular concentration of vitamin B₁₂ rises. The active metabolite of vitamin B₁₂ is required for the methylation of homocysteine in the production of methionine, which is involved in a number of biochemical processes including the monoamine neurotransmitters metabolism. Thus, a deficiency in vitamin B₁₂ may impact the production and function of those neurotransmitters.

Medical uses

Photograph of a vitamin B₁₂ solution (hydroxycobalamin) in a multi-dose bottle, with a single dose drawn up into a syringe for injection. Preparations are usually bright red.

Repletion of deficiency

Severe vitamin B₁₂ deficiency is corrected with frequent intramuscular injections of large doses of the vitamin, followed by maintenance doses at longer intervals. Tablets are sometimes used for repletion in mild deficiency; and for maintenance regardless of severity. Vitamin B12 supplementation sometimes leads to acne development.

Cyanide poisoning

For cyanide poisoning, a large amount of hydroxocobalamin may be given intravenously and sometimes in combination with sodium thiosulfate. The mechanism of action is straightforward: the hydroxycobalamin hydroxide ligand is displaced by the toxic cyanide ion, and the resulting harmless B₁₂ complex is excreted in urine. In the United States, the Food and Drug Administration approved the use of hydroxocobalamin for acute treatment of cyanide poisoning.

Drug interactions

H₂-receptor antagonists and proton-pump inhibitors

Gastric acid is needed to release vitamin B₁₂ from protein for absorption. Reduced secretion of gastric acid and pepsin produced by H₂ blocker or proton-pump inhibitor (PPI) drugs can reduce absorption of protein-bound (dietary) vitamin B₁₂, although not of supplemental vitamin B₁₂. H₂-receptor antagonist examples include cimetidine, famotidine, nizatidine, and ranitidine. PPIs examples include omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. Clinically significant vitamin B₁₂ deficiency and megaloblastic anemia are unlikely, unless these drug therapies are prolonged for two or more years, or if in addition the person's diet is below recommended intakes. Symptomatic vitamin deficiency is more likely if the person is rendered achlorhydric (complete absence of gastric acid secretion), which occurs more frequently with proton pump inhibitors than H₂ blockers.

Metformin

Reduced serum levels of vitamin B₁₂ occur in up to 30% of people taking long-term anti-diabetic metformin. Deficiency does not develop if dietary intake of vitamin B₁₂ is adequate or prophylactic B₁₂ supplementation is given. If the deficiency is detected, metformin can be continued while the deficiency is corrected with B₁₂ supplements.

Industrial production

Industrial production of B₁₂ is achieved through fermentation of selected microorganisms. Streptomyces griseus, a bacterium once thought to be a fungus, was the commercial source of vitamin B₁₂ for many years. The species Pseudomonas denitrificans and Propionibacterium freudenreichii subsp. shermanii are more commonly used today. These are frequently grown under special conditions to enhance yield, and at least one company uses genetically engineered versions of one or both of these species. Since a number of species of Propionibacterium produce no exotoxins or endotoxins and are generally recognized as safe (have been granted GRAS status) by the Food and Drug Administration of the United States, they are presently the FDA-preferred bacterial fermentation organisms for vitamin B₁₂ production.

The total world production of vitamin B₁₂, by four companies (the French Sanofi-Aventis and three Chinese companies) in 2008 was 35 tonnes.

Laboratory synthesis

No eukaryotic organisms (including plants, animals, and fungi) are independently capable of constructing vitamin B₁₂. Only bacteria and archaea have the enzymes required for its biosynthesis. Like all tetrapyrroles, it is derived from uroporphyrinogen III. This porphyrinogen is methylated at two pyrrole rings to give dihydrosirohydrochlorin, which is oxidized to sirohydrochlorin, which undergoes further reactions, notably a ring contraction, to give the corrin ring. 

The complete laboratory synthesis of B₁₂ was achieved by Robert Burns Woodward and Albert Eschenmoser in 1972, and remains one of the classic feats of organic synthesis, requiring the effort of 91 postdoctoral fellows (mostly at Harvard) and 12 PhD students (at ETH Zurich) from 19 nations. The synthesis constitutes a formal total synthesis, since the research groups only prepared the known intermediate cobyric acid, whose chemical conversion to vitamin B₁₂ was previously reported. Though it constitutes an intellectual achievement of the highest caliber, the Eschenmoser–Woodward synthesis of vitamin B₁₂ is of no practical consequence due to its length, taking 72 chemical steps and giving an overall chemical yield well under 0.01%. And although there have been sporadic synthetic efforts since 1972, the Eschenmoser–Woodward synthesis remains the only completed (formal) total synthesis. Bacterial (or, perhaps archaeal) fermentation remains the only industrially viable source of the vitamin for food production and medicine. 

Species from the following genera and species are known to synthesize B₁₂: Propionibacterium shermanii, Pseudomonas denitrificans, Streptomyces griseus, Acetobacterium, Aerobacter, Agrobacterium, Alcaligenes, Azotobacter, Bacillus, Clostridium, Corynebacterium, Flavobacterium, Lactobacillus, Micromonospora, Mycobacterium, Nocardia, Protaminobacter, Proteus, Rhizobium, Salmonella, Serratia, Streptococcus and Xanthomonas.

History

• 1849 - Thomas Addison first described a case of pernicious anemia.
• 1877 - William Osler and William Gardner first described a case of neuropathy in this condition.
• 1878 - Hayem first described large red cells in the peripheral blood in this condition, which he called "giant blood corpuscles", now called macrocytes.
• 1880 - Paul Ehrlich first identified megaloblasts in the bone marrow in this condition.
• 1887 - Ludwig Lichtheim first described a case of myopathy in this condition.
• 1920 - George Whipple discovered that ingesting large amounts of liver seemed to most rapidly cure the anemia of blood loss in dogs, and hypothesized that eating liver might treat pernicious anemia.
• 1926 - George Minot shared the 1934 Nobel Prize with William Murphy and George Whipple, for discovery of an effective treatment for pernicious anemia using liver concentrate, later found to contain a large amount of vitamin B₁₂.
• 1928 - Edwin Cohn prepared a liver extract that was 50 to 100 times more potent in treating pernicious anema than the natural liver products. Whipple, Minot, and Murphy shared the 1934 Nobel Prize in Physiology or Medicine.
• 1929 - William Castle demonstrated that gastric juice contained an "intrinsic factor" which when combined with meat ingestion resulted in absorption of the vitamin in this condition.
• 1947 - Mary Shaw Shorb, in a collaborative project with Karl Folkers, was provided with a US$400 grant to develop the so-called "LLD assay" for B₁₂. LLD stood for Lactobacillus lactis Dorner, a strain of bacterium which required "LLD factor" for growth, which was eventually identified as B₁₂.
• 1948 - Shorb and colleagues Karl A. Folkers and Alexander R. Todd used the LLD assay to rapidly extract the anti-pernicious anemia factor from liver extracts, and pure B₁₂ was isolated.
• 1949 - Shorb and Folkers received the Mead Johnson Award from the American Society of Nutritional Sciences for their discovery.
• 1956 - The chemical structure of the molecule was determined by Dorothy Hodgkin, based on crystallographic data. She was awarded the 1964 Nobel Prize in Chemistry for determining the structure of vitamin B₁₂ and other complex molecules.
• 1959 - methods of producing the vitamin in large quantities from bacteria cultures were developed.
• 1981 - Observations of stereospecificity encountered by R. B. Woodward during the synthesis of vitamin B₁₂ led to the formulation of the principle of the conservation of orbital symmetry, which would result in a Nobel Prize in Chemistry by R. Hoffmann and K. Fukui.

Six Nobel Prizes have been awarded for direct and indirect studies of vitamin B₁₂.

Coordination complex (chemistry)

From Wikipedia, the free encyclopedia

Cisplatin, PtCl₂(NH₃)₂, is a coordination complex of platinum(II) with two chloride and two ammonia ligands. It is one of the most successful anticancer drugs.

In chemistry, a coordination complex consists of a central atom or ion, which is usually metallic and is called the coordination centre, and a surrounding array of bound molecules or ions, that are in turn known as ligands or complexing agents. Many metal-containing compounds, especially those of transition metals, are coordination complexes. A coordination complex whose centre is a metal atom is called a metal complex.

Nomenclature and terminology

Coordination complexes are so pervasive that their structures and reactions are described in many ways, sometimes confusingly. The atom within a ligand that is bonded to the central metal atom or ion is called the donor atom. In a typical complex, a metal ion is bonded to several donor atoms, which can be the same or different. A polydentate (multiple bonded) ligand is a molecule or ion that bonds to the central atom through several of the ligand's atoms; ligands with 2, 3, 4 or even 6 bonds to the central atom are common. These complexes are called chelate complexes; the formation of such complexes is called chelation, complexation, and coordination.

The central atom or ion, together with all ligands, comprise the coordination sphere. The central atoms or ion and the donor atoms comprise the first coordination sphere.

Coordination refers to the "coordinate covalent bonds" (dipolar bonds) between the ligands and the central atom. Originally, a complex implied a reversible association of molecules, atoms, or ions through such weak chemical bonds. As applied to coordination chemistry, this meaning has evolved. Some metal complexes are formed virtually irreversibly and many are bound together by bonds that are quite strong.

The number of donor atoms attached to the central atom or ion is called the coordination number. The most common coordination numbers are 2, 4, and especially 6. A hydrated ion is one kind of a complex ion (or simply a complex), a species formed between a central metal ion and one or more surrounding ligands, molecules or ions that contain at least one lone pair of electrons. 

If all the ligands are monodentate, then the number of donor atoms equals the number of ligands. For example, the cobalt(II) hexahydrate ion or the hexaaquacobalt(II) ion [Co(H₂O)₆]²⁺ is a hydrated-complex ion that consists of six water molecules attached to a metal ion Co. The oxidation state and the coordination number reflect the number of bonds formed between the metal ion and the ligands in the complex ion. However, the coordination number of Pt(en)²⁺
₂ is 4 (rather than 2) since it has two bidentate ligands, which contain four donor atoms in total. 

Any donor atom will give a pair of electrons. There are some donor atoms or groups which can offer more than one pair of electrons. Such are called bidentate (offers two pairs of electrons) or polydentate (offers more than two pairs of electrons). In some cases an atom or a group offers a pair of electrons to two similar or different central metal atoms or acceptors—by division of the electron pair—into a three-center two-electron bond. These are called bridging ligands.

History

Coordination complexes have been known since the beginning of modern chemistry. Early well-known coordination complexes include dyes such as Prussian blue. Their properties were first well understood in the late 1800s, following the 1869 work of Christian Wilhelm Blomstrand. Blomstrand developed what has come to be known as the complex ion chain theory. The theory claimed that the reason coordination complexes form is because in solution, ions would be bound via ammonia chains. He compared this effect to the way that various carbohydrate chains form. 

Alfred Werner

 

Following this theory, Danish scientist Sophus Mads Jørgensen made improvements to it. In his version of the theory, Jørgensen claimed that when a molecule dissociates in a solution there were two possible outcomes: the ions would bind via the ammonia chains Blomstrand had described or the ions would bind directly to the metal.

It was not until 1893 that the most widely accepted version of the theory today was published by Alfred Werner. Werner’s work included two important changes to the Blomstrand theory. The first was that Werner described the two different ion possibilities in terms of location in the coordination sphere. He claimed that if the ions were to form a chain this would occur outside of the coordination sphere while the ions that bound directly to the metal would do so within the coordination sphere. In one of Werner’s most important discoveries however he disproved the majority of the chain theory. Werner was able to discover the spatial arrangements of the ligands that were involved in the formation of the complex hexacoordinate cobalt. His theory allows one to understand the difference between a coordinated ligand and a charge balancing ion in a compound, for example the chloride ion in the cobaltammine chlorides and to explain many of the previously inexplicable isomers.

Structure of hexol

 

In 1914, Werner first resolved the coordination complex, called hexol, into optical isomers, overthrowing the theory that only carbon compounds could possess chirality.

Structures

The ions or molecules surrounding the central atom are called ligands. Ligands are generally bound to the central atom by a coordinate covalent bond (donating electrons from a lone electron pair into an empty metal orbital), and are said to be coordinated to the atom. There are also organic ligands such as alkenes whose pi bonds can coordinate to empty metal orbitals. An example is ethene in the complex known as Zeise's salt, K⁺[PtCl₃(C₂H₄)]⁻.

Geometry

In coordination chemistry, a structure is first described by its coordination number, the number of ligands attached to the metal (more specifically, the number of donor atoms). Usually one can count the ligands attached, but sometimes even the counting can become ambiguous. Coordination numbers are normally between two and nine, but large numbers of ligands are not uncommon for the lanthanides and actinides. The number of bonds depends on the size, charge, and electron configuration of the metal ion and the ligands. Metal ions may have more than one coordination number. 

Typically the chemistry of transition metal complexes is dominated by interactions between s and p molecular orbitals of the donor-atoms in the ligands and the d orbitals of the metal ions. The s, p, and d orbitals of the metal can accommodate 18 electrons. The maximum coordination number for a certain metal is thus related to the electronic configuration of the metal ion (to be more specific, the number of empty orbitals) and to the ratio of the size of the ligands and the metal ion. Large metals and small ligands lead to high coordination numbers, e.g. [Mo(CN)₈]⁴⁻. Small metals with large ligands lead to low coordination numbers, e.g. Pt[P(CMe₃)]₂. Due to their large size, lanthanides, actinides, and early transition metals tend to have high coordination numbers.

Different ligand structural arrangements result from the coordination number. Most structures follow the points-on-a-sphere pattern (or, as if the central atom were in the middle of a polyhedron where the corners of that shape are the locations of the ligands), where orbital overlap (between ligand and metal orbitals) and ligand-ligand repulsions tend to lead to certain regular geometries. The most observed geometries are listed below, but there are many cases that deviate from a regular geometry, e.g. due to the use of ligands of different types (which results in irregular bond lengths; the coordination atoms do not follow a points-on-a-sphere pattern), due to the size of ligands, or due to electronic effects:

• Linear for two-coordination
• Trigonal planar for three-coordination
• Tetrahedral or square planar for four-coordination
• Trigonal bipyramidal for five-coordination
• Octahedral for six-coordination
• Pentagonal bipyramidal for seven-coordination
• Square antiprismatic for eight-coordination
• Tricapped trigonal prismatic for nine-coordination

The idealized descriptions of 5-, 7-, 8-, and 9- coordination are often indistinct geometrically from alternative structures with slightly different L-M-L (ligand-metal-ligand) angles, e.g. the difference between square pyramidal and trigonal bipyramidal structures.

• Square pyramidal for five-coordination
• Capped octahedral or capped trigonal prismatic for seven-coordination
• Dodecahedral or bicapped trigonal prismatic for eight-coordination
• Capped square antiprismatic for nine-coordination

In systems with low d electron count, due to special electronic effects such as (second-order) Jahn–Teller stabilization, certain geometries (in which the coordination atoms do not follow a points-on-a-sphere pattern) are stabilized relative to the other possibilities, e.g. for some compounds the trigonal prismatic geometry is stabilized relative to octahedral structures for six-coordination.

• Bent for two-coordination
• Trigonal pyramidal for three-coordination
• Trigonal prismatic for six-coordination

Isomerism

The arrangement of the ligands is fixed for a given complex, but in some cases it is mutable by a reaction that forms another stable isomer. 

There exist many kinds of isomerism in coordination complexes, just as in many other compounds.

Stereoisomerism

Stereoisomerism occurs with the same bonds in different orientations relative to one another. Stereoisomerism can be further classified into:

Cis–trans isomerism and facial–meridional isomerism

Cis–trans isomerism occurs in octahedral and square planar complexes (but not tetrahedral). When two ligands are adjacent they are said to be cis, when opposite each other, trans. When three identical ligands occupy one face of an octahedron, the isomer is said to be facial, or fac. In a fac isomer, any two identical ligands are adjacent or cis to each other. If these three ligands and the metal ion are in one plane, the isomer is said to be meridional, or mer. A mer isomer can be considered as a combination of a trans and a cis, since it contains both trans and cis pairs of identical ligands.

• 

  cis-[CoCl₂(NH₃)₄]⁺
  
• 

  trans-[CoCl₂(NH₃)₄]⁺
  
• 

  fac-[CoCl₃(NH₃)₃]
  
• 

  mer-[CoCl₃(NH₃)₃]
  

Optical isomerism

Optical isomerism occurs when a molecule is not superimposable with its mirror image. It is so called because the two isomers are each optically active, that is, they rotate the plane of polarized light in opposite directions. The symbol Λ (lambda) is used as a prefix to describe the left-handed propeller twist formed by three bidentate ligands, as shown. Likewise, the symbol Δ (delta) is used as a prefix for the right-handed propeller twist.

• 

  Λ-[Fe(ox)₃]³⁻
  
• 

  Δ-[Fe(ox)₃]³⁻
  
• 

  Λ-cis-[CoCl₂(en)₂]⁺
  
• 

  Δ-cis-[CoCl₂(en)₂]⁺
  

Structural isomerism

Structural isomerism occurs when the bonds are themselves different. There are four types of structural isomerism: ionisation isomerism, solvate or hydrate isomerism, linkage isomerism and coordination isomerism.

1. Ionisation isomerism – the isomers give different ions in solution although they have the same composition. This type of isomerism occurs when the counter ion of the complex is also a potential ligand. For example, pentaamminebromocobalt(III) sulphate [Co(NH₃)₅Br]SO₄ is red violet and in solution gives a precipitate with barium chloride, confirming the presence of sulphate ion, while pentaamminesulphatecobalt(III) bromide [Co(NH₃)₅SO₄]Br is red and tests negative for sulphate ion in solution, but instead gives a precipitate of AgBr with silver nitrate.
2. Solvate or hydrate isomerism – the isomers have the same composition but differ with respect to the number of molecules of solvent that serve as ligand vs simply occupying sites in the crystal. Examples: [Cr(H₂O)₆]Cl₃ is violet colored, [CrCl(H₂O)₅]Cl₂·H₂O is blue-green, and [CrCl₂(H₂O)₄]Cl·2H₂O is dark green. See water of crystallization.
3. Linkage isomerism occurs with ambidentate ligands that can bind in more than one place. For example, NO₂ is an ambidentate ligand: It can bind to a metal at either the N atom or an O atom.
4. Coordination isomerism – this occurs when both positive and negative ions of a salt are complex ions and the two isomers differ in the distribution of ligands between the cation and the anion. For example, [Co(NH₃)₆][Cr(CN)₆] and [Cr(NH₃)₆][Co(CN)₆].

Electronic properties

Many of the properties of transition metal complexes are dictated by their electronic structures. The electronic structure can be described by a relatively ionic model that ascribes formal charges to the metals and ligands. This approach is the essence of crystal field theory (CFT). Crystal field theory, introduced by Hans Bethe in 1929, gives a quantum mechanically based attempt at understanding complexes. But crystal field theory treats all interactions in a complex as ionic and assumes that the ligands can be approximated by negative point charges. 

More sophisticated models embrace covalency, and this approach is described by ligand field theory (LFT) and Molecular orbital theory (MO). Ligand field theory, introduced in 1935 and built from molecular orbital theory, can handle a broader range of complexes and can explain complexes in which the interactions are covalent. The chemical applications of group theory can aid in the understanding of crystal or ligand field theory, by allowing simple, symmetry based solutions to the formal equations. 

Chemists tend to employ the simplest model required to predict the properties of interest; for this reason, CFT has been a favorite for the discussions when possible. MO and LF theories are more complicated, but provide a more realistic perspective. 

The electronic configuration of the complexes gives them some important properties:

Color of transition metal complexes

Synthesis of copper(II)-tetraphenylporphyrin, a metal complex, from tetraphenylporphyrin and copper(II) acetate monohydrate.

 

Transition metal complexes often have spectacular colors caused by electronic transitions by the absorption of light. For this reason they are often applied as pigments. Most transitions that are related to colored metal complexes are either d–d transitions or charge transfer bands. In a d–d transition, an electron in a d orbital on the metal is excited by a photon to another d orbital of higher energy, therefore d–d transitions occur only for partially-filled d-orbital complexes (d^1–9). For complexes having d⁰ or d¹⁰ configuration, charge transfer is still possible even though d–d transitions are not. A charge transfer band entails promotion of an electron from a metal-based orbital into an empty ligand-based orbital (metal-to-ligand charge transfer or MLCT). The converse also occurs: excitation of an electron in a ligand-based orbital into an empty metal-based orbital (ligand-to-metal charge transfer or LMCT). These phenomena can be observed with the aid of electronic spectroscopy; also known as UV-Vis. For simple compounds with high symmetry, the d–d transitions can be assigned using Tanabe–Sugano diagrams. These assignments are gaining increased support with computational chemistry.

Colors of lanthanide complexes

Superficially lanthanide complexes are similar to those of the transition metals in that some are coloured. However, for the common Ln³⁺ ions (Ln = lanthanide) the colors are all pale, and hardly influenced by the nature of the ligand. The colors are due to 4f electron transitions. As the 4f orbitals in lanthanides are “buried” in the xenon core and shielded from the ligand by the 5s and 5p orbitals they are therefore not influenced by the ligands to any great extent leading to a much smaller crystal field splitting than in the transition metals. The absorption spectra of an Ln³⁺ ion approximates to that of the free ion where the electronic states are described by spin-orbit coupling. This contrasts to the transition metals where the ground state is split by the crystal field. Absorptions for Ln³⁺ are weak as electric dipole transitions are parity forbidden (Laporte Rule forbidden) but can gain intensity due to the effect of a low-symmetry ligand field or mixing with higher electronic states (e.g. d orbitals). Also absorption bands are extremely sharp which contrasts with those observed for transition metals which generally have broad bands. This can lead to extremely unusual effects, such as significant color changes under different forms of lighting.

Magnetism

Metal complexes that have unpaired electrons are magnetic. Considering only monometallic complexes, unpaired electrons arise because the complex has an odd number of electrons or because electron pairing is destabilized. Thus, monomeric Ti(III) species have one "d-electron" and must be (para)magnetic, regardless of the geometry or the nature of the ligands. Ti(II), with two d-electrons, forms some complexes that have two unpaired electrons and others with none. This effect is illustrated by the compounds TiX₂[(CH₃)₂PCH₂CH₂P(CH₃)₂]₂: when X = Cl, the complex is paramagnetic (high-spin configuration), whereas when X = CH₃, it is diamagnetic (low-spin configuration). It is important to realize that ligands provide an important means of adjusting the ground state properties. 

In bi- and polymetallic complexes, in which the individual centres have an odd number of electrons or that are high-spin, the situation is more complicated. If there is interaction (either direct or through ligand) between the two (or more) metal centres, the electrons may couple (antiferromagnetic coupling, resulting in a diamagnetic compound), or they may enhance each other (ferromagnetic coupling). When there is no interaction, the two (or more) individual metal centers behave as if in two separate molecules.

Reactivity

Complexes show a variety of possible reactivities:

• Electron transfers

  A common reaction between coordination complexes involving ligands are inner and outer sphere electron transfers. They are two different mechanisms of electron transfer redox reactions, largely defined by the late Henry Taube. In an inner sphere reaction, a ligand with two lone electron pairs acts as a bridging ligand, a ligand to which both coordination centres can bond. Through this, electrons are transferred from one centre to another.

• (Degenerate) ligand exchange

  One important indicator of reactivity is the rate of degenerate exchange of ligands. For example, the rate of interchange of coordinate water in [M(H₂O)₆]ⁿ⁺ complexes varies over 20 orders of magnitude. Complexes where the ligands are released and rebound rapidly are classified as labile. Such labile complexes can be quite stable thermodynamically. Typical labile metal complexes either have low-charge (Na⁺), electrons in d-orbitals that are antibonding with respect to the ligands (Zn²⁺), or lack covalency (Ln³⁺, where Ln is any lanthanide). The lability of a metal complex also depends on the high-spin vs. low-spin configurations when such is possible. Thus, high-spin Fe(II) and Co(III) form labile complexes, whereas low-spin analogues are inert. Cr(III) can exist only in the low-spin state (quartet), which is inert because of its high formal oxidation state, absence of electrons in orbitals that are M–L antibonding, plus some "ligand field stabilization" associated with the d³ configuration.

• Associative processes

  Complexes that have unfilled or half-filled orbitals often show the capability to react with substrates. Most substrates have a singlet ground-state; that is, they have lone electron pairs (e.g., water, amines, ethers), so these substrates need an empty orbital to be able to react with a metal centre. Some substrates (e.g., molecular oxygen) have a triplet ground state, which results that metals with half-filled orbitals have a tendency to react with such substrates (it must be said that the dioxygen molecule also has lone pairs, so it is also capable to react as a 'normal' Lewis base).

If the ligands around the metal are carefully chosen, the metal can aid in (stoichiometric or catalytic) transformations of molecules or be used as a sensor.

Classification

Metal complexes, also known as coordination compounds, include all metal compounds, aside from metal vapors, plasmas, and alloys. The study of "coordination chemistry" is the study of "inorganic chemistry" of all alkali and alkaline earth metals, transition metals, lanthanides, actinides, and metalloids. Thus, coordination chemistry is the chemistry of the majority of the periodic table. Metals and metal ions exist, in the condensed phases at least, only surrounded by ligands. 

The areas of coordination chemistry can be classified according to the nature of the ligands, in broad terms:

• Classical (or "Werner Complexes"): Ligands in classical coordination chemistry bind to metals, almost exclusively, via their lone pairs of electrons residing on the main-group atoms of the ligand. Typical ligands are H₂O, NH₃, Cl⁻, CN⁻, en. Some of the simplest members of such complexes are described in metal aquo complexes, metal ammine complexes,

Examples: [Co(EDTA)]⁻, [Co(NH₃)₆]Cl₃, [Fe(C₂O₄)₃]K₃

• Organometallic Chemistry: Ligands are organic (alkenes, alkynes, alkyls) as well as "organic-like" ligands such as phosphines, hydride, and CO.

Example: (C₅H₅)Fe(CO)₂CH₃

• Bioinorganic Chemistry: Ligands are those provided by nature, especially including the side chains of amino acids, and many cofactors such as porphyrins.

Example: hemoglobin contains heme, a porphyrin complex of iron

Example: chlorophyll contains a porphyrin complex of magnesium

Many natural ligands are "classical" especially including water.

• Cluster Chemistry: Ligands are all of the above also include other metals as ligands.

Example Ru₃(CO)₁₂

• In some cases there are combinations of different fields:

Example: [Fe₄S₄(Scysteinyl)₄]²⁻, in which a cluster is embedded in a biologically active species.

Mineralogy, materials science, and solid state chemistry – as they apply to metal ions – are subsets of coordination chemistry in the sense that the metals are surrounded by ligands. In many cases these ligands are oxides or sulfides, but the metals are coordinated nonetheless, and the principles and guidelines discussed below apply. In hydrates, at least some of the ligands are water molecules. It is true that the focus of mineralogy, materials science, and solid state chemistry differs from the usual focus of coordination or inorganic chemistry. The former are concerned primarily with polymeric structures, properties arising from a collective effects of many highly interconnected metals. In contrast, coordination chemistry focuses on reactivity and properties of complexes containing individual metal atoms or small ensembles of metal atoms.

Nomenclature of Coordination complexes

The basic procedure for naming a complex:

1. When naming a complex ion, the ligands are named before the metal ion.
2. Write the names of the ligands in alphabetical order. (Numerical prefixes do not affect the order.)
   • Multiple occurring monodentate ligands receive a prefix according to the number of occurrences: di-, tri-, tetra-, penta-, or hexa. Polydentate ligands (e.g., ethylenediamine, oxalate) receive bis-, tris-, tetrakis-, etc.
   • Anions end in o. This replaces the final 'e' when the anion ends with '-ide', '-ate' or '-ite', e.g. chloride becomes chlorido and sulfate becomes sulfato. Formerly, '-ide' was changed to '-o' (e.g. chloro and cyano), but this rule has been modified in the 2005 IUPAC recommendations and the correct forms for these ligands are now chlorido and cyanido.
   • Neutral ligands are given their usual name, with some exceptions: NH₃ becomes ammine; H₂O becomes aqua or aquo; CO becomes carbonyl; NO becomes nitrosyl.
3. Write the name of the central atom/ion. If the complex is an anion, the central atom's name will end in -ate, and its Latin name will be used if available (except for mercury).
4. The oxidation state of the central atom is to be specified (when it is one of several possible, or zero), and should be written as a Roman numeral (or 0) enclosed in parentheses.
5. Name of the cation should be preceded by the name of anion. (if applicable, as in last example)

Examples:

metal	changed to
cobalt	cobaltate
aluminium	aluminate
chromium	chromate
vanadium	vanadate
copper	cuprate
iron	ferrate

[Cu(H₂O)₆] ²⁺ → hexaaquacopper(II) ion

[NiCl₄]²⁻ → tetrachloridonickelate(II) ion (The use of chloro- was removed from IUPAC naming convention)

[CuCl₅NH₃]³⁻ → amminepentachloridocuprate(II) ion

[Cd(CN)₂(en)₂] → dicyanidobis(ethylenediamine)cadmium(II)

[CoCl(NH₃)₅]SO₄ → pentaamminechloridocobalt(III) sulfate

K₄[Fe(CN)₆] → potassium hexacyanidoferrate(II)

The coordination number of ligands attached to more than one metal (bridging ligands) is indicated by a subscript to the Greek symbol μ placed before the ligand name. Thus the dimer of aluminium trichloride is described by Al₂Cl₄(μ₂-Cl)₂. 

Any anionic group can be electronically stabilized by any cation. An anionic complex can be stabilised by a hydrogen cation, becoming an acidic complex which can dissociate to release the cationic hydrogen. This kind of complex compound has a name with "ic" added after the central metal. For example, H₂[Pt(CN)₄] has the name tetracyanoplatinic (II) acid.

Stability constant

The affinity of metal ions for ligands is described by a stability constant, also called the formation constant, and is represented by the symbol K_f. It is the equilibrium constant for its assembly from the constituent metal and ligands, and can be calculated accordingly, as in the following example for a simple case:

(X)Metal_(aq) + (Y)Lewis Base_(aq) ⇌ (Z)Complex Ion_(aq)

${\displaystyle K_{f}={\frac {[{\text{Complex ion}}]^{Z}}{[{\text{Metal ion}}]^{X}[{\text{Lewis base}}]^{Y}}}}$

where X, Y, and Z are the stoichiometric coefficients of each species. Formation constants vary widely. Large values indicate that the metal has high affinity for the ligand, provided the system is at equilibrium.

Sometimes the stability constant will be in a different form known as the constant of destability. This constant is expressed as the inverse of the constant of formation and is denoted as K_d = 1/K_f . This constant represents the reverse reaction for the decomposition of a complex ion into its individual metal and ligand components. When comparing the values for K_d, the larger the value is the more unstable the complex ion is. 

As a result of these complex ions forming in solutions they also can play a key role in solubility of other compounds. When a complex ion is formed it can alter the concentrations of its components in the solution. For example:

Ag⁺
_(aq) + 2NH₄OH_(aq) ⇌ Ag(NH₃)⁺
₂ + H₂O

AgCl_(s) + H₂O_(l) ⇌ Ag⁺
_(aq) + Cl⁻
_(aq)

If these reactions both occurred in the same reaction vessel, the solubility of the silver chloride would be increased by the presence of NH₄OH because formation of the silver(I)–ammine complex consumes a significant portion of the free silver ions from the solution. By Le Chatelier's principle, this causes the equilibrium reaction for the dissolving of the silver chloride, which has silver ion as a product, to shift to the right. 

This new solubility can be calculated given the values of K_f and K_sp for the original reactions. The solubility is found essentially by combining the two separate equilibria into one combined equilibrium reaction and this combined reaction is the one that determines the new solubility. So K_c, the new solubility constant, is denoted by:

${\displaystyle K_{c}=K_{sp}*K_{f}}$

Application of coordination compounds

Metals only exist in solution as coordination complexes, it follows then that this class of compounds is useful in a wide variety of ways.

Bioinorganic chemistry

In bioinorganic chemistry and bioorganometallic chemistry, coordination complexes serve either structural or catalytic functions. An estimated 30% of proteins contain metal ions. Examples include the intensely colored vitamin B₁₂, the heme group in hemoglobin, the cytochromes, the chlorin group in chlorophyll, and carboxypeptidase, a hydrolytic enzyme important in digestion. Another complex ion enzyme is catalase, which decomposes the cell's waste hydrogen peroxide.

Industry

Homogeneous catalysis is a major application of coordination compounds for the production of organic substances. Processes include hydrogenation, hydroformylation, oxidation. In one example, a combination of titanium trichloride and triethylaluminium gives rise to Ziegler–Natta catalysts, used for the polymerization of ethylene and propylene to give polymers of great commercial importance as fibers, films, and plastics. 

Nickel, cobalt, and copper can be extracted using hydrometallurgical processes involving complex ions. They are extracted from their ores as ammine complexes. Metals can also be separated using the selective precipitation and solubility of complex ions. Cyanide is used chiefly for extraction of gold and silver from their ores.

Phthalocyanine complexes are an important class of pigments.

Analysis

At one time, coordination compounds were used to identify the presence of metals in a sample. Qualitative inorganic analysis has largely been superseded by instrumental methods of analysis such as atomic absorption spectroscopy (AAS), inductively coupled plasma atomic emission spectroscopy (ICP-AES) and inductively coupled plasma mass spectrometry (ICP-MS).