Organotechnetium chemistry

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Organotechnetium chemistry is the science of describing the physical properties, synthesis, and reactions of organotechnetium compounds, which are organometallic compounds containing carbon-to-technetium chemical bonds. The most common organotechnetium compounds are coordination complexes used as radiopharmaceutical imaging agents. [1] [2]

Contents

In general, organotechnetium compounds are not typically used in chemical reactions or catalysis due to their radioactivity. Research on technetium chemistry is often done in conjunction with rhenium as a isoelectronic non-radioactive alternative to technetium. [3]

Brief history

Technetium were first used as a radiopharmaceutical in 1961. [4] Of the radiopharmaceuticals in clinical use for SPECT (single photon emission computed tomography), a majority of the compounds are 99mTc complexes. [5] Three generations of technetium radiopharmaceuticals currently exist and are used. The first generation do not localize specifically and are considered perfusion agents. Second generation has a peptide based targeting portion. The third generation of technetium radiopharmaceuticals features organotechnetium compounds that can localize in the body in a biomimetic manner. [6] [7] [8]

Generations of technetium radio-pharmaceuticals Generations of technetium radio-pharmaceuticals.png
Generations of technetium radio-pharmaceuticals

Examples

A vast majority of technetium compounds used in radiopharmaceutical imaging and diagnosis are inorganic coordination complexes. There are a number of “classical” organometallic organotechnetium compounds, specifically containing carbon-technetium bonds are in clinical use. These organotechnetium compounds are mostly seen as technetium tri-carbonyl compounds and technetium cyclopentadienyl compounds.

99mTc-Sestamibi 99mTc-Sestamibi.png
99mTc-Sestamibi

One of the most prominent radio pharmaceutical compounds in clinical use is Cardiolie®, also known as 99mTc-Sestamibi. This organotechnetium compound is applied for myocardial imaging. The d6 electron configuration is highly stable due to its low oxidation state. [9] The Tc(I) complex is further stabilized by the high reducing potential of the isonitrile ligands. [10]

The above piano-stool organotechnetium complex is a third generation radiopharmaceutical. The cyclopentadienyl ligand acts as a bio isostere to a phenyl group in the amino acid phenylalanine. [11]

Synthesis

Radioactive 99mTc is obtained in the pertechnetate form in dilute aqueous solution from 99Mo/99mTc generators. Pertechnetate can then be made into more useful carbonyl and hydrate precursors for subsequent synthesis into technetate complexes.

As the starting radiometals are most available in aqueous solution due to method of isolation, the chemistry for synthesis of technetate compounds must be done in aqueous solution.

The study of technetium compounds is typically done in conjugation with rhenium as an isoelectronic and non-radioactive alternative to technetium.

Precursors

For 99mTc and 188Re, the synthesis of compounds start with pertechnetate or perrhenate in saline at low concentration, obtained from 99Mo/99mTc and 188W/188Re generators. The aquo tricarbonyl precursors are useful for accessing Tc and Re complexes. The metals have d6 low-spin electronic configuration, providing high kinetic stability, and highly stable M-C bonds. Consequently, the three CO ligands always remain coordinated, while ligands readily replace the three water molecules. Typical organotechnetium compounds thus feature the tricarbonyl motif.

Technetium and Rhenium precursors Technetium and Rhenium precursors.png
Technetium and Rhenium precursors

Typical methods of organometallic compounds synthesis difficult to utilize. To be useful as a radiopharmaceutical, the reaction should be done in an aqueous saline solution that can be injected into the body intravenously.

Double Ligand Transfer

A double ligand transfer (DLT) reaction was developed by Martin Wenzel for synthesis of organotechnetium/organorhenium complexes. [12] The reaction features the synthesis of organotechnetium piano-stool compounds from ferrocene. The reaction was further studied and optimized by Katzenellegbogen. [13] Unfortunately, the utility of this method in the synthesis of radiopharmaceuticals is limited by the use of organic solvent.

Wenzel double-ligand-transfer Wenzel double-ligand-transfer.png
Wenzel double-ligand-transfer

Mechanism

This mechanism is proposed to proceed by ring slippage. First, reduction and carbonylation of the pertechnetate/perrhenate with CrCl3 and/or Cr(CO)6 to from the 6 coordinate intermediate. Subsequent reaction with the substituted ferrocene through ring-slipped, bridged intermediates then gives product. The transfer of the more electron deficient ring is favored by the stabilization of the transition state of η5- η3 ring slip of ferrocene.

Double-ligand-transfer mechanism Double-ligand-transfer mechanism.png
Double-ligand-transfer mechanism

Metal-Mediated Retro Diels-Alder

Aqueous synthesis enables development for medically relevant radiopharmaceuticals. First aqueous synthesis of fac-[99mTc(η5 -Cp-C(O)CH3)(CO)3] was described by the Alberto lab utilized a metal-mediated retro Diels-Alder to synthesize the organotechnetium complexes. [14]

Mechanism

In a step-wise manner, the carboxylate first coordinates to technetium followed by coordination to the adjacent cyclopentadiene (Path A). The reaction is thermodynamically driven, given a strong electronic interaction between [99mTc(CO)3]+ and the cyclopentadiene.

Alberto retro-diels-alder.png

The favorable formation of the {(η5-Cp)Tc} as a driving force for formation of the product 2, prompted the use of the Diels-Ader dimer (HCp-COOH)2 (Thiele’s acid) as a precursor to the cyclopentadiene. Thermal cracking of 3 typically requires T >160 °C. Reaction of 3 and 1 at 95 °C for 30 min in buffer gave quantitative formation of 2. As no free HCp-COOH was observed, in situ retro Diels-Alder and subsequent entry into path A was excluded.

Examples

The metal-mediated retro Diels-Alder reaction suggests a general approach to [(Cp-R)99mTc(CO)3], enable access to a variety of R groups on the Cp ring.

Alberto retro-diels-alder examples Alberto retro-diels-alder examples.png
Alberto retro-diels-alder examples

With the development of this retro Diels-Alder method for synthesis of 99mTc and Re complexes in aqueous media by the Alberto lab, The labeling of biomolecules with piano-stool like complexes is now possible. Enabling access to the development of novel radiopharmaceuticals.

Reactivity

Technetium has been shown to react similarity to osmium. Able to catalyze a cis dihydroxylation.

Technetium dihydroxylation Technetium dihydroxylation.png
Technetium dihydroxylation

Related Research Articles

<span class="mw-page-title-main">Metallocene</span>

A metallocene is a compound typically consisting of two cyclopentadienyl anions (C
5H−
5, abbreviated Cp) bound to a metal center (M) in the oxidation state II, with the resulting general formula (C5H5)2M. Closely related to the metallocenes are the metallocene derivatives, e.g. titanocene dichloride or vanadocene dichloride. Certain metallocenes and their derivatives exhibit catalytic properties, although metallocenes are rarely used industrially. Cationic group 4 metallocene derivatives related to [Cp2ZrCH3]+ catalyze olefin polymerization.

<span class="mw-page-title-main">Organometallic chemistry</span> Study of organic compounds containing metal(s)

Organometallic chemistry is the study of organometallic compounds, chemical compounds containing at least one chemical bond between a carbon atom of an organic molecule and a metal, including alkali, alkaline earth, and transition metals, and sometimes broadened to include metalloids like boron, silicon, and selenium, as well. Aside from bonds to organyl fragments or molecules, bonds to 'inorganic' carbon, like carbon monoxide, cyanide, or carbide, are generally considered to be organometallic as well. Some related compounds such as transition metal hydrides and metal phosphine complexes are often included in discussions of organometallic compounds, though strictly speaking, they are not necessarily organometallic. The related but distinct term "metalorganic compound" refers to metal-containing compounds lacking direct metal-carbon bonds but which contain organic ligands. Metal β-diketonates, alkoxides, dialkylamides, and metal phosphine complexes are representative members of this class. The field of organometallic chemistry combines aspects of traditional inorganic and organic chemistry.

<span class="mw-page-title-main">Technetium</span> Chemical element, symbol Tc and atomic number 43

Technetium is a chemical element with the symbol Tc and atomic number 43. It is the lightest element whose isotopes are all radioactive. All available technetium is produced as a synthetic element. Naturally occurring technetium is a spontaneous fission product in uranium ore and thorium ore, the most common source, or the product of neutron capture in molybdenum ores. This silvery gray, crystalline transition metal lies between manganese and rhenium in group 7 of the periodic table, and its chemical properties are intermediate between those of both adjacent elements. The most common naturally occurring isotope is 99Tc, in traces only.

Ferrocene is an organometallic compound with the formula Fe(C5H5)2. The molecule is a complex consisting of two cyclopentadienyl rings bound to a central iron atom. It is an orange solid with a camphor-like odor, that sublimes above room temperature, and is soluble in most organic solvents. It is remarkable for its stability: it is unaffected by air, water, strong bases, and can be heated to 400 °C without decomposition. In oxidizing conditions it can reversibly react with strong acids to form the ferrocenium cation Fe(C5H5)+2.

Cyclopentadiene is an organic compound with the formula C5H6. It is often abbreviated CpH because the cyclopentadienyl anion is abbreviated Cp−.

<span class="mw-page-title-main">Group 7 element</span> Group of chemical elements

Group 7, numbered by IUPAC nomenclature, is a group of elements in the periodic table. They are manganese (Mn), technetium (Tc), rhenium (Re), and bohrium (Bh). All known elements of group 7 are transition metals.

<span class="mw-page-title-main">Cyclopentadienyl complex</span> Coordination complex of a metal and Cp⁻ ions

A cyclopentadienyl complex is a coordination complex of a metal and cyclopentadienyl groups. Cyclopentadienyl ligands almost invariably bind to metals as a pentahapto (η5-) bonding mode. The metal–cyclopentadienyl interaction is typically drawn as a single line from the metal center to the center of the Cp ring.

<span class="mw-page-title-main">Pertechnetate</span> Chemical compound or ion

The pertechnetate ion is an oxyanion with the chemical formula TcO−
4. It is often used as a convenient water-soluble source of isotopes of the radioactive element technetium (Tc). In particular it is used to carry the 99mTc isotope which is commonly used in nuclear medicine in several nuclear scanning procedures.

<span class="mw-page-title-main">Norbornadiene</span> Chemical compound

Norbornadiene is an organic compound and a bicyclic hydrocarbon. Norbornadiene is of interest as a metal-binding ligand, whose complexes are useful for homogeneous catalysis. It has been intensively studied owing to its high reactivity and distinctive structural property of being a diene that cannot isomerize. Norbornadiene is also a useful dienophile in Diels-Alder reactions.

<span class="mw-page-title-main">Sodium pertechnetate</span> Chemical compound

Sodium pertechnetate is the inorganic compound with the formula NaTcO4. This colourless salt contains the pertechnetate anion, TcO−
4. The radioactive 99m
Tc
O−
4 anion is an important radiopharmaceutical for diagnostic use. The advantages to 99m
Tc
 include its short half-life of 6 hours and the low radiation exposure to the patient, which allow a patient to be injected with activities of more than 30 millicuries. Na[99m
Tc
O
4] is a precursor to a variety of derivatives that are used to image different parts of the body.

Technetium compounds are chemical compounds containing the chemical element technetium. Technetium can form multiple oxidation states, but often forms in the +4 and +7 oxidation states. Because technetium is radioactive, technetium compounds are extremely rare on Earth.

<span class="mw-page-title-main">Methylcyclopentadiene</span> Chemical compound

Methylcyclopentadiene is any of three isomeric cyclic dialkenes with the formula C5MeH5 (Me = CH3). These isomers are the organic precursor to the methylcyclopentadienyl ligand (C5H4Me, often denoted as Cp′), commonly found in organometallic chemistry.

<span class="mw-page-title-main">Sodium cyclopentadienide</span> Chemical compound

Sodium cyclopentadienide is an organosodium compound with the formula C5H5Na. The compound is often abbreviated as NaCp, where Cp− is the cyclopentadienide anion. Sodium cyclopentadienide is a colorless solid, although samples often are pink owing to traces of oxidized impurities.

Organoiron chemistry is the chemistry of iron compounds containing a carbon-to-iron chemical bond. Organoiron compounds are relevant in organic synthesis as reagents such as iron pentacarbonyl, diiron nonacarbonyl and disodium tetracarbonylferrate. While iron adopts oxidation states from Fe(−II) through to Fe(VII), Fe(IV) is the highest established oxidation state for organoiron species. Although iron is generally less active in many catalytic applications, it is less expensive and "greener" than other metals. Organoiron compounds feature a wide range of ligands that support the Fe-C bond; as with other organometals, these supporting ligands prominently include phosphines, carbon monoxide, and cyclopentadienyl, but hard ligands such as amines are employed as well.

<span class="mw-page-title-main">Ferrocenium tetrafluoroborate</span> Chemical compound

Ferrocenium tetrafluoroborate is an organometallic compound with the formula [Fe(C5H5)2]BF4. This salt is composed of the cation [Fe(C5H5)2]+ and the tetrafluoroborate anion (BF−
4). The related hexafluorophosphate is also a popular reagent with similar properties. The cation is often abbreviated Fc+ or Cp2Fe+. The salt is deep blue in color and paramagnetic. Ferrocenium salts are sometimes used as one-electron oxidizing agents, and the reduced product, ferrocene, is inert and readily separated from ionic products. The ferrocene–ferrocenium couple is often used as a reference in electrochemistry. The standard potential of ferrocene-ferrocenium is dependent on specific electrochemical conditions.

<span class="mw-page-title-main">Rhodocene</span> Organometallic chemical compound

Rhodocene is a chemical compound with the formula [Rh(C5H5)2]. Each molecule contains an atom of rhodium bound between two planar aromatic systems of five carbon atoms known as cyclopentadienyl rings in a sandwich arrangement. It is an organometallic compound as it has (haptic) covalent rhodium–carbon bonds. The [Rh(C5H5)2] radical is found above 150 °C (302 °F) or when trapped by cooling to liquid nitrogen temperatures (−196 °C [−321 °F]). At room temperature, pairs of these radicals join via their cyclopentadienyl rings to form a dimer, a yellow solid.

<span class="mw-page-title-main">Transition metal fullerene complex</span>

A transition metal fullerene complex is a coordination complex wherein fullerene serves as a ligand. Fullerenes are typically spheroidal carbon compounds, the most prevalent being buckminsterfullerene, C60.

Magnesocene, also known as bis(cyclopentadienyl)magnesium(II) and sometimes abbreviated as MgCp2, is an organometallic compound with the formula Mg(η5-C5H5)2. It is an example of an s-block main group sandwich compound, structurally related to the d-block element metallocenes, and consists of a central magnesium atom sandwiched between two cyclopentadienyl rings.

<span class="mw-page-title-main">Technetium(IV) oxide</span> Chemical compound

Technetium(IV) oxide, also known as technetium dioxide, is a chemical compound with the formula TcO2 which forms the dihydrate, TcO2·2H2O, which is also known as technetium(IV) hydroxide. It is a radioactive black solid which slowly oxidizes in air.

A molecular electron-reservoir complex is one of a class of redox-active systems which can store and transfer electrons stoichiometrically or catalytically without decomposition. The concept of electron-reservoir complexes was introduced by the work of French chemist, Didier Astruc. From Astruc's discoveries, a whole family of thermally stable, neutral, 19-electron iron(I) organometallic complexes were isolated and characterized, and found to have applications in redox catalysis and electrocatalysis. The following page is a reflection of the prototypal electron-reservoir complexes discovered by Didier Astruc.

References

  1. ↑ Kowalsky RJ (2006). "Technetium Radiopharmaceutical Chemistry" (PDF). The University of New Mexico. Health Sciences Center, College of Pharmacy. pp. 1–77.
  2. ↑ Ritter SK (April 2017). "Good reasons to study technetium chemistry". Chemical & Engineering News. 95 (15). Retrieved 2021-06-12.
  3. ↑ Jürgens, Sophie; Herrmann, Wolfgang A.; Kühn, Fritz E. (February 2014). "Rhenium and technetium based radiopharmaceuticals: Development and recent advances". Journal of Organometallic Chemistry. 751: 83–89. doi:10.1016/j.jorganchem.2013.07.042.
  4. ↑ Scerri, Eric (July 2009). "Tales of technetium". Nature Chemistry. 1 (4): 332. Bibcode:2009NatCh...1..332S. doi:10.1038/nchem.271. ISSN   1755-4330. PMID   21378873.
  5. ↑ Morais, Goreti Ribeiro; Paulo, António; Santos, Isabel (2012-08-27). "Organometallic Complexes for SPECT Imaging and/or Radionuclide Therapy". Organometallics. 31 (16): 5693–5714. doi:10.1021/om300501d. ISSN   0276-7333.
  6. ↑ Schibli, Roger; Schubiger, August (2002-11-01). "Current use and future potential of organometallic radiopharmaceuticals". European Journal of Nuclear Medicine and Molecular Imaging. 29 (11): 1529–1542. doi:10.1007/s00259-002-0900-8. ISSN   1619-7070. PMID   12397472. S2CID   19897272.
  7. ↑ Liu, Shuang (2004-09-08). "The role of coordination chemistry in the development of target-specific radiopharmaceuticals". Chemical Society Reviews. 33 (7): 445–461. doi:10.1039/B309961J. ISSN   1460-4744. PMID   15354226.
  8. ↑ Hirao, Toshikazu (2018). Advances in Bioorganometallic Chemistry. Toshiyuki Moriuchi. San Diego: Elsevier. ISBN   978-0-12-814198-4. OCLC   1079003267.
  9. ↑ Alberto, Roger; Herrmann, Wolfgang A.; Bryan, Jeff C.; Schubiger, P. August; Baumgartner, Franz; Mihalios, Dimitrios (1993-01-01). "New Organometallic Technetium Complexes in High and Low Oxidation States". Radiochimica Acta. 63 (s1): 153–162. doi:10.1524/ract.1993.63.special-issue.153. ISSN   2193-3405. S2CID   99371461.
  10. ↑ Claude, Guilhem; Salsi, Federico; Hagenbach, Adelheid; Gembicky, Milan; Neville, Michael; Chan, Chinglin; Figueroa, Joshua S.; Abram, Ulrich (2020-06-22). "Structural and Redox Variations in Technetium Complexes Supported by m -Terphenyl Isocyanides". Organometallics. 39 (12): 2287–2294. doi:10.1021/acs.organomet.0c00238. ISSN   0276-7333. S2CID   219912503.
  11. ↑ Johannsen, Bernd; Syhre, Rosemarie; Spies, Hartmut; Münze, Rudolf (1978-07-01). "Chemical and Biological Characterization of Different Tc Complexes of Cysteine and Cysteine Derivatives". Journal of Nuclear Medicine. 19 (7): 816–824. ISSN   0161-5505. PMID   660286.
  12. ↑ Spradau, Todd W.; Katzenellenbogen, John A. (1998-05-01). "Preparation of Cyclopentadienyltricarbonylrhenium Complexes Using a Double Ligand-Transfer Reaction". Organometallics. 17 (10): 2009–2017. doi:10.1021/om971018u. ISSN   0276-7333.
  13. ↑ "John A. Katzenellenbogen | Chemistry at Illinois". chemistry.illinois.edu. Retrieved 2021-06-12.
  14. ↑ Liu, Yu; Spingler, Bernhard; Schmutz, Paul; Alberto, Roger (2008-02-06). "Metal-Mediated Retro Diels−Alder of Dicyclopentadiene Derivatives: A Convenient Synthesis of [(Cp-R)M(CO)3] (M = 99mTc, Re) Complexes". Journal of the American Chemical Society. 130 (5): 1554–1555. doi:10.1021/ja077741l. ISSN   0002-7863. PMID   18186638.
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