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Hypervalent molecule

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Hypervalent_molecule

In chemistry, a hypervalent molecule (the phenomenon is sometimes colloquially known as expanded octet) is a molecule that contains one or more main group elements apparently bearing more than eight electrons in their valence shells. Phosphorus pentachloride (PCl₅), sulfur hexafluoride (SF₆), chlorine trifluoride (ClF₃), the chlorite (ClO−2) ion in chlorous acid and the triiodide (I−3) ion are examples of hypervalent molecules.

Definitions and nomenclature

Hypervalent molecules were first formally defined by Jeremy I. Musher in 1969 as molecules having central atoms of group 15–18 in any valence other than the lowest (i.e. 3, 2, 1, 0 for Groups 15, 16, 17, 18 respectively, based on the octet rule).

Several specific classes of hypervalent molecules exist:

Hypervalent iodine compounds are useful reagents in organic chemistry (e.g. Dess–Martin periodinane)
Tetra-, penta- and hexavalent phosphorus, silicon, and sulfur compounds (e.g. PCl₅, PF₅, SF₆, sulfuranes and persulfuranes)
Noble gas compounds (ex. xenon tetrafluoride, XeF₄)
Halogen polyfluorides (ex. chlorine pentafluoride, ClF₅)

N-X-L notation

N-X-L nomenclature, introduced collaboratively by the research groups of Martin, Arduengo, and Kochi in 1980, is often used to classify hypervalent compounds of main group elements, where:

N represents the number of valence electrons
X is the chemical symbol of the central atom
L the number of ligands to the central atom

Examples of N-X-L nomenclature include:

XeF₂, 10-Xe-2
PCl₅, 10-P-5
SF₆, 12-S-6
IF₇, 14-I-7

History and controversy

The debate over the nature and classification of hypervalent molecules goes back to Gilbert N. Lewis and Irving Langmuir and the debate over the nature of the chemical bond in the 1920s. Lewis maintained the importance of the two-center two-electron (2c–2e) bond in describing hypervalence, thus using expanded octets to account for such molecules. Using the language of orbital hybridization, the bonds of molecules like PF₅ and SF₆ were said to be constructed from sp³dⁿ orbitals on the central atom. Langmuir, on the other hand, upheld the dominance of the octet rule and preferred the use of ionic bonds to account for hypervalence without violating the rule (e.g. "SF²⁺
₄ 2F⁻" for SF₆).

In the late 1920s and 1930s, Sugden argued for the existence of a two-center one-electron (2c–1e) bond and thus rationalized bonding in hypervalent molecules without the need for expanded octets or ionic bond character; this was poorly accepted at the time. In the 1940s and 1950s, Rundle and Pimentel popularized the idea of the three-center four-electron bond, which is essentially the same concept which Sugden attempted to advance decades earlier; the three-center four-electron bond can be alternatively viewed as consisting of two collinear two-center one-electron bonds, with the remaining two nonbonding electrons localized to the ligands.

The attempt to actually prepare hypervalent organic molecules began with Hermann Staudinger and Georg Wittig in the first half of the twentieth century, who sought to challenge the extant valence theory and successfully prepare nitrogen and phosphorus-centered hypervalent molecules. The theoretical basis for hypervalency was not delineated until J.I. Musher's work in 1969.

In 1990, Magnusson published a seminal work definitively excluding the significance of d-orbital hybridization in the bonding of hypervalent compounds of second-row elements. This had long been a point of contention and confusion in describing these molecules using molecular orbital theory. Part of the confusion here originates from the fact that one must include d-functions in the basis sets used to describe these compounds (or else unreasonably high energies and distorted geometries result), and the contribution of the d-function to the molecular wavefunction is large. These facts were historically interpreted to mean that d-orbitals must be involved in bonding. However, Magnusson concludes in his work that d-orbital involvement is not implicated in hypervalency.

Nevertheless, a 2013 study showed that although the Pimentel ionic model best accounts for the bonding of hypervalent species, the energetic contribution of an expanded octet structure is also not null. In this modern valence bond theory study of the bonding of xenon difluoride, it was found that ionic structures account for about 81% of the overall wavefunction, of which 70% arises from ionic structures employing only the p orbital on xenon while 11% arises from ionic structures employing an ${s d}_{z^{2}}$ hybrid on xenon. The contribution of a formally hypervalent structure employing an orbital of sp³d hybridization on xenon accounts for 11% of the wavefunction, with a diradical contribution making up the remaining 8%. The 11% sp³d contribution results in a net stabilization of the molecule by 7.2 kcal (30 kJ) mol⁻¹, a minor but significant fraction of the total energy of the total bond energy (64 kcal (270 kJ) mol⁻¹). Other studies have similarly found minor but non-negligible energetic contributions from expanded octet structures in SF₆ (17%) and XeF₆ (14%).

Despite the lack of chemical realism, the IUPAC recommends the drawing of expanded octet structures for functional groups like sulfones and phosphoranes, in order to avoid the drawing of a large number of formal charges or partial single bonds.

Hypervalent hydrides

A special type of hypervalent molecules is hypervalent hydrides. Most known hypervalent molecules contain substituents more electronegative than their central atoms. Hypervalent hydrides are of special interest because hydrogen is usually less electronegative than the central atom. A number of computational studies have been performed on chalcogen hydrides and pnictogen hydrides. Recently, a new computational study has shown that most hypervalent halogen hydrides XH_n can exist. It is suggested that IH₃ and IH₅ are stable enough to be observable or, possibly, even isolable.

Criticism

Both the term and concept of hypervalency still fall under criticism. In 1984, in response to this general controversy, Paul von Ragué Schleyer proposed the replacement of 'hypervalency' with use of the term hypercoordination because this term does not imply any mode of chemical bonding and the question could thus be avoided altogether.

The concept itself has been criticized by Ronald Gillespie who, based on an analysis of electron localization functions, wrote in 2002 that "as there is no fundamental difference between the bonds in hypervalent and non-hypervalent (Lewis octet) molecules there is no reason to continue to use the term hypervalent."

For hypercoordinated molecules with electronegative ligands such as PF₅, it has been demonstrated that the ligands can pull away enough electron density from the central atom so that its net content is again 8 electrons or fewer. Consistent with this alternative view is the finding that hypercoordinated molecules based on fluorine ligands, for example PF₅ do not have hydride counterparts, e.g. phosphorane (PH₅) which is unknown.

The ionic model holds up well in thermochemical calculations. It predicts favorable exothermic formation of PF⁺
₄F⁻
from phosphorus trifluoride PF₃ and fluorine F₂ whereas a similar reaction forming PH⁺
₄H⁻
is not favorable.

Alternative definition

Durrant has proposed an alternative definition of hypervalency, based on the analysis of atomic charge maps obtained from atoms in molecules theory. This approach defines a parameter called the valence electron equivalent, γ, as “the formal shared electron count at a given atom, obtained by any combination of valid ionic and covalent resonance forms that reproduces the observed charge distribution”. For any particular atom X, if the value of γ(X) is greater than 8, that atom is hypervalent. Using this alternative definition, many species such as PCl₅, SO²⁻
₄, and XeF₄, that are hypervalent by Musher's definition, are reclassified as hypercoordinate but not hypervalent, due to strongly ionic bonding that draws electrons away from the central atom. On the other hand, some compounds that are normally written with ionic bonds in order to conform to the octet rule, such as ozone O₃, nitrous oxide NNO, and trimethylamine N-oxide (CH
₃)
₃NO, are found to be genuinely hypervalent. Examples of γ calculations for phosphate PO³⁻
₄ (γ(P) = 2.6, non-hypervalent) and orthonitrate NO³⁻
₄ (γ(N) = 8.5, hypervalent) are shown below.

Bonding in hypervalent molecules

Early considerations of the geometry of hypervalent molecules returned familiar arrangements that were well explained by the VSEPR model for atomic bonding. Accordingly, AB₅ and AB₆ type molecules would possess a trigonal bipyramidal and octahedral geometry, respectively. However, in order to account for the observed bond angles, bond lengths, and apparent violation of the Lewis octet rule, several alternative models have been proposed.

In the 1950s, an expanded valence shell treatment of hypervalent bonding was proposed, in which the central atom of penta- and hexacoordinated molecules was thought to utilize vacant d atomic orbitals in addition to its valence s and p orbitals to form hybrid orbitals. For example, phosphorus in PCl₅ was described as undergoing sp³d hybridization to accommodate five bonding pairs in a trigonal bipyramidal geometry, while sulfur in SF₆ was treated as sp³d² hybridized, consistent with an octahedral structure. This model provided a straightforward explanation within the valence bond framework for how atoms in the third period and beyond could exceed the octet rule by expanding their valence shells into the 3d subshell.

However, advances in ab initio quantum chemical calculations have suggested that the energetic contribution of d-orbitals to bonding in main group hypervalent molecules might be minimal. The high energy and poor radial overlap of the 3d orbitals with ligand orbitals result in negligible participation in bond formation. It was shown that in the case of hexacoordinated SF₆, d-orbitals might not be significantly involved in S–F bond formation; rather, charge transfer between the central atom and ligands, along with appropriate resonance structures, can adequately explain the bonding characteristics and apparent hypervalency (see below). As a result, the d-orbital hybridization model is now regarded primarily as a historical or pedagogical tool.

Additional modifications to the octet rule have been attempted to involve ionic characteristics in hypervalent bonding. As one of these modifications, in 1951, the concept of the three-center four-electron (3c–4e) bond, which described hypervalent bonding using a qualitative molecular orbital framework, was proposed. The 3c–4e bond is described as three molecular orbitals formed by the combination of a p atomic orbital on the central atom with atomic orbitals from two ligands positioned linearly. Only one of the two pairs of electrons occupies a bonding orbital involving the central atom, while the second pair is nonbonding and delocalized between the two ligands. This model, which preserves the octet rule by distributing electrons across a delocalized system, was also later advocated by Musher.

Qualitative model for a three-center four-electron bond

Molecular orbital theory

A complete description of hypervalent molecules arises from consideration of molecular orbital theory through quantum mechanical methods. An LCAO in, for example, sulfur hexafluoride, taking a basis set of the one sulfur 3s-orbital, the three sulfur 3p-orbitals, and six octahedral geometry symmetry-adapted linear combinations (SALCs) of fluorine orbitals, a total of ten molecular orbitals are obtained (four fully occupied bonding MOs of the lowest energy, two fully occupied intermediate energy non-bonding MOs and four vacant antibonding MOs with the highest energy) providing room for all 12 valence electrons. This is a stable configuration only for SX₆ molecules containing electronegative ligand atoms like fluorine, which explains why SH₆ is not a stable molecule. In the bonding model, the two non-bonding MOs (1e_g) are localized equally on all six fluorine atoms.

d-Orbital Hybridization Model for Hypervalent Molecules

In classical valence bond theory, hypervalent molecules are explained using d-orbital hybridization. This model is commonly applied to elements in the third period and beyond of the periodic table (e.g., phosphorus, sulfur, chlorine), where low-lying vacant d orbitals are available.

According to this model, the central atom expands its valence shell by hybridizing its valence s and p orbitals with one or more d orbitals to form hybrid orbitals capable of accommodating more than four electron pairs. For example:

In phosphorus pentachloride (PCl₅), the phosphorus atom is said to use sp³d hybridization to form five equivalent bonding orbitals arranged in a trigonal bipyramidal geometry.
In sulfur hexafluoride (SF₆), the sulfur atom is described as undergoing sp³d² hybridization, resulting in six equivalent orbitals arranged octahedrally.

This use of d orbitals allows the molecule to accommodate five or six electron domains, respectively, thereby explaining the observed molecular geometries and bonding patterns within the valence bond framework.

Although the d-orbital hybridization model is still widely taught and used, it has been challenged by more advanced quantum chemical analyses. Computational studies and molecular orbital theory suggest that:

The contribution of d orbitals to bonding in main group hypervalent molecules might be less then thought before due to their relatively high energy and poor radial overlap with bonding partners.
Instead, bonding in such molecules can be explained using three-center four-electron (3c–4e) bonds or delocalized molecular orbitals that do not require invoking d-orbital participation.

Nevertheless, the d-orbital hybridization model remains a popular and widely used model to this day despite the controversy.

Three-Center Four-Electron Bond Model

An important alternative to expanded shell models is the three-center four-electron (3c–4e) bond, introduced in 1951 by Rundle and Pimentel. This model describes hypervalent bonding in terms of molecular orbital theory rather than invoking participation of d-orbitals or violation of the octet rule. In this framework, hypervalent bonding arises when a central atom shares a bonding interaction simultaneously with two ligands through a delocalized orbital system. Specifically, a 3c–4e bond involves three atoms—typically two ligands and a central atom—sharing four electrons across three molecular orbitals: one bonding, one nonbonding, and one antibonding. Only the bonding and nonbonding orbitals are occupied, leading to an overall stable configuration.

This model is particularly effective in describing linear arrangements such as those found in I₃⁻ and XeF₂, where the central atom retains a formal octet while bonding with more than four atoms. The central atom contributes a p orbital which overlaps with ligand orbitals from opposite sides, forming a delocalized interaction across all three atoms. The presence of one bonding and one nonbonding pair of electrons in the system provides an energetically favorable arrangement without requiring d-orbital participation. The 3c–4e model thus preserves the octet rule and aligns with modern quantum mechanical calculations, offering a more accurate depiction of bonding in many hypervalent compounds than earlier d-orbital hybridization approaches.

Structure, reactivity, and kinetics

Structure

Hexacoordinated phosphorus

Hexacoordinate phosphorus molecules involving nitrogen, oxygen, or sulfur ligands provide examples of Lewis acid-Lewis base hexacoordination. For the two similar complexes shown below, the length of the C–P bond increases with decreasing length of the N–P bond; the strength of the C–P bond decreases with increasing strength of the N–P Lewis acid–Lewis base interaction.

Pentacoordinated silicon

This trend is also generally true of pentacoordinated main-group elements with one or more lone-pair-containing ligand, including the oxygen-pentacoordinated silicon examples shown below.

The Si-halogen bonds range from close to the expected van der Waals value in A (a weak bond) almost to the expected covalent single bond value in C (a strong bond).

Reactivity

Silicon

Observed third-order reaction rate constants
for hydrolysis (displacement of chloride from silicon)
Chlorosilane	Nucleophile	k_obs (M⁻²s⁻¹) at 20 °C in anisole
Ph₃SiCl	HMPT	1200
Ph₃SiCl	DMSO	50
Ph₃SiCl	DMF	6
MePh₂SiCl	HMPT	2000
MePh₂SiCl	DMSO	360
MePh₂SiCl	DMF	80
Me(1-Np)PhSiCl	HMPT	3500
Me(1-Np)PhSiCl	DMSO	180
Me(1-Np)PhSiCl	DMF	40
(1-Np)Ph(vinyl)SiCl	HMPT	2200
(1-Np)Ph(vinyl)SiCl	DMSO	90
(1-Np)(m-CF₃Ph)HSiCl	DMSO	1800
(1-Np)(m-CF₃Ph)HSiCl	DMF	300

Corriu and coworkers performed early work characterizing reactions thought to proceed through a hypervalent transition state. Measurements of the reaction rates of hydrolysis of tetravalent chlorosilanes incubated with catalytic amounts of water returned a rate that is first order in chlorosilane and second order in water. This indicated that two water molecules interacted with the silane during hydrolysis and from this a binucleophilic reaction mechanism was proposed. Corriu and coworkers then measured the rates of hydrolysis in the presence of nucleophilic catalyst HMPT, DMSO or DMF. It was shown that the rate of hydrolysis was again first order in chlorosilane, first order in catalyst and now first order in water. Appropriately, the rates of hydrolysis also exhibited a dependence on the magnitude of charge on the oxygen of the nucleophile.

Taken together this led the group to propose a reaction mechanism in which there is a pre-rate determining nucleophilic attack of the tetracoordinated silane by the nucleophile (or water) in which a hypervalent pentacoordinated silane is formed. This is followed by a nucleophilic attack of the intermediate by water in a rate determining step leading to hexacoordinated species that quickly decomposes giving the hydroxysilane.

Silane hydrolysis was further investigated by Holmes and coworkers in which tetracoordinated Mes
₂SiF
₂ (Mes = mesityl) and pentacoordinated Mes
₂SiF⁻
₃ were reacted with two equivalents of water. Following twenty-four hours, almost no hydrolysis of the tetracoordinated silane was observed, while the pentacoordinated silane was completely hydrolyzed after fifteen minutes. Additionally, X-ray diffraction data collected for the tetraethylammonium salts of the fluorosilanes showed the formation of hydrogen bisilonate lattice supporting a hexacoordinated intermediate from which HF⁻
₂ is quickly displaced leading to the hydroxylated product. This reaction and crystallographic data support the mechanism proposed by Corriu et al..

The apparent increased reactivity of hypervalent molecules, contrasted with tetravalent analogues, has also been observed for Grignard reactions. The Corriu group measured Grignard reaction half-times by NMR for related 18-crown-6 potassium salts of a variety of tetra- and pentacoordinated fluorosilanes in the presence of catalytic amounts of nucleophile.

Though the half reaction method is imprecise, the magnitudinal differences in reactions rates allowed for a proposed reaction scheme wherein, a pre-rate determining attack of the tetravalent silane by the nucleophile results in an equilibrium between the neutral tetracoordinated species and the anionic pentavalent compound. This is followed by nucleophilic coordination by two Grignard reagents as normally seen, forming a hexacoordinated transition state and yielding the expected product.

The mechanistic implications of this are extended to a hexacoordinated silicon species that is thought to be active as a transition state in some reactions. The reaction of allyl- or crotyl-trifluorosilanes with aldehydes and ketones only precedes with fluoride activation to give a pentacoordinated silicon. This intermediate then acts as a Lewis acid to coordinate with the carbonyl oxygen atom. The further weakening of the silicon–carbon bond as the silicon becomes hexacoordinate helps drive this reaction.

Phosphorus

Similar reactivity has also been observed for other hypervalent structures such as the miscellany of phosphorus compounds, for which hexacoordinated transition states have been proposed. Hydrolysis of phosphoranes and oxyphosphoranes have been studied and shown to be second order in water. Bel'skii et al.. have proposed a prerate determining nucleophilic attack by water resulting in an equilibrium between the penta- and hexacoordinated phosphorus species, which is followed by a proton transfer involving the second water molecule in a rate determining ring-opening step, leading to the hydroxylated product.

Alcoholysis of pentacoordinated phosphorus compounds, such as trimethoxyphospholene with benzyl alcohol, have also been postulated to occur through a similar octahedral transition state, as in hydrolysis, however without ring opening.

It can be understood from these experiments that the increased reactivity observed for hypervalent molecules, contrasted with analogous nonhypervalent compounds, can be attributed to the congruence of these species to the hypercoordinated activated states normally formed during the course of the reaction.

Ab initio calculations

The enhanced reactivity at pentacoordinated silicon is not fully understood. Corriu and coworkers suggested that greater electropositive character at the pentavalent silicon atom may be responsible for its increased reactivity. Preliminary ab initio calculations supported this hypothesis to some degree, but used a small basis set.

A software program for ab initio calculations, Gaussian 86, was used by Dieters and coworkers to compare tetracoordinated silicon and phosphorus to their pentacoordinate analogues. This ab initio approach is used as a supplement to determine why reactivity improves in nucleophilic reactions with pentacoordinated compounds. For silicon, the 6-31+G* basis set was used because of its pentacoordinated anionic character and for phosphorus, the 6-31G* basis set was used.

Pentacoordinated compounds should theoretically be less electrophilic than tetracoordinated analogues due to steric hindrance and greater electron density from the ligands, yet experimentally show greater reactivity with nucleophiles than their tetracoordinated analogues. Advanced ab initio calculations were performed on series of tetracoordinated and pentacoordinated species to further understand this reactivity phenomenon. Each series varied by degree of fluorination. Bond lengths and charge densities are shown as functions of how many hydride ligands are on the central atoms. For every new hydride, there is one less fluoride.

For silicon and phosphorus bond lengths, charge densities, and Mulliken bond overlap, populations were calculated for tetra and pentacoordinated species by this ab initio approach. Addition of a fluoride ion to tetracoordinated silicon shows an overall average increase of 0.1 electron charge, which is considered insignificant. In general, bond lengths in trigonal bipyramidal pentacoordinate species are longer than those in tetracoordinate analogues. Si-F bonds and Si-H bonds both increase in length upon pentacoordination and related effects are seen in phosphorus species, but to a lesser degree. The reason for the greater magnitude in bond length change for silicon species over phosphorus species is the increased effective nuclear charge at phosphorus. Therefore, silicon is concluded to be more loosely bound to its ligands.

Effects of fluorine substitution on positive charge density

Comparison of Charge Densities with Degree of Fluorination for Tetra and Pentacoordinated Silicon

In addition Dieters and coworkers show an inverse correlation between bond length and bond overlap for all series. Pentacoordinated species are concluded to be more reactive because of their looser bonds as trigonal-bipyramidal structures.

Calculated bond length and bond overlap with degree of fluorination

Comparison of Bond Lengths with Degree of Fluorination for Tetra and Pentacoordinated Silicon

Comparison of Bond Lengths with Degree of Fluorination for Tetra and Pentacoordinated Phosphorus

By calculating the energies for the addition and removal of a fluoride ion in various silicon and phosphorus species, several trends were found. In particular, the tetracoordinated species have much higher energy requirements for ligand removal than do pentacoordinated species. Further, silicon species have lower energy requirements for ligand removal than do phosphorus species, which is an indication of weaker bonds in silicon.

Molecular neuroscience

From Wikipedia, the free encyclopedia

Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.

Locating neurotransmitters

In molecular biology, communication between neurons typically occurs by chemical transmission across gaps between the cells called synapses. The transmitted chemicals, known as neurotransmitters, regulate a significant fraction of vital body functions. It is possible to anatomically locate neurotransmitters by labeling techniques. It is possible to chemically identify certain neurotransmitters such as catecholamines by fixing neural tissue sections with formaldehyde. This can give rise to formaldehyde-induced fluorescence when exposed to ultraviolet light. Dopamine, a catecholamine, was identified in the nematode C. elegans by using this technique. Immunocytochemistry, which involves raising antibodies against targeted chemical or biological entities, includes a few other techniques of interest. A targeted neurotransmitter could be specifically tagged by primary and secondary antibodies with radioactive labeling in order to identify the neurotransmitter by autoradiography. The presence of neurotransmitters (though not necessarily the location) can be observed in enzyme-linked immunocytochemistry or enzyme-linked immunosorbent assays (ELISA) in which substrate-binding in the enzymatic assays can induce precipitates, fluorophores, or chemiluminescence. In the event that neurotransmitters cannot be histochemically identified, an alternative method is to locate them by their neural uptake mechanisms.

Voltage-gated ion channels

Excitable cells in living organisms have voltage-gated ion channels. These can be observed throughout the nervous system in neurons. The first ion channels to be characterized were the sodium and potassium ion channels by A.L. Hodgkin and A.F. Huxley in the 1950s upon studying the giant axon of the squid genus Loligo. Their research demonstrated the selective permeability of cellular membranes, dependent on physiological conditions, and the electrical effects that result from these permeabilities to produce action potentials.

Sodium ion channels

Sodium channels were the first voltage-gated ion channels to be isolated in 1984 from the eel Electrophorus electricus by Shosaku Numa. The pufferfish toxin tetrodotoxin (TTX), a sodium channel blocker, was used to isolate the sodium channel protein by binding it using the column chromatography technique for chemical separation. The amino acid sequence of the protein was analyzed by Edman degradation and then used to construct a cDNA library which could be used to clone the channel protein. Cloning the channel itself allowed for applications such as identifying the same channels in other animals. Sodium channels are known for working in concert with potassium channels during the development of graded potentials and action potentials. Sodium channels allow an influx of Na⁺ ions into a neuron, resulting in a depolarization from the resting membrane potential of a neuron to lead to a graded potential or action potential, depending on the degree of depolarization.

Potassium ion channels

Potassium channels come in a variety of forms, are present in most eukaryotic cells, and typically tend to stabilize the cell membrane at the potassium equilibrium potential. As with sodium ions, graded potentials and action potentials are also dependent on potassium channels. While influx of Na⁺ ions into a neuron induce cellular depolarization, efflux of K⁺ ions out of a neuron causes a cell to repolarize to resting membrane potential. The activation of potassium ion channels themselves are dependent on the depolarization resulting from Na⁺ influx during an action potential. As with sodium channels, the potassium channels have their own toxins that block channel protein action. An example of such a toxin is the large cation, tetraethylammonium (TEA), but it is notable that the toxin does not have the same mechanism of action on all potassium channels, given the variety of channel types across species. The presence of potassium channels was first identified in Drosophila melanogaster mutant flies that shook uncontrollably upon anesthesia due to problems in cellular repolarization that led to abnormal neuron and muscle electrophysiology. Potassium channels were first identified by manipulating molecular genetics (of the flies) instead of performing channel protein purification because there were no known high-affinity ligands for potassium channels (such as TEA) at the time of discovery.

Calcium ion channels

Calcium channels are important for certain cell-signaling cascades as well as neurotransmitter release at axon terminals. A variety of different types of calcium ion channels are found in excitable cells. As with sodium ion channels, calcium ion channels have been isolated and cloned by chromatographic purification techniques. It is notable, as with the case of neurotransmitter release, that calcium channels can interact with intracellular proteins and plays a strong role in signaling, especially in locations such as the sarcoplasmic reticulum of muscle cells.

Receptors

Various types of receptors can be used for cell signaling and communication and can include ionotropic receptors and metabotropic receptors. These cell surface receptor types are differentiated by the mechanism and duration of action with ionotropic receptors being associated with fast signal transmission and metabotropic receptors being associated with slow signal transmission. Metabotropic receptors happen to cover a wide variety of cell-surface receptors with notably different signaling cascades.

Ionotropic receptors

Prototypical depiction of ionotropic receptor in the case of Ca²⁺ ion flow

Ionotropic receptors, otherwise known as ligand-gated ion channels, are fast acting receptors that mediate neural and physiological function by ion channel flow with ligand-binding. Nicotinic, GABA, and Glutamate receptors are among some of the cell surface receptors regulated by ligand-gated ion channel flow. GABA is the brain's main inhibitory neurotransmitter and glutamate is the brain's main excitatory neurotransmitter.

GABA receptors

GABA_A and GABA_C receptors are known to be ionotropic, while the GABA_B receptor is metabotropic. GABA_A receptors mediate fast inhibitory responses in the central nervous system (CNS) and are found on neurons, glial cells, and adrenal medulla cells. It is responsible for inducing Cl⁻ ion influx into cells, thereby reducing the probability that membrane depolarization will occur upon the arrival of a graded potential or an action potential. GABA receptors can also interact with non-endogenous ligands to influence activity. For example, the compound diazepam (marketed as Valium) is an allosteric agonist which increases the affinity of the receptor for GABA. The increased physiological inhibitory effects resulting from increased GABA binding make diazepam a useful tranquilizer or anticonvulsant (antiepileptic drugs). On the other hand, GABA receptors can also be targeted by decreasing Cl⁻ cellular influx with the effect of convulsants like picrotoxin. The antagonistic mechanism of action for this compound is not directly on the GABA receptor, but there are other compounds that are capable of allosteric inactivation, including T-butylbicyclophorothionate (TBPS) and pentylenetetrazole (PZT). Compared with GABA_A, GABA_C receptors have a higher affinity for GABA, they are likely to be longer-lasting in activity, and their responses are likely to be generated by lower GABA concentrations.

Glutamate receptors

Ionotropic glutamate receptors can include NMDA, AMPA, and kainate receptors. These receptors are named after agonists that facilitate glutamate activity. NMDA receptors are notable for their excitatory mechanisms to affect neuronal plasticity in learning and memory, as well as neuropathologies such as stroke and epilepsy. NDMA receptors have multiple binding sites just like ionotropic GABA receptors and can be influenced by co-agonists such the glycine neurotransmitter or phencyclidine (PCP). The NMDA receptors carry a current by Ca²⁺ ions and can be blocked by extracellular Mg²⁺ ions depending on voltage and membrane potential. This Ca²⁺ influx is increased by excitatory postsynaptic potentials (EPSPs) produced by NMDA receptors, activating Ca²⁺-based signaling cascades (such as neurotransmitter release). AMPA generate shorter and larger excitatory postsynaptic currents than other ionotropic glutamate receptors.

Nicotinic ACh receptors

Nicotinic receptors bind the acetylcholine (ACh) neurotransmitter to produce non-selective cation channel flow that generates excitatory postsynaptic responses. Receptor activity, which can be influenced by nicotine consumption, produces feelings of euphoria, relaxation, and inevitably addiction in high levels.

Metabotropic receptors

Metabotropic receptors, are slow response receptors in postsynaptic cells. Typically these slow responses are characterized by more elaborate intracellular changes in biochemistry. Responses of neurotransmitter uptake by metabotropic receptors can result in the activation of intracellualar enzymes and cascades involving second messengers, as is the case with G protein-linked receptors. Various metabotropic receptors can include certain glutamate receptors, muscarinic ACh receptors, GABA_B receptors, and receptor tyrosine kinases.

G protein-linked receptors

The G protein-linked signaling cascade can significantly amplify the signal of a particular neurotransmitter to produce hundreds to thousands of second messengers in a cell. The mechanism of action by which G protein-linked receptors cause a signaling cascade is as follows:

Neurotransmitter binds to the receptor
The receptor undergoes a conformational change to allow G-protein complex binding
GDP is exchanged with GTP upon G protein complex binding to the receptor
The α-subunit of the G protein complex is bound to GTP and separates to bind with a target protein such as adenylate cyclase
The binding to the target protein either increases or decreases the rate of second messenger (such as cyclic AMP) production
GTPase hydrolyzes the α-subunit so that is bound to GDP and the α-subunit returns to the G protein complex inactive

Neurotransmitter release

Neurotransmitters are released in discrete packets known as quanta from the axon terminal of one neuron to the dendrites of another across a synapse. These quanta have been identified by electron microscopy as synaptic vesicles. Two types of vesicles are small synaptic vessicles (SSVs), which are about 40-60nm in diameter, and large dense-core vesicles (LDCVs), electron-dense vesicles approximately 120-200nm in diameter. The former is derived from endosomes and houses neurotransmitters such as acetylcholine, glutamate, GABA, and glycine. The latter is derived from the Golgi apparatus and houses larger neurotransmitters such as catecholamines and other peptide neurotransmitters. Neurotransmitters are released from an axon terminal and bind to postsynaptic dendrites in the following procession:

Mobilization/recruitment of synaptic vesicle from cytoskeleton
Docking of vesicle (binding) to presynaptic membrane
Priming of vesicle by ATP (relatively slow step)
Fusion of primed vesicle with presynaptic membrane and exocytosis of the housed neurotransmitter
Uptake of neurotransmitters in receptors of a postsynaptic cell
Initiation or inhibition of action potential in postsynaptic cell depending on whether the neurotransmitters are excitatory or inhibitory (excitatory will result in depolarization of the postsynaptic membrane)

Neurotransmitter release is calcium-dependent

Neurotransmitter release is dependent on an external supply of Ca²⁺ ions which enter axon terminals via voltage-gated calcium channels. Vesicular fusion with the terminal membrane and release of the neurotransmitter is caused by the generation of Ca²⁺ gradients induced by incoming action potentials. The Ca²⁺ ions cause the mobilization of newly synthesized vesicles from a reserve pool to undergo this membrane fusion. This mechanism of action was discovered in squid giant axons. Lowering intracellular Ca²⁺ ions provides a direct inhibitory effect on neurotransmitter release. After release of the neurotransmitter occurs, vesicular membranes are recycled to their origins of production. Calcium ion channels can vary depending on the location of incidence. For example, the channels at an axon terminal differ from the typical calcium channels of a cell body (whether neural or not). Even at axon terminals, calcium ion channel types can vary, as is the case with P-type calcium channels located at the neuromuscular junction.

Neuronal gene expression

Sex differences

Differences in sex determination are controlled by sex chromosomes. Sex hormonal releases have a significant effect on sexual dimorphisms (phenotypic differentiation of sexual characteristics) of the brain. Recent studies seem to suggest that regulating these dimorphisms has implications for understanding normal and abnormal brain function. Sexual dimorphisms may be significantly influenced by sex-based brain gene expression which varies from species to species.

Animal models such as rodents, Drosophila melanogaster, and Caenorhabditis elegans, have been used to observe the origins and/or extent of sex bias in the brain versus the hormone-producing gonads of an animal. With the rodents, studies on genetic manipulation of sex chromosomes resulted in an effect on one sex that was completely opposite of the effect in the other sex. For example, a knockout of a particular gene only resulted in anxiety-like effects in males. With studies on D. menlanogaster it was found that a large brain sex bias of expression occurred even after the gonads were removed, suggesting that sex bias could be independent of hormonal control in certain aspects.

Observing sex-biased genes has the potential for clinical significance in observing brain physiology and the potential for related (whether directly or indirectly) neurological disorders. Examples of diseases with sex biases in development include Huntington's disease, cerebral ischemia, and Alzheimer's disease.

Epigenetics of the brain

Many brain functions can be influenced at the cellular and molecular level by variations and changes in gene expression, without altering the sequence of DNA in an organism. This is otherwise known as epigenetic regulation. Examples of epigenetic mechanisms include histone modifications and DNA methylation. Such changes have been found to be strongly influential in the incidence of brain disease, mental illness, and addiction. Epigenetic control has been shown to be involved in high levels of plasticity in early development, thereby defining its importance in the critical period of an organism. Examples of how epigenetic changes can affect the human brain are as follows:

Higher methylation levels in rRNA genes in the hippocampus of the brain results in a lower production of proteins and thus limited hippocampal function can result in learning and memory impairment and resultant suicidal tendencies.
In a study comparing genetic differences between healthy people and psychiatric patients 60 different epigenetic markers associated with brain cell signaling were found.
Environmental factors such as child abuse appears to cause the expression of an epigenetic tag on glucocorticoid receptors (associated with stress responses) that was not found in suicide victims. This is an example of experience-dependent plasticity.
Environmental enrichment in individuals is associated with increased hippocampal gene histone acetylation and thus improved memory consolidation (notably spatial memory).

Molecular mechanisms of neurodegenerative diseases

Excitotoxicity and glutamate receptors

Excitotoxicity is phenomenon in which glutamate receptors are inappropriately activated. It can be caused by prolonged excitatory synaptic transmission in which high levels of glutamate neurotransmitter cause excessive activation in a postsynaptic neuron that can result in the death of the postsynaptic neuron. Following brain injury (such as from ischemia), it has been found that excitotoxicity is a significant cause of neuronal damage. This can be understandable in the case where sudden perfusion of blood after reduced blood flow to the brain can result in excessive synaptic activity caused by the presence of increased glutamate and aspartate during the period of ischemia.

Alzheimer's disease

Alzheimer's disease is the most common neurodegenerative disease and is the most common form of dementia in the elderly. The disorder is characterized by progressive loss of memory and various cognitive functions. It is hypothesized that the deposition of amyloid-β peptide (40-42 amino acid residues) in the brain is integral in the incidence of Alzheimer's disease. Accumulation is purported to block hippocampal long-term potentiation. It is also possible that a receptor for amyloid-β oligomers could be a prion protein.

Parkinson's disease

Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease. It is a hypokinetic movement basal ganglia disease caused by the loss of dopaminergic neurons in the substantia nigra of the human brain. The inhibitory outflow of the basal ganglia is thus not decreased, and so upper motor neurons, mediated by the thalamus, are not activated in a timely manner. Specific symptoms include rigidity, postural problems, slow movements, and tremors. Blocking GABA receptor input from medium spiny neurons to reticulata cells, causes inhibition of upper motor neurons similar to the inhibition that occurs in Parkinson's disease.

Huntington's disease

Huntington's disease is a hyperkinetic movement basal ganglia disease caused by lack of normal inhibitory inputs from medium spiny neurons of the basal ganglia. This poses the opposite effects of those associated with Parkinson's disease, including inappropriate activation of upper motor neurons. As with the GABAergic mechanisms observed in relation to Parkinson's disease, a GABA agonist injected into the substantia nigra pars reticulata decreases inhibition of upper motor neurons, resulting in ballistic involuntary motor movements, similar to symptoms of Huntington's disease.

Nuclear propulsion

From Wikipedia, the free encyclopedia

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

Pressurised water reactors are the most common reactors used in ships and submarines. The pictorial diagram shows the operating principles. Primary coolant is in orange and the secondary coolant (steam and later feedwater) is in blue.

Nuclear propulsion includes a wide variety of propulsion methods that use some form of nuclear reaction as their primary power source. Many aircraft carriers and submarines currently use uranium fueled nuclear reactors that can provide propulsion for long periods without refueling. There are also applications in the space sector with nuclear thermal and nuclear electric engines which could be more efficient than conventional rocket engines.

The idea of using nuclear material for propulsion dates back to the beginning of the 20th century. In 1903 it was hypothesized that radioactive material, radium, might be a suitable fuel for engines to propel cars, planes, and boats. H. G. Wells picked up this idea in his 1914 fiction work The World Set Free.

Surface ships, submarines, and torpedoes

Nuclear-powered vessels are mainly military submarines, and aircraft carriers. Russia is the only country that currently has nuclear-powered civilian surface ships, mainly icebreakers. The US Navy currently (as of 2022) has 11 aircraft carriers and 70 submarines in service, that are all powered by nuclear reactors. For more detailed articles see:

Civilian maritime use

Military maritime use

Torpedo

Russia's Channel One Television news broadcast a picture and details of a nuclear-powered torpedo called Status-6 on about 12 November 2015. The torpedo was stated as having a range of up to 10,000 km, a cruising speed of 100 knots, and an operational depth of up to 1000 metres below the surface. The torpedo carried a 100-megaton nuclear warhead.

One of the suggestions emerging in the summer of 1958 from the first meeting of the scientific advisory group that became JASON was for "a nuclear-powered torpedo that could roam the seas almost indefinitely".

Aircraft and missiles

Research into nuclear-powered aircraft was pursued during the Cold War by the United States and the Soviet Union as they would presumably allow a country to keep nuclear bombers in the air for extremely long periods of time, a useful tactic for nuclear deterrence. Neither country created any operational nuclear aircraft. One design problem, never adequately solved, was the need for heavy shielding to protect the crew from radiation sickness. Since the advent of ICBMs in the 1960s the tactical advantage of such aircraft was greatly diminished and respective projects were cancelled. Because the technology was inherently dangerous it was not considered in non-military contexts. Nuclear-powered missiles were also researched and discounted during the same period.

Aircraft

Convair X-6
Myasishchev M-50 – Aviation Week hoax
Aircraft Nuclear Propulsion – General Electric's project to build a nuclear-powered bomber
Tupolev Tu-95LAL

Missiles

Project Pluto – which developed the SLAM missile, that used a nuclear-powered air ramjet for propulsion
Burevestnik nuclear-powered cruise missile announced by Vladimir Putin in 2018.

Spacecraft

The attraction of nuclear propulsion and power in space is built on the high efficiency and theoretical capability that can be delivered with a nuclear system, namely energy efficiency of the system and endurance/capacity of the system to function over long distances. In balance, the systems needed to protect humans in both the space-lift and operations phase are significant detriments. Many types of nuclear propulsion have been proposed as follows.

Nuclear pulse propulsion

Project Orion, first engineering design study of nuclear pulse (i.e., atomic explosion) propulsion
Project Daedalus, 1970s British Interplanetary Society study of a fusion rocket
Project Longshot, US Naval Academy-NASA nuclear pulse propulsion design
AIMStar, a proposed Antimatter-catalyzed nuclear pulse propulsion craft that uses clouds of antiprotons to initiate fission and fusion within fuel pellets
ICAN-II, a proposed crewed interplanetary spacecraft that used the antimatter-catalyzed nuclear pulse propulsion engine as its main form of propulsion
External Pulsed Plasma Propulsion (EPPP), a propulsion concept by NASA that derives its thrust from plasma waves generated from a series of small, supercritical fission/fusion pulses behind an object in space.

Nuclear thermal rocket

Bimodal nuclear thermal rockets conduct nuclear fission reactions similar to those employed at nuclear power plants including submarines. The energy is used to heat the liquid hydrogen propellant. Advocates of nuclear-powered spacecraft point out that at the time of launch, there is almost no radiation released from the nuclear reactors. Nuclear-powered rockets are not used to lift off the Earth. Nuclear thermal rockets can provide great performance advantages compared to chemical propulsion systems. Nuclear power sources could also be used to provide the spacecraft with electrical power for operations and scientific instrumentation. Examples:

NERVA (Nuclear Energy for Rocket Vehicle Applications), a US nuclear thermal rocket program.
Project Rover, an American project to develop a nuclear thermal rocket. The program ran at the Los Alamos Scientific Laboratory from 1955 through 1972.
Project Timberwind (1987–1991), part of the Strategic Defense Initiative
RD-0410, a Soviet nuclear thermal rocket engine developed from 1965 through the 1980s
Demonstration Rocket for Agile Cislunar Operations (DRACO), under development in the 2020s

Ramjet

Bussard ramjet, a conceptual interstellar fusion ramjet named after Robert W. Bussard.

Direct nuclear

Nuclear electric

Nuclear electric propulsion is a type of spacecraft propulsion system where a nuclear reactor generates thermal energy which is converted to electrical energy, that drives an ion thruster or other electrical spacecraft propulsion technology. Examples of nuclear electric systems:

SNAP-10A, launched into orbit by USAF in 1965, was the first use of a nuclear reactor in space and of an ion thruster in orbit.
US-A satellite series, launched by into orbit by the USSR, included Kosmos 1818 and Kosmos 1867 in 1987, using the TOPAZ nuclear reactor and a "Plazma-2 SPT" Hall-effect thruster.
Project Prometheus, NASA development of nuclear propulsion for long-duration spaceflight, begun in 2003.
Transport and Energy Module (TEM). In April 2011, Anatoly Perminov, head of the Russian Federal Space Agency, announced that it is going to develop a nuclear-powered spacecraft for deep space travel. Preliminary design was done by 2013, and 9 more years are planned for development (in space assembly). The price is set at 17 billion rubles (600 million dollars). The nuclear propulsion would offer mega-watt class power and would consist of a space nuclear power and a matrix of ion engines According to Perminov, the propulsion will be able to support human mission to Mars, with cosmonauts staying on the Red planet for 30 days. This journey to Mars with nuclear propulsion and a steady acceleration would take six weeks, instead of eight months by using chemical propulsion – assuming thrust of 300 times higher than that of chemical propulsion.

Ground vehicles

Automobiles

The idea of making cars that used radioactive material, radium, for fuel dates back to at least 1903. Analysis of the concept in 1937 indicated that the driver of such a vehicle might need a 50-ton lead barrier to shield them from radiation.

In 1941, a Caltech physicist named R. M. Langer espoused the idea of a car powered by uranium-235 in the January edition of Popular Mechanics. He was followed by William Bushnell Stout, designer of the Stout Scarab and former Society of Engineers president, on 7 August 1945 in The New York Times. The problem of shielding the reactor continued to render the idea impractical. In December 1945, a John Wilson of London, announced he had created an atomic car. This created considerable interest. The Minister of Fuel and Power along with a large press contingent turned out to view it. The car did not show and Wilson claimed that it had been sabotaged. A later court case found that he was a fraud and there was no nuclear-powered car.

Despite the shielding problem, through the late 1940s and early 1950s debate continued around the possibility of nuclear-powered cars. The development of nuclear-powered submarines and ships, and experiments to develop a nuclear-powered aircraft at that time kept the idea alive. Russian papers in the mid-1950s reported the development of a nuclear-powered car by Professor V P Romadin, but again shielding proved to be a problem. It was claimed that its laboratories had overcome the shielding problem with a new alloy that absorbed the rays.

In 1958, at the height of the 1950s American automobile culture there were at least four theoretical nuclear-powered concept cars proposed, the American Ford Nucleon and Studebaker Packard Astral, as well as the French Simca Fulgur designed by Robert Opron and the Arbel Symétric. Apart from these concept models, none were built and no automotive nuclear power plants ever made. Chrysler engineer C R Lewis had discounted the idea in 1957 because of estimates that an 80,000 lb (36,000 kg) engine would be required by a 3,000 lb (1,400 kg) car. His view was that an efficient means of storing energy was required for nuclear power to be practical. Despite this, Chrysler's stylists in 1958 drew up some possible designs.

In 1959 it was reported that Goodyear Tire and Rubber Company had developed a new rubber compound that was light and absorbed radiation, obviating the need for heavy shielding. A reporter at the time considered it might make nuclear-powered cars and aircraft a possibility.

Ford made another potentially nuclear-powered model in 1962 for the Seattle World's Fair, the Ford Seattle-ite XXI. This also never went beyond the initial concept.

In 2009, for the hundredth anniversary of General Motors' acquisition of Cadillac, Loren Kulesus created concept art depicting a car powered by thorium.

Other

The Chrysler TV-8 was an experimental concept tank designed by Chrysler in the 1950s. The tank was intended to be a nuclear-powered medium tank capable of land and amphibious warfare. The design was never mass-produced.

The X-12 was a nuclear powered locomotive, proposed in a feasibility study done in 1954 at the University of Utah.

The Mars rovers Curiosity and Perseverance are powered by a radioisotope thermoelectric generator (RTG), like the successful Viking 1 and Viking 2 Mars landers in 1976.

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