RNA therapeutics

From Wikipedia, the free encyclopedia

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

 

See also: DNA vaccine and RNA vaccine

RNA therapeutics are a new class of medications based on ribonucleic acid (RNA). Research has been working on clinical use since the 1990s, with significant success in cancer therapy in the early 2010s. In 2020 and 2021, mRNA vaccines have been developed globally for use in combating the coronavirus disease (COVID-19 pandemic). The Pfizer–BioNTech COVID-19 vaccine was the first mRNA vaccine approved by a medicines regulator, followed by the Moderna COVID-19 vaccine, and others.

The main types of RNA therapeutics are those based on messenger RNA (mRNA), antisense RNA (asRNA), RNA interference (RNAi), RNA activation (RNAa) and RNA aptamers. Of the four types, mRNA-based therapy is the only type which is based on triggering synthesis of proteins within cells, making it particularly useful in vaccine development. Antisense RNA is complementary to coding mRNA and is used to trigger mRNA inactivation to prevent the mRNA from being used in protein translation. RNAi-based systems use a similar mechanism, and involve the use of both small interfering RNA (siRNA) and micro RNA (miRNA) to prevent mRNA translation and/or degrade mRNA. Small activating RNA (saRNA) represents a novel class of RNA therapeutics that upregulates gene expression via the RNAa mechanism, offering a unique mechanism compared to other RNA-based therapies. However, RNA aptamers are short, single stranded RNA molecules produced by directed evolution to bind to a variety of biomolecular targets with high affinity thereby affecting their normal in vivo activity.

RNA is synthesized from template DNA by RNA polymerase with messenger RNA (mRNA) serving as the intermediary biomolecule between DNA expression and protein translation. Because of its unique properties (such as its typically single-stranded nature and its 2' OH group) and its ability to adopt many different secondary/tertiary structures, both coding and noncoding RNAs have attracted attention in medicine. Research has begun to explore RNAs potential to be used for therapeutic benefit, and unique challenges have occurred during drug discovery and implementation of RNA therapeutics.

mRNA

Messenger RNA (mRNA) is a single-stranded RNA molecule that is complementary to one of the DNA strands of a gene. An mRNA molecule transfers a portion of the DNA code to other parts of the cell for making proteins. DNA therapeutics needs access to the nucleus to be transcribed into RNA, and its functionality depends on nuclear envelope breakdown during cell division. However, mRNA therapeutics do not need to enter into the nucleus to be functional since it will be translated immediately once it has reached to the cytoplasm. Moreover, unlike plasmids and viral vectors, mRNAs do not integrate into the genome and therefore do not have the risk of insertional mutagenesis, making them suitable for use in cancer vaccines, tumor immunotherapy and infectious disease prevention.

Discovery and development

In 1953, Alfred Day Hershey reported that soon after infection with phage, bacteria produced a form of RNA at a high level and this RNA was also broken down rapidly. However, the first clear indication of mRNA was from the work of Elliot Volkin and Lazarus Astrachan in 1956 by infecting E.coli with T2 bacteriophages and putting them into the medium with ³²P. They found out that the protein synthesis of E.coli was stopped and phage proteins were synthesized. Then, in May 1961, their collaborated researchers Sydney Brenner, François Jacob, and Jim Watson announced the isolation of mRNA. For a few decades after mRNA discovery, people focused on understanding the structural, functional, and metabolism pathway aspects of mRNAs. However, in 1990, Jon A. Wolff demonstrated the idea of nucleic acid-encoded drugs by direct injecting in vitro transcribed (IVT) mRNA or plasmid DNA (pDNA) into the skeletal muscle of mice which expressed the encoded protein in the injected muscle.

Once IVT mRNA has reached the cytoplasm, the mRNA is translated instantly. Thus, it does not need to enter the nucleus to be functional. Also, it does not integrate into the genome and therefore does not have the risk of insertional mutagenesis. Moreover, IVT mRNA is only transiently active and is completely degraded via physiological metabolic pathways. Due to these reasons, IVT mRNA has undergone extensive preclinical investigation.

Mechanisms

In vitro transcription (IVT) is performed on a linearized DNA plasmid template containing the targeted coding sequence. Then, naked mRNA or mRNA complexed in a nanoparticle will be delivered systemically or locally. Subsequently, a part of the exogenous naked mRNA or complexed mRNA will go through cell-specific mechanisms. Once in the cytoplasm, the IVT mRNA is translated by the protein synthesis machinery.

There are two identified RNA sensors, toll-like receptors (TLRs) and the RIG-I-like receptor family. TLRs are localized in the endosomal compartment of cells, such as DCs and macrophages. RIG-I-like family is as a pattern recognition receptor (PRR). However, the immune response mechanisms and process of mRNA vaccine recognition by cellular sensors and the mechanism of sensor activation are still unclear.

Applications

Cancer immunotherapy

In 1995, Robert Conry demonstrated that intramuscular injection of naked RNA encoding carcinoembryonic antigen elicited antigen-specific antibody responses. Then, it was elaborated by demonstrating that dendritic cells(DCs) exposed to mRNA coding for specific antigens or to total mRNA extracted from tumor cells and injected into tumor-bearing mice induced T cell immune responses and inhibited the growth of tumors. Then, researchers started to approach mRNA transfected DCs using vaccines based on ex vivo IVT mRNA-transfected DCs. Meanwhile, Argos Therapeutics had initiated a Phase III clinical trial using DCs with advanced renal cell carcinoma in 2015 (NCT01582672) but it was terminated due to the lack of efficacy.

For further application, IVT mRNA was optimized for in situ transfections of DCs in vivo. It improved the translation efficiency and stability of IVT mRNA and enhanced the presentation of the mRNA-encoded antigen on MHC class I and II molecules. Then, they found out that the direct injection of naked IVT mRNA into lymph nodes was the most effective way to induce T cell responses. Based on this discovery, first-in-human testing of the injection of naked IVT mRNA encoding cancer antigens by BioNTech has started with patients with melanoma (NCT01684241).

Recently, the new cancer immunotherapy, the combining of self-delivering RNA(sd-rxRNA) and adoptive cell transfer(ACT) therapy, was invented by RXi Pharmaceuticals and the Karolinska Institute. In this therapy, the sd-rxRNA eliminated the expression of immunosuppressive receptors and proteins in therapeutic immune cells so it improved the ability of immune cells to destroy the tumor cells. Then, the PD-1 targeted sd-rxRNA helped increasing the anti-tumor activity of tumor-infiltrating lymphocytes (TIL) against melanoma cells. Based on this idea, the mRNA-4157 has been tested and passed phase I clinical trial.

Cytosolic nucleic acid-sensing pathways can enhance immune response to cancer. RIG-I agonist, stem loop RNA (SLR) 14. Tumor growth was significantly delayed and extended survival in mice. SLR14 improved antitumor efficacy of anti-PD1 antibody over single-agent treatment. SLR14 was absorbed by CD11b+ myeloid cells in the tumor microenvironment. Genes associated with immune defense were significantly up-regulated, along with increased CD8+ T lymphocytes, NK cells, and CD11b+ cells. SLR14 inhibited nonimmunogenic B16 tumor growth, leaving immune memory.

Vaccines

Main article: RNA vaccine

In 1993, the first success of an mRNA vaccine was reported in mice, by using liposome-encapsulated IVT mRNA which is encoding the nucleoprotein of influenza that induced virus-specific T cells. Then, IVT mRNA was formulated with synthetic lipid nanoparticles and it induced protective antibody responses against the respiratory syncytial virus(RSV) and influenza virus in mice.

There are a few different types of IVT mRNA-based vaccine development for infectious diseases. One of the successful types is using self-amplifying IVT mRNA that has sequences of positive-stranded RNA viruses. It was originally developed for a flavivirus and it was workable with intradermal injection. One of the other ways is injecting a two-component vaccine which is containing an mRNA adjuvant and naked IVT mRNA encoding influenza hemagglutinin antigen only or in combination with neuraminidase encoding IVT mRNA.

For example, for the HIV treatment, vaccines are using DCs transfected with IVT mRNA that is encoding HIV proteins. There are a few phase I and II clinical trials using IVT mRNA encoding combinations and it shows that antigen-specific CD8+ and CD4+ T cell responses can be induced. However, no antiviral effects have been observed in the clinical trial.

One of the other mRNA vaccines is for COVID-19. The Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) outbreaks in December 2019 and spread all over the world, causing a pandemic of respiratory illness designated coronavirus disease 2019 (COVID-19). The Moderna COVID-19 vaccine, manufactured by Moderna since 2020, is a lipid nanoparticle (LNP) encapsulated mRNA-based vaccine that encodes for a full-length, prefusion stabilized spike(S)-2P antigen of SARS-CoV-2 with a transmembrane anchor.

Anti-viral

In 2021, SLR14 was reported to prevent infection in the lower respiratory tract and severe disease in an interferon type I (IFN-I)–dependent manner in mice. Immunodeficient mice with chronic SARS-CoV-2 infection experienced near-sterilizing innate immunity with no help from the adaptive immune system.

Tissue regeneration

A 2022 study by researchers from the Mayo Clinic, Maastricht University, and Ethris GmBH, a biotech company that focuses on RNA therapeutics, found that chemically modified mRNA encoding BMP-2 promoted dosage-dependent healing of femoral osteotomies in male rats. The mRNA molecules were complexed within nonviral lipid particles, loaded onto sponges, and surgically implanted into the bone defects. They remained localized around the site of application. Compared to receiving rhBMP-2 directly, bony tissues regenerated after mRNA treatment displayed superior strength and less formation of massive callus.

Limitations

There are many challenges for the successful translation of mRNA into drugs because mRNA is a very large and heavy molecule(10^5 ~ 10^6 Da). Moreover, mRNA is unstable and easily degraded by nucleases, and it also activates the immune systems. Furthermore, mRNA has a high negative charge density and it reduces the permeation of mRNA across cellular membranes. Due to these reasons, without the appropriate delivery system, mRNA is degraded easily and the half-life of mRNA without a delivery system is only around 7 hours. Even though some degrees of challenges could be overcome by chemical modifications, delivery of mRNA remains an obstacle. The methods that have been researched to improve the delivery system of mRNA are using microinjection, RNA patches (mRNA loaded in a dissolving micro-needle), gene gun, protamine condensation, RNA adjuvants, and encapsulating mRNA in nanoparticles with lipids.

Even though In Vitro Translated (IVT) mRNA with delivery agents showed improved resistance against degradation, it needs more studies on how to improve the efficiency of the delivery of naked mRNA in vivo.

Approved RNA Therapeutics

• patisiran
• givosiran
• lumasiran
• inclisiran

Antisense RNA

Antisense RNA is the non-coding and single-stranded RNA that is complementary to a coding sequence of mRNA. It inhibits the ability of mRNA to be translated into proteins. Short antisense RNA transcripts are produced within the nucleus by the action of the enzyme Dicer, which cleaves double-stranded RNA precursors into 21–26 nucleotide long RNA species.

There is an antisense-based discovery strategy, rationale and design of screening assays, and the application of such assays for screening of natural product extracts and the discovery of fatty acid condensing enzyme inhibitors. Antisense RNA is used for treating cancer and inhibition of metastasis and vectors for antisense sequestration. Particularly MicroRNAs(miRs) 15 and 16 to a patient in need of the treatment for diagnosis and prophylaxis of cancer. Antisense drugs are based on the fact that antisense RNA hybridizes with and inactivates mRNA. These drugs are short sequences of RNA that attach to mRNA and stop a particular gene from producing the protein for which it encodes. Antisense drugs are being developed to treat lung cancer, diabetes and diseases such as arthritis and asthma with a major inflammatory component. It shows that the decreased expression of MLLT4 antisense RNA 1 (MLLT4‑AS1) is a potential biomarker and a predictor of a poor prognosis for gastric cancer. So far, applications of antisense RNAs in antivirus and anticancer treatments and in regulating the expression of related genes in plants and microorganisms have been explored.

Non-viral vectors, virus vectors and liposomes have been used to deliver the antisense RNA through the cell membrane into the cytoplasm and nucleus. It has been found that the viral vector based delivery is the most advantageous among different delivery systems because it has a high transfection efficacy. However, it is difficult to deliver antisense RNA only to the targeted sites. Also, due to the size and the stability issues of antisense RNA, there are some limitations to its use. To improve the delivery issues, chemical modifications, and new oligonucleotide designs have been studied to enhance the drug distribution, side effects, and tolerability.

RNAi

Interfering RNA are a class of short, noncoding RNA that act to translationally or post-translationally repress gene expression. Their discovery and subsequent identification as key effectors of post-transcriptional gene regulation have made small interfering RNA (siRNA) and micro RNA (miRNA) potential therapeutics for systemic diseases. The RNAi system was originally discovered in 1990 by Jorgensen et al., who were doing research involving the introduction of coloration genes into petunias, and it is thought that this system originally developed as a means of innate immunity against double-stranded RNA viruses.

siRNA

A schematic of the mechanism for siRNA and miRNA gene regulation in vivo.

Small interfering (siRNA) are short, 19-23 base-pair (with a 3' overhang of two nucleotides), double-stranded pieces of RNA that participate in the RNA-induced silencing complex (RISC) for gene silencing. Specifically, siRNA is bound by the RISC complex where it is unwound using ATP hydrolysis. It is then used as a guide by the enzyme "Slicer" to target mRNAs for degradation based on complementary base-pairing to the target mRNA. As a therapeutic, siRNA is able to be delivered locally, through the eye or nose, to treat various diseases. Local delivery benefits from simple formulation and drug delivery and high bioavailability of the drug. Systemic delivery is necessary to target cancers and other diseases. Targeting the siRNA when delivered locally is one of the main challenges in siRNA therapeutics. While it is possible to use intravenous injection to deliver siRNA therapies, concerns have been raised about the large volumes used in the injection, as these must often be ~20-30% of the total blood volume. Other methods of delivery include liposome packaging, conjugation to membrane-permeable peptides, and direct tissue/organ electroporation. Additionally, it has been found that exogeneous siRNAs only last a few days (a few weeks at most in non-dividing cells) in vivo. If siRNA is able to successfully reach its target, it has the potential to therapeutically regulate gene expression through its ability to base-pair to mRNA targets and promote their degradation through the RISC system. Currently, siRNA-based therapy is in a phase I clinical trial for the treatment of age-related macular degeneration, although it is also being explored for use in cancer therapy. For instance, siRNA can be used to target mRNAs that code for proteins that promote tumor growth such as the VEGF receptor and telomerase enzyme.

miRNA

Micro RNAs (miRNAs) are short, ~19-23 base pair long RNA oligonucleotides that are involved in the microRNA-induced silencing complex. Specifically, once loaded onto the ARGONAUTE enzyme, miRNAs work with mRNAs to repress translation and post-translationally destabilize mRNA. While they are functionally similar to siRNAs, miRNAs do not require extensive base-pairing for mRNA silencing (can require as few as seven base-pairs with target), thus allowing them to broadly affect a wider range of mRNA targets. In the cell, miRNA uses switch, tuning, and neutral interactions to finely regulate gene repression. As a therapeutic, miRNA has the potential to affect biochemical pathways throughout the organism.

With more than 400 miRNA identified in humans, discerning their target gene for repression is the first challenge. Multiple databases have been built, for example TargetScan, using miRNA seed matching. In vitro assays assist in determining the phenotypic effects of miRNAs, but due to the complex nature of gene regulation not all identified miRNAs have the expected effect. Additionally, several miRNAs have been found to act as either tumor suppressors or oncogenes in vivo, such as the oncogenic miR-155 and miR-17-92.

In clinical trials, miRNA are commonly used as biomarkers for a variety of diseases, potentially providing earlier diagnosis as well as disease progression, stage, and genetic links. Phase 1 and 2 trials currently test miRNA mimics (to express genes) and miRNA (to repress genes) in patients with cancers and other diseases. In particular, mimic miRNAs are used to introduce miRNAs that act as tumor suppressors into cancerous tissues, while miRNA antagonists are used to target oncogenic miRNAs to prevent their cancer-promoting activity. Therapeutic miRNA is also used in addition to common therapies (such as cancer therapies) that are known to overexpress or destabilize the patient miRNA levels. An example of one mimic miRNA therapy that demonstrated efficacy in impeding lung cancer tumor growth in mouse studies is miR-34a.

One concerning aspect of miRNA-based therapies is the potential for the exogeneous miRNA to affect miRNA silencing mechanisms within normal body cells, thereby affecting normal cellular biochemical pathways. However, in vivo studies have indicated that miRNAs display little to no effect in non-target tissues/organs.

Small activating RNAs (saRNAs)

Main article: Small activating RNA

Small activating RNAs (saRNAs) are short double-stranded RNA molecules (typically 19–21 nucleotides in length) that induce transcriptional activation of target genes through a process known as RNA activation (RNAa). Unlike RNA interference (RNAi), which silences gene expression, saRNAs upregulate gene expression by targeting promoter regions of DNA and recruiting transcriptional machinery.

The mechanism of RNAa involves the formation of an RNA-induced transcriptional activation (RITA) complex. This complex includes Argonaute proteins (particularly Ago2), RNA helicase A (RHA), and other transcriptional coactivators, which facilitate the activation of RNA polymerase II at the targeted promoter. This process is often associated with epigenetic changes, such as histone modifications, that promote active transcription.

saRNAs have demonstrated potential in preclinical studies for treating diseases caused by insufficient gene expression, such as cancer and metabolic disorders. For example, saRNAs have been used to reactivate tumor suppressor genes in cancer cells, offering a promising therapeutic approach. Additionally, saRNAs are being explored for their ability to upregulate genes involved in metabolic regulation, neurodegenerative diseases, and other conditions.

An example of an saRNA therapeutic in clinical development is MTL-CEBPA, which targets the CEBPA gene to treat liver cancer. This drug, developed by MiNA Therapeutics, has shown promise in early-phase clinical trials. Another saRNA therapeutic, RAG-01, developed by Ractigen Therapeutics, is being investigated for the treatment of non-muscle invasive bladder cancer (NMIBC) and has shown promising early complete responses (CRs) in Phase I trial for BCG-unresponsive patients.

saRNAs represent a significant advancement in RNA therapeutics, expanding the scope of RNA-based therapies to include gene activation in addition to gene silencing.

RNA aptamers

An RNA aptamer known as "Spinach" was created as a fluorescent imaging tool in vivo. Its fluorescent activity is based upon binding to 3,5-difluoro-4-hydroxybenzylidene imidazolidinone (DFHBI).

Broadly, aptamers are small molecules composed of either single-stranded DNA or RNA and are typically 20-100 nucleotides in length, or ~3-60 kDa. Because of their single-stranded nature, aptamers are capable of forming many secondary structures, including pseudoknots, stem loops, and bulges, through intra-strand base pairing interactions. The combinations of secondary structures present in an aptamer confer it a particular tertiary structure which in turn dictates the specific target the aptamer will selectively bind to. Because of the selective binding ability of aptamers, they are considered a promising biomolecule for use in pharmaceuticals. Additionally, aptamers exhibit tight binding to targets, with dissociation constants often in the pM to nM range. Besides their strong binding ability, aptamers are also valued because they can be used on targets that are not capable of being bound by small peptides generated by phage display or by antibodies, and they are able to differentiate between conformational isomers and amino acid substitutions. Also, because aptamers are nucleic-acid based, they can be directly synthesized, eliminating the need for cell-based expression and extraction as is the case in antibody production. RNA aptamers in particular are capable of producing a myriad of different structures, leading to speculations that they are more discriminating in their target affinity compared to DNA aptamers.

Discovery and development

Aptamers were originally discovered in 1990 when Lary Gold and Craig Tuerk utilized a method of directed evolution known as SELEX to isolate a small single stranded RNA molecule that was capable of binding to T4 bacteriophage DNA polymerase. Additionally, the term “aptamer” was coined by Andrew Ellington, who worked with Jack Szostak to select an RNA aptamer that was capable of tight binding to certain organic dye molecules. The term itself is a conglomeration of the Latin “aptus” or “to fit” and the Greek “meros” or “part."

RNA aptamers are not so much “created” as “selected.” To develop an RNA aptamer capable of selective binding to a molecular target, a method known as Systematic Evolution of Ligands by EXponential Enrichment (SELEX) is used to isolate a unique RNA aptamer from a pool of ~10^13 to 10^16 different aptamers, otherwise known as a library. The library of potential aptamer oligonucleotides is then incubated with a non-target species so as to remove aptamers that exhibit non-specific binding. After subsequent removal of the non-specific aptamers, the remaining library members are then exposed to the desired target, which can be a protein, peptide, cell type, or even an organ (in the case of live animal-based SELEX). From there, the RNA aptamers which were bound to the target are transcribed to cDNA which then is amplified through PCR, and the PCR products are then re-transcribed to RNA. These new RNA transcripts are then used to repeat the selection cycle many times, thus eventually producing a homogeneous pool of RNA aptamers capable of highly specific, high-affinity target binding.

Examples

RNA aptamers can be designed to act as antagonists, agonists, or so-called ”RNA decoy aptamers." In the case of antagonists, the RNA aptamer is used either to prevent binding of a certain protein to its cell membrane receptor or to prevent the protein from performing its activity by binding to the protein's target. Currently, the only RNA aptamer-based therapies that have advanced to clinical trials act as antagonists. When RNA aptamers are designed to act as agonists, they promote immune cell activation as a co-stimulatory molecule, thus aiding in the mobilization of the body's own defense system. For RNA decoy aptamers, the synthetic RNA aptamer resembles a native RNA molecule. As such, proteins(s) which bind to the native RNA target instead bind to the RNA aptamer, possibly interfering with the biomolecular pathway of a particular disease. In addition to their utility as direct therapeutic agents, RNA aptamers are also being considered for other therapeutic roles. For instance, by conjugating the RNA aptamer to a drug compound, the RNA aptamer can act as a targeted delivery system for that drug. Such RNA aptamers are known as ApDCs. Additionally, through conjugation to radioisotope or a fluorescent dye molecule, RNA aptamers may be useful in diagnostic imaging.

Because of the SELEX process utilized to select RNA aptamers, RNA aptamers can be generated for many potential targets. By directly introducing the RNA aptamers to the target during SELEX, a very selective, high-affinity, homogeneous pool of RNA aptamers can be produced. As such, RNA aptamers can be made to target small peptides and proteins, as well as cell fragments, whole cells, and even specific tissues. Examples of RNA aptamer molecular targets and potential targets include vascular endothelial growth factor, osteoblasts, and C-X-C Chemokine Ligand 12 (CXCL2).

The chemical structure of the RNA aptamer known as Pegaptanib, a treatment for age-related macular degeneration.

An example of an RNA aptamer therapy includes Pegaptanib (aka Macugen ® ), the only FDA-approved RNA aptamer treatment. Originally approved in 2004 to treat age-related macular degeneration, Pegaptanib is a 28 nucleotide RNA aptamer that acts as a VEGF antagonist. However, it is not as effective as antibody-based treatments such as bevacizumab and ranibizumab. Another example of an RNA aptamer therapeutic is NOX-A12, a 45 nucleotide RNA aptamer that is in clinical trials for chronic lymphocytic leukemia, pancreatic cancer, as well as other cancers. NOX-A12 acts as antagonist for CXCL12/SDF-1, a chemokine involved in tumor growth.

Limitations

While the high-selectivity and tight-binding of RNA aptamers have generated interest in their use as pharmaceuticals, there are many problems which have prevented them from being successful in vivo. For one, without modifications RNA aptamers are degraded after being introduced into the body by nucleases in the span of a few minutes. Also, due to their small size, RNA aptamers can be removed from the bloodstream by the renal system. Because of their negative charge, RNA aptamers are additionally known to bind proteins in the bloodstream, leading to non-target tissue delivery and toxicity. Care must also be taken when isolating the RNA aptamers, as aptamers which contain repeated Cytosine-Phosphate-Guanine (CpG) sequences will cause immune system activation through the Toll-like receptor pathway.

In order to combat some of the in vivo limitations of RNA aptamers, various modifications can be added to the nucleotides to aid in efficacy of the aptamer. For instance, a polyethylene glycol (PEG) moiety can be attached to increase the size of the aptamer, thereby preventing its removal from the bloodstream by the renal glomerulus. However, PEG has been implicated in allergic reactions during in vivo testing. Furthermore, modifications can be added to prevent nuclease degradation, such as a 2’ fluoro or amino group as well as a 3’ inverted thymidine. Additionally, the aptamer can be synthesized so that the ribose sugar is in the L-form instead of the D-form, further preventing nuclease recognition. Such aptamers are known as Spiegelmers. In order to prevent Toll-like receptor pathway activation, the cytosine nucleobases within the aptamer can be methylated. Nevertheless, despite these potential solutions to reduced in vivo efficacy, it is possible that chemically modifying the aptamer may weaken its binding affinity towards its target.

Alternative fuel

From Wikipedia, the free encyclopedia

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

Typical Brazilian filling station with four alternative fuels for sale: biodiesel (B3), gasohol (E25), neat ethanol (E100), and compressed natural gas (CNG). Piracicaba, São Paulo, Brazil.

Alternative fuels, also known as non-conventional and advanced fuels, are fuels derived from sources other than petroleum. Alternative fuels include gaseous fossil fuels like propane, natural gas, methane, and ammonia; biofuels like biodiesel, bioalcohol, and refuse-derived fuel; and other renewable fuels like hydrogen and electricity.

These fuels are intended to substitute for more carbon intensive energy sources like gasoline and diesel in transportation and can help to contribute to decarbonization and reductions in pollution. Alternative fuel is also shown to reduce non-carbon emissions such as the release of nitric oxide and nitrogen dioxide, as well as sulfur dioxide and other harmful gases in the exhaust. This is especially important in industries such as mining, where toxic gases can accumulate more easily.

Official definitions

Definition in the European Union

In the European Union, alternative fuel is defined by Directive 2014/94/EU of the European Parliament and of the Council of 22 October 2014 on the deployment of alternative fuels infrastructure.

'alternative fuels' means fuels or power sources which serve, at least partly, as a substitute for fossil oil sources in the energy supply to transport and which have the potential to contribute to its decarbonisation and enhance the environmental performance of the transport sector. They include, inter alia:

• electricity,
• hydrogen,
• biofuels as defined in point (i) of Article 2 of Directive 2009/28/EC,
• synthetic and paraffinic fuels,
• natural gas, including biomethane, in gaseous form (compressed natural gas (CNG)) and liquefied form (liquefied natural gas (LNG)), and
• liquefied petroleum gas (LPG);

— Directive 2014/94/EU of the European Parliament and of the Council of 22 October 2014 on the deployment of alternative fuels infrastructure.

Definition in the US

In the US, the EPA defines alternative fuel as

Alternative fuel including gaseous fuels such as hydrogen, natural gas, and propane; alcohols such as ethanol, methanol, and butanol; vegetable and waste-derived oils; and electricity. These fuels may be used in a dedicated system that burns a single fuel, or in a mixed system with other fuels including traditional gasoline or diesel, such as in hybrid-electric or flexible fuel vehicles.

— EPA

Definition in Canada

In Canada, since 1996, Alternative Fuels Regulations SOR/96-453 Alternative Fuels Act defined alternative fuel:

For the purposes of the definition alternative fuel in subsection 2(1) of the Act, the following, when used as the sole source of direct propulsion energy of a motor vehicle, are prescribed to be alternative fuels:

(a) ethanol;

(b) methanol;

(c) propane gas;

(d) natural gas;

(e) hydrogen;

(f) electricity;

(g) for the purposes of subsections 4(1) and 5(1) of the Act, any blended fuel that contains at least 50 per cent of one of the fuels referred to in paragraphs (a) to (e); and

(h) for the purposes of subsections 4(2) and 5(2) of the Act, any blended fuel that contains one of the fuels mentioned in paragraphs (a) to (e).

— Alternative Fuels Regulations (SOR/96-453)

China

In China, alternative fuel vehicles should comply with technical guidelines for the local production of alternative-fuel vehicles: they should have a shelf life of more than 100,000 kilometres (62,000 mi), and a complete charge should take less than seven hours. Up to 80% of a charge must be available after less than 30 minutes of charging. In addition, pure-electric vehicles must consume electric energy of less than 0.16 kWh/km.

Biofuel

Main article: Biofuel

Alternative fuel dispensers at a regular gasoline station in Arlington, Virginia. B20 biodiesel at the left and E85 ethanol at the right.

Biofuels are also considered a renewable source. Although renewable energy is used mostly to generate electricity, it is often assumed that some form of renewable energy or a percentage is used to create alternative fuels. Research is ongoing into finding more suitable biofuel crops and improving the oil yields of these crops. Using the current yields, vast amounts of arable land and fresh water would be needed to produce enough oil to completely replace fossil fuel usage.

Biomass

Main article: Biomass

Biomass in the energy production industry is living and recently dead biological material which can be used as fuel or for industrial production. It has become popular among coal power stations, which switch from coal to biomass in order to convert to renewable energy generation without wasting existing generating plant and infrastructure. Biomass most often refers to plants or plant-based materials that are not used for food or feed, and are specifically called nitrocellulose biomass. As an energy source, biomass can either be used directly via combustion to produce heat, or indirectly after converting it to various forms of biofuel.

Algae fuel

Main article: Algae fuel

Algae-based biofuels have been promoted in the media as a potential panacea to crude oil-based transportation problems. Algae could yield more than 2000 gallons of fuel per acre per year of production. Algae based fuels are being successfully tested by the U.S. Navy Algae-based plastics show potential to reduce waste and the cost per pound of algae plastic is expected to be cheaper than traditional plastic prices.

Biodiesel

Main article: Biodiesel

Vegetable oil fuelled bus at South by South West festival, Austin, Texas (March 2008).

Biodiesel is made from animal fats or vegetable oils, renewable resources that come from plants such as atrophy, soybean, sunflowers, corn, olive, peanut, palm, coconut, safflower, canola, sesame, cottonseed, etc. Once these fats or oils are filtered from their hydrocarbons and then combined with alcohol like methanol, diesel is produced from this chemical reaction. These raw materials can either be mixed with pure diesel to make various proportions or used alone. Despite one’s mixture preference, biodiesel will release a smaller number of pollutants (carbon monoxide, particulates and hydrocarbons) than conventional diesel, because biodiesel burns both cleanly and more efficiently. Even with regular diesel’s reduced quantity of sulfur from the LSD (ultra-low sulfur diesel) invention, biodiesel exceeds those levels because it is sulfur-free.

Alcohol fuels

Main articles: Alcohol fuel, Butanol fuel, Ethanol fuel, and Methanol fuel

Methanol and ethanol fuel are primary sources of energy; they are convenient fuels for storing and transporting energy. These alcohols can be used in internal combustion engines as alternative fuels. Butane has another advantage: it is the only alcohol-based motor fuel that can be transported readily by existing petroleum-product pipeline networks, instead of only by tanker trucks and railroad cars.

Ammonia

Research and patenting activities into using ammonia as a marine fuel have increased significantly between 2004 and 2023.

Ammonia (NH₃) can be used as fuel. Benefits of ammonia for ships include reducing greenhouse gas emissions. Nitrogen reduction is being considered as a possible component for fuel cells and combustion engines through research of conversion of ammonia to nitrogen gas and hydrogen gas.

Ammonia is the simplest molecule that carries hydrogen in a liquid form. It is carbon-free and can be produced using renewable energy. Ammonia can become a transitional fuel soon because of its relative easiness of storage and distribution.

Emulsion fuel

Emulsified fuels include multiple components that are mixed to a water-in-oil emulsion, which are created to improve the fuels combustive properties. Diesel can also be emulsified with water to be used as a fuel. It helps in improving engine efficiency and reducing exhaust emissions.

Carbon-neutral and negative fuels

Carbon-neutral fuel is synthetic fuel—such as methane, gasoline, diesel fuel or jet fuel—produced from renewable or nuclear energy used to hydrogenate waste carbon dioxide recycled from power plant flue exhaust gas or derived from carbolic acid in seawater. Such fuels are potentially carbon neutral because they do not result in a net increase in atmospheric greenhouse gases. To the extent that carbon neutral fuels displace fossil fuels, or if they are produced from waste carbon or seawater carbolic acid, and their combustion is subject to carbon capture at the flue or exhaust pipe, they result in negative carbon dioxide emission and net carbon dioxide removal from the atmosphere, and thus constitute a form of greenhouse gas remediation. Such carbon neutral and negative fuels can be produced by the electrolysis of water to make hydrogen used in the Sabatier reaction to produce methane which may then be stored to be burned later in power plants as synthetic natural gas, transported by pipeline, truck, or tanker ship, or be used in gas to liquids processes such as the Fischer–Tropsch process to make traditional transportation or heating fuels.

Carbon-neutral fuels have been proposed for distributed storage for renewable energy, minimizing problems of wind and solar intermittent, and enabling transmission of wind, water, and solar power through existing natural gas pipelines. Such renewable fuels could alleviate the costs and dependency issues of imported fossil fuels without requiring either electrification of the vehicle fleet or conversion to hydrogen or other fuels, enabling continued compatible and affordable vehicles. Germany has built a 250-kilowatt synthetic methane plant which they are scaling up to 10 megawatts. Audi has constructed a carbon neutral liquefied natural gas (LNG) plant in Werlte, Germany. The plant is intended to produce transportation fuel to offset LNG used in their A3 Sportback g-tron automobiles, and can keep 2,800 metric tons of CO₂ out of the environment per year at its initial capacity. Other commercial developments are taking place in Columbia, South Carolina, Camarillo, California, and Darlington, England.

The least expensive source of carbon for recycling into fuel is flue-gas emissions from fossil-fuel combustion, where it can be extracted for about US $7.50 per ton. Automobile exhaust gas capture has also been proposed to be economical but would require extensive design changes or retrofitting. Since carbonic acid in seawater is in chemical equilibrium with atmospheric carbon dioxide, extraction of carbon from seawater has been studied. Researchers have estimated that carbon extraction from seawater would cost about $50 per ton. Carbon capture from ambient air is more costly, at between $600 and $1000 per ton and is considered impractical for fuel synthesis or carbon sequestration.

Nighttime wind power is considered the most economical form of electrical power with which to synthesize fuel, because the load curve for electricity peaks sharply during the warmest hours of the day, but wind tends to blow slightly more at night than during the day. Therefore, the price of nighttime wind power is often much less expensive than any alternative. Off-peak wind power prices in high wind penetration areas of the U.S. averaged 1.64 cents per kilowatt-hour in 2009, but only 0.71 cents/kWh during the least expensive six hours of the day. Typically, wholesale electricity costs 2 to 5 cents/kWh during the day. Commercial fuel synthesis companies suggest they can produce fuel for less than petroleum fuels when oil costs more than $55 per barrel. The U.S. Navy estimates that shipboard production of jet fuel from nuclear power would cost about $6 per gallon. While that was about twice the petroleum fuel cost in 2010, it is expected to be much less than the market price in less than five years if recent trends continue. Moreover, since the delivery of fuel to a carrier battle group costs about $8 per gallon, shipboard production is already much less expensive. However, U.S. civilian nuclear power is considerably more expensive than wind power. The Navy's estimate that 100 megawatts can produce 41,000 gallons of fuel per day indicates that terrestrial production from wind power would cost less than $1 per gallon.

Hydrogen and formic acid

Main article: Hydrogen fuel

Hydrogen is an emissionless fuel. The byproduct of hydrogen burning is water, although some mono-nitrogen oxides NOx are produced when hydrogen is burned with air.

Main article: Formic acid

Another fuel is formic acid. The fuel is used by converting it first to hydrogen and using that in a fuel cell. Formic acid is much more easy to store than hydrogen.

Hydrogen/compressed natural gas mixture

Main article: HCNG

HCNG (or H2CNG) is a mixture of compressed natural gas and 4–9 percent hydrogen by energy. Hydrogen could also be used as hydroxy gas for better combustion characteristics of compression-ignition engines. Hydroxy gas is obtained through electrolysis of water.

Compressed air

The air engine is an emission-free piston engine using compressed air as fuel.

Propane autogas

Main article: Autogas

Propane is a cleaner burning, high-performance fuel derived from multiple sources. It is known by many names including propane, LPG (liquified propane gas), LPA (liquid propane autogas), Autogas and others. Propane is a hydrocarbon fuel and is a member of the natural gas family.

Propane as an automotive fuel shares many of the physical attributes of gasoline while reducing tailpipe emissions and well to wheel emissions overall. Propane is the number one alternative fuel in the world and offers an abundance of supply, liquid storage at low pressure, an excellent safety record and large cost savings when compared to traditional fuels.

Propane delivers an octane rating between 104 and 112 depending on the composition of the butane/propane ratios of the mixture. Propane autogas in a liquid injection format captures the phase change from liquid to gas state within the cylinder of the combustion engine producing an "intercooler" effect, reducing the cylinder temperature and increasing air density. The resultant effect allows more advance on the ignition cycle and a more efficient engine combustion.

Propane lacks additives, detergents or other chemical enhancements further reducing the exhaust output from the tailpipe. The cleaner combustion also has fewer particulate emissions, lower NO_x due to the complete combustion of the gas within the cylinder, higher exhaust temperatures increasing the efficiency of the catalyst and deposits less acid and carbon inside the engine which extends the useful life of the lubricating oil.

Propane autogas is generated at the well alongside other natural gas and oil products. It is also a by-product of the refining processes which further increase the supply of Propane to the market.

Propane is stored and transported in a liquid state at roughly 5 bar (73 psi) of pressure. Fueling vehicles are similar to gasoline in the speed of delivery with modern fueling equipment. Propane filling stations only require a pump to transfer vehicle fuel and do not require expensive and slow compression systems when compared to compressed natural gas which is usually kept at over 3,000 psi (210 bar).

In a vehicle format, propane autogas can be retrofitted to almost any engine and provide fuel cost savings and lowered emissions while being more efficient as an overall system due to the large, pre-existing propane fueling infrastructure that does not require compressors and the resultant waste of other alternative fuels in well to wheel lifecycles.

Compressed natural gas

Compressed natural gas (CNG) and liquefied natural gas (LNG) are two cleaner combustible alternatives to conventional liquid automobile fuels.

Compressed natural gas fuel types

CNG vehicles can use both renewable CNG and non-renewable CNG.

Conventional CNG is a fossil fuel. New technologies such as horizontal drilling and hydraulic fracturing to economically access unconventional gas resources, appear to have increased the supply of natural gas in a fundamental way.

Renewable natural gas or biogas is a methane-based gas with similar properties to natural gas that can be used as transportation fuel. Present sources of biogas are mainly landfills, sewage, and animal/agri-waste. Based on the process type, biogas can be divided into the following: biogas produced by anaerobic digestion, landfill gas collected from landfills, treated to remove trace contaminants, and synthetic natural gas (SNG).

Practicality

CNG powers more than 5 million vehicles worldwide, and just over 150,000 of these are in the U.S. American usage is growing at a dramatic rate.

Environmental analysis

Because natural gas emits less smog-forming pollutants than other fossil fuels when combusted, cleaner air has been measured in urban localities switching to natural gas vehicles. Tailpipe CO₂ can be reduced by 15–25% compared to gasoline, diesel. The greatest reductions occur in medium and heavy duty, light duty and refuse truck segments.

CO₂ reductions of up to 88% are possible by using biogas.

Natural gas and hydrogen are both lighter than air and can be mixed together.

Nuclear power and radiothermal generators

Main articles: Nuclear power and radiothermal generator

Nuclear reactors

Nuclear power is any nuclear technology designed to extract usable energy from atomic nuclei via controlled nuclear reactions. Currently, the only controlled method uses nuclear fission in a fissile fuel (with a small fraction of the power coming from subsequent radioactive decay). Use of nuclear fusion for controlled power generation is not yet practical, but is an active area of research.

Nuclear power generally requires a nuclear reactor to heat a working fluid such as water, which is then used to create steam pressure, which is converted into mechanical work for the purpose of generating electricity or propulsion in water. Today, more than 15% of the world's electricity comes from nuclear power, and over 150 nuclear-powered naval vessels have been built.

In theory, electricity from nuclear reactors could also be used for propulsion in space, but this has yet to be demonstrated in a space flight. Some smaller reactors, such as the TOPAZ nuclear reactor, are built to minimize moving parts and use methods that convert nuclear energy to electricity more directly, making them useful for space missions, but this electricity has historically been used for other purposes. Power from nuclear fission has been used in a number of spacecraft, all of them uncrewed. The Soviets up to 1988 orbited 33 nuclear reactors in RORSAT military radar satellites, where electric power generated was used to power a radar unit that located ships on the Earth's oceans. The U.S. also orbited one experimental nuclear reactor in 1965, in the SNAP-10A mission.

Thorium fuelled nuclear reactors

Thorium-based nuclear power reactors have also become an area of active research in recent years. It is being backed by many scientists and researchers, and Professor James Hansen, the former Director at NASA Goddard Institute for Space Studies has reportedly said, "After studying climate change for over four decades, it's clear to me that the world is heading for a climate catastrophe unless we develop adequate energy sources to replace fossil fuels. Safer, cleaner and cheaper nuclear power can replace coal and is desperately needed as an essential part of the solution". Thorium is 3–4 times more abundant within nature than uranium, and its ore, monazite, is commonly found in sands along bodies of water. Thorium has also gained interest because it could be easier to obtain than uranium. While uranium mines are enclosed underground and thus very dangerous for the miners, thorium is taken from open pits. Monazite is present in countries such as Australia, the United States and India, in quantities large enough to power the earth for thousands of years. As an alternative to uranium-fuelled nuclear reactors, thorium has been proven to add to proliferation, produces radioactive waste for deep geological repositories like technetium-99 (half-life over 200,000 years), and has a longer fuel cycle.

For a list of experimental and presently-operating thorium-fueled reactors, see Thorium fuel cycle § List of thorium-fueled reactors.

Radiothermal generators

In addition, radioisotopes have been used as alternative fuels, on both lands, and in space. Their use on land is declining due to the danger of theft of isotope and environmental damage if the unit is opened. The decay of radioisotopes generates both heat and electricity in many space probes, particularly probes to outer planets where sunlight is weak, and low temperatures is a problem. Radiothermal generators (RTGs) which use radioisotopes as fuels do not sustain a nuclear chain reaction, but rather generate electricity from the decay of a radioisotope.

d electron count

From Wikipedia, the free encyclopedia

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

The d electron count or number of d electrons is a chemistry formalism used to describe the electron configuration of the valence electrons of a transition metal center in a coordination complex. The d electron count is an effective way to understand the geometry and reactivity of transition metal complexes. The formalism has been incorporated into the two major models used to describe coordination complexes; crystal field theory and ligand field theory, which is a more advanced version based on molecular orbital theory. However the d electron count of an atom in a complex is often different from the d electron count of a free atom or a free ion of the same element.

Electron configurations of transition metal atoms

For free atoms, electron configurations have been determined by atomic spectroscopy. Lists of atomic energy levels and their electron configurations have been published by the National Institute of Standards and Technology (NIST) for both neutral and ionized atoms.

For neutral atoms of all elements, the ground-state electron configurations are listed in general chemistry and inorganic chemistry textbooks. The ground-state configurations are often explained using two principles: the Aufbau principle that subshells are filled in order of increasing energy, and the Madelung rule that this order corresponds to the order of increasing values of (n + l) where n is the principal quantum number and l is the azimuthal quantum number. This rule predicts for example that the 4s orbital (n = 4, l = 0, n + l = 4) is filled before the 3d orbital (n = 3, l = 2, n + l = 5), as in titanium with configuration [Ar]4s²3d².

There are a few exceptions with only one electron (or zero for palladium) in the ns orbital in favor of completing a half or a whole d shell. The usual explanation in chemistry textbooks is that half-filled or completely filled subshells are particularly stable arrangements of electrons. An example is chromium whose electron configuration is [Ar]4s¹3d⁵ with a d electron count of 5 for a half-filled d subshell, although Madelung's rule predicts [Ar]4s²3d⁴. Similarly copper is [Ar]4s¹3d¹⁰ with a full d subshell, and not [Ar]4s²3d⁹. The configuration of palladium is [Kr]4d¹⁰ with zero 5s electrons. However this trend is not consistent: tungsten, a group VI element like Cr and Mo has a Madelung-following [Xe]6s²4f¹⁴5d⁴, and niobium has a [Kr]5s¹4d⁴ as opposed to the Madelung rule predicted [Kr]5s²4d³ which creates two partially-filled subshells.

When a transition metal atom loses one or more electrons to form a positive ion, overall electron repulsion is reduced and the n d orbital energy is lowered more than the (n+1) s orbital energy. The ion is formed by removal of the outer s electrons and tends to have a dⁿ configuration, even though the s subshell is added to neutral atoms before the d subshell. For example, the Ti²⁺ ion has the ground-state configuration [Ar]3d² with a d electron count of 2, even though the total number of electrons is the same as the neutral calcium atom which is [Ar]4s².

In coordination complexes between an electropositive transition metal atom and an electronegative ligand, the transition metal is approximately in an ionic state as assumed in crystal field theory, so that the electron configuration and d electron count are those of the transition metal ion rather than the neutral atom.

Ligand field perspective

Ligand field scheme summarizing σ-bonding in the octahedral complex [Ti(H₂O)₆]³⁺.

According to Ligand Field Theory, the ns orbital is involved in bonding to the ligands and forms a strongly bonding orbital which has predominantly ligand character and the correspondingly strong anti-bonding orbital which is unfilled and usually well above the lowest unoccupied molecular orbital (LUMO). Since the orbitals resulting from the ns orbital are either buried in bonding or elevated well above the valence, the ns orbitals are not relevant to describing the valence. Depending on the geometry of the final complex, either all three of the np orbitals or portions of them are involved in bonding, similar to the ns orbitals. The np orbitals if any that remain non-bonding still exceed the valence of the complex. That leaves the (n − 1)d orbitals to be involved in some portion of the bonding and in the process also describes the metal complex's valence electrons. The final description of the valence is highly dependent on the complex's geometry, in turn highly dependent on the d electron count and character of the associated ligands.

For example, in the MO diagram provided for the [Ti(H₂O)₆]³⁺ the ns orbital – which is placed above (n − 1)d in the representation of atomic orbitals (AOs) – is used in a linear combination with the ligand orbitals, forming a very stable bonding orbital with significant ligand character as well as an unoccupied high energy antibonding orbital which is not shown. In this situation the complex geometry is octahedral, which means two of the d orbitals have the proper geometry to be involved in bonding. The other three d orbitals in the basic model do not have significant interactions with the ligands and remain as three degenerate non-bonding orbitals. The two orbitals that are involved in bonding form a linear combination with two ligand orbitals with the proper symmetry. This results in two filled bonding orbitals and two orbitals which are usually the lowest unoccupied molecular orbitals (LUMO) or the highest partially filled molecular orbitals – a variation on the highest occupied molecular orbitals (HOMO).

Crystal field theory is an alternative description of electronic configurations that is simplified relative to LFT. It rationalizes a number of phenomena, but does not describe bonding nor offer an explanation for why ns electrons are ionized before (n − 1)d electrons.

Tanabe–Sugano diagram

Each of the ten possible d electron counts has an associated Tanabe–Sugano diagram describing gradations of possible ligand field environments a metal center could experience in an octahedral geometry. The Tanabe–Sugano diagram with a small amount of information accurately predicts absorptions in the UV and visible electromagnetic spectrum resulting from d to d orbital electron transitions. It is these d–d transitions, ligand to metal charge transfers (LMCT), or metal to ligand charge transfers (MLCT) that generally give metals complexes their vibrant colors.

Limitation

Counting d electrons is a formalism. Often it is difficult or impossible to assign electrons and charge to the metal center or a ligand. For a high-oxidation-state metal center with a +4 charge or greater it is understood that the true charge separation is much smaller. But referring to the formal oxidation state and d electron count can still be useful when trying to understand the chemistry.

Possible d electron counts

There are many examples of every possible d electron configuration. What follows is a short description of common geometries and characteristics of each possible d electron count and representative examples.

d⁰

Commonly tetrahedral; however it is possible for d⁰ complexes to accommodate many electron pairs (bonds/coordination number) since their d orbitals are empty and well away from the 18-electron ceiling. Often colorless due to the lack of d to d transitions.

Examples: titanium tetrachloride, titanocene dichloride, Schwartz's reagent.

d¹

Examples: molybdenum(V) chloride, vanadyl acetylacetonate, vanadocene dichloride, vanadium tetrachloride.

d²

Examples: titanocene dicarbonyl.

d³

Examples: Reinecke's salt.

d⁴

Octahedral high-spin: 4 unpaired electrons, paramagnetic, substitutionally labile.

Octahedral low-spin: 2 unpaired electrons, paramagnetic, substitutionally inert.

d⁵

High-spin [Fe(NO₂)₆]³⁻ crystal field diagram

Low-spin [Fe(NO₂)₆]³⁻ crystal field diagram

Octahedral high-spin: 5 unpaired electrons, paramagnetic, substitutionally labile.

Octahedral low-spin: 1 unpaired electron, paramagnetic, substitutionally inert.

Examples: potassium ferrioxalate, vanadium carbonyl.

d⁶

Commonly octahedral complexes in both high spin and low spin.

Octahedral high-spin: 4 unpaired electrons, paramagnetic, substitutionally labile.

Octahedral low-spin: no unpaired electrons, diamagnetic, substitutionally inert.

Examples: hexamminecobalt(III) chloride, sodium cobaltinitrite, molybdenum hexacarbonyl, ferrocene, ferroin, chromium carbonyl.

d⁷

Octahedral high spin: 3 unpaired electrons, paramagnetic, substitutionally labile.

Octahedral low spin: 1 unpaired electron, paramagnetic, substitutionally labile.

Examples: cobaltocene.

d⁸

Complexes which are d⁸ high-spin are usually octahedral (or tetrahedral) while low-spin d⁸ complexes are generally 16-electron square planar complexes. For first row transition metal complexes such as Ni²⁺ and Cu⁺ also form five-coordinate 18-electron species which vary from square pyramidal to trigonal bipyramidal.

Octahedral high spin: 2 unpaired electrons, paramagnetic, substitutionally labile.

Square planar low spin: no unpaired electrons, diamagnetic, substitutionally inert.

Examples: cisplatin, nickelocene, dichlorobis(ethylenediamine)nickel(II), iron pentacarbonyl, Zeise's salt, Vaska's complex, Wilkinson's catalyst.

d⁹

Stable complexes with this electron count are more common for first row (period four) transition metals center than they are for complexes based around second or third row transition metals centers. These include both four-coordinate 17-electron species and five-coordinate 19-electron species.

Examples: Schweizer's reagent.

d¹⁰

Often tetrahedral complexes limited to form 4 additional bonds (8 additional electrons) by the 18-electron ceiling. Often colorless due to the lack of d to d transitions.

Examples: tetrakis(triphenylphosphine)palladium(0), nickel carbonyl.