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Organophosphorus Chemistry: A New Perspective

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Organic Chemistry".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 21251

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Guest Editor
1. Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4, 44-100 Gliwice, Poland
2. Biotechnology Center of Silesian University of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland
Interests: organic synthesis; electroorganic synthesis; organophosphorus chemistry; phosphonium salts; amino acids; NMR; IR
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Special Issue Information

Dear Colleagues,

Organophosphorus chemistry is undoubtedly important and one of the fastest-growing branches of organic chemistry. It is often said that we are living now in “the golden age of phosphorus chemistry”. In the laboratory, phosphorus-containing compounds (P-compounds) are widely used as reagents (starting materials, precursors of active intermediates such as ylides or iminium-type cations, etc.), catalysts (PTC, organocatalysis), and solvents (PILs). Due to the interesting properties of P-compounds (especially their biological activity), they are used on a large scale in medicine (e.g., bone disorders drugs, anticancer and antiviral agents, or antihelminthics in veterinary applications), agriculture (e.g., pesticides), and industry (e.g., production of lubricants or plastic materials).

However, in the age of much-needed care for the natural environment, we face new challenges. Innovative approaches to the synthesis and isolation of P-compounds (taking into account the aspects of green chemistry and sustainability) followed by responsible use and disposal (neutralization) may prove crucial in the near future.

It is my great pleasure to invite experts in the field of organophosphorus chemistry to submit manuscripts in the form of short communications, full-length papers, and reviews to this Special Issue. I would like to extend a special invitation to young scientists to present their ideas and a fresh approach to the issues related to phosphorus chemistry.

Dr. Jakub Adamek
Guest Editor

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • organophosphorus chemistry
  • P-compounds
  • reactivity of P-compounds
  • new methods for the synthesis of P-compounds
  • P-C bond formation
  • phosphorus-based organocatalysis
  • phosphonium-based ionic liquids (PILs)
  • mitochondria-targeted triphenylphosphonium-based compounds
  • neutralization of P-compounds
  • chemical warfare agents
  • structure elucidation of P-compounds

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Published Papers (11 papers)

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Editorial

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3 pages, 193 KiB  
Editorial
Special Issue “Organophosphorus Chemistry: A New Perspective”
by Jakub Adamek
Molecules 2023, 28(12), 4752; https://doi.org/10.3390/molecules28124752 - 14 Jun 2023
Cited by 1 | Viewed by 827
Abstract
The European Chemical Society (EuChemS) and the European Parliament (Science and Policy Workshop, 25 May 2023) recognize phosphorus as one of the key chemical elements in daily life [...] Full article
(This article belongs to the Special Issue Organophosphorus Chemistry: A New Perspective)

Research

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0 pages, 1381 KiB  
Article
One-Pot Phosphonylation of Heteroaromatic Lithium Reagents: The Scope and Limitations of Its Use for the Synthesis of Heteroaromatic Phosphonates
by Ewa Chmielewska, Natalia Miodowska, Błażej Dziuk, Mateusz Psurski and Paweł Kafarski
Molecules 2023, 28(7), 3135; https://doi.org/10.3390/molecules28073135 - 31 Mar 2023
Cited by 1 | Viewed by 1632
Abstract
A one-pot lithiation–phosphonylation procedure was elaborated as a method to prepare heteroaromatic phosphonic acids. It relied on the direct lithiation of heteroaromatics followed by phosphonylation with diethyl chlorophosphite and then oxidation with hydrogen peroxide. This protocol provided the desired phosphonates with satisfactory yields. [...] Read more.
A one-pot lithiation–phosphonylation procedure was elaborated as a method to prepare heteroaromatic phosphonic acids. It relied on the direct lithiation of heteroaromatics followed by phosphonylation with diethyl chlorophosphite and then oxidation with hydrogen peroxide. This protocol provided the desired phosphonates with satisfactory yields. This procedure also had some limitations in its dependence on the accessibility and stability of the lithiated heterocyclic compounds. The same procedure could be applied to phosphonylation of aromatic compounds, which do not undergo direct lithiation and thus require the use of their bromides as substrates. The obtained compounds showed weak antiproliferative activity when tested on three cancer cell lines. Full article
(This article belongs to the Special Issue Organophosphorus Chemistry: A New Perspective)
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16 pages, 22481 KiB  
Article
Deamination of 1-Aminoalkylphosphonic Acids: Reaction Intermediates and Selectivity
by Anna Brol and Tomasz K. Olszewski
Molecules 2022, 27(24), 8849; https://doi.org/10.3390/molecules27248849 - 13 Dec 2022
Cited by 2 | Viewed by 1508
Abstract
Deamination of 1-aminoalkylphosphonic acids in the reaction with HNO2 (generated “in situ” from NaNO2) yields a mixture of substitution products (1-hydroxyalkylphosphonic acids), elimination products (vinylphosphonic acid derivatives), rearrangement and substitution products (2-hydroxylkylphosphonic acids) as well as H3PO4 [...] Read more.
Deamination of 1-aminoalkylphosphonic acids in the reaction with HNO2 (generated “in situ” from NaNO2) yields a mixture of substitution products (1-hydroxyalkylphosphonic acids), elimination products (vinylphosphonic acid derivatives), rearrangement and substitution products (2-hydroxylkylphosphonic acids) as well as H3PO4. The variety of formed reaction products suggests that 1-phosphonoalkylium ions may be intermediates in such deamination reactions. Full article
(This article belongs to the Special Issue Organophosphorus Chemistry: A New Perspective)
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22 pages, 2426 KiB  
Article
Synthesis of Tetrasubstituted Phosphorus Analogs of Aspartic Acid as Antiproliferative Agents
by Xabier del Corte, Aitor Maestro, Adrián López-Francés, Francisco Palacios and Javier Vicario
Molecules 2022, 27(22), 8024; https://doi.org/10.3390/molecules27228024 - 18 Nov 2022
Cited by 2 | Viewed by 1224
Abstract
An efficient general method for the synthesis of a wide family of α-aminophosphonate analogs of aspartic acid bearing tetrasubstituted carbons is reported through an aza-Reformatsky reaction of α-iminophosphonates, generated from α-aminophosphonates, in an umpolung process. In addition, the α-aminophosphonate substrates showed in vitro [...] Read more.
An efficient general method for the synthesis of a wide family of α-aminophosphonate analogs of aspartic acid bearing tetrasubstituted carbons is reported through an aza-Reformatsky reaction of α-iminophosphonates, generated from α-aminophosphonates, in an umpolung process. In addition, the α-aminophosphonate substrates showed in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell lines A549 (carcinomic human alveolar basal epithelial cell) and SKOV3 (human ovarian carcinoma). In view of the possibilities in the diversity of the substituents that offer the synthetic methodology, an extensive profile structure–activity is presented, measuring IC50 values up to 0.34 µM in the A549 and 9.8 µM in SKOV3 cell lines. Full article
(This article belongs to the Special Issue Organophosphorus Chemistry: A New Perspective)
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9 pages, 7881 KiB  
Article
Highly Z-Selective Horner–Wadsworth–Emmons Olefination Using Modified Still–Gennari-Type Reagents
by Ignacy Janicki and Piotr Kiełbasiński
Molecules 2022, 27(20), 7138; https://doi.org/10.3390/molecules27207138 - 21 Oct 2022
Cited by 3 | Viewed by 2402
Abstract
In this report, new, easily accessible reagents for highly Z-selective HWE reactions are presented. Alkyl di-(1,1,1,3,3,3-hexafluoroisopropyl)phosphonoacetates, structurally similar to Still–Gennari type reagents, were tested in HWE reactions with a series of various aldehydes. Very good Z-selectivity (up to a 98:2 Z [...] Read more.
In this report, new, easily accessible reagents for highly Z-selective HWE reactions are presented. Alkyl di-(1,1,1,3,3,3-hexafluoroisopropyl)phosphonoacetates, structurally similar to Still–Gennari type reagents, were tested in HWE reactions with a series of various aldehydes. Very good Z-selectivity (up to a 98:2 Z:E ratio) was achieved in most cases along with high yields. Application of the new reagents may be a valuable, practical alternative to the well-established Still–Gennari or Ando Z-selective carbonyl group olefination protocols. Full article
(This article belongs to the Special Issue Organophosphorus Chemistry: A New Perspective)
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13 pages, 2688 KiB  
Article
Drug-Inclusive Inorganic–Organic Hybrid Systems for the Controlled Release of the Osteoporosis Drug Zoledronate
by Maria Vassaki, Savvina Lazarou, Petri Turhanen, Duane Choquesillo-Lazarte and Konstantinos D. Demadis
Molecules 2022, 27(19), 6212; https://doi.org/10.3390/molecules27196212 - 21 Sep 2022
Cited by 8 | Viewed by 1545
Abstract
Bisphosphonates (BPs) are common pharmaceutical treatments used for calcium- and bone-related disorders, the principal one being osteoporosis. Their antiresorptive action is related to their high affinity for hydroxyapatite, the main inorganic substituent of bone. On the other hand, the phosphonate groups on their [...] Read more.
Bisphosphonates (BPs) are common pharmaceutical treatments used for calcium- and bone-related disorders, the principal one being osteoporosis. Their antiresorptive action is related to their high affinity for hydroxyapatite, the main inorganic substituent of bone. On the other hand, the phosphonate groups on their backbone make them excellent ligands for metal ions. The combination of these properties finds potential application in the utilization of such systems as controlled drug release systems (CRSs). In this work, the third generation BP drug zoledronate (ZOL) was combined with alkaline earth metal ions (e.g., Sr2+ and Ba2+) in an effort to synthesize new materials. These metal–ZOL compounds can operate as CRSs when exposed to appropriate experimental conditions, such as the low pH of the human stomach, thus releasing the active drug ZOL. CRS networks containing Sr2+ or Ba2 and ZOL were physicochemically and structurally characterized and were evaluated for their ability to release the free ZOL drug during an acid-driven hydrolysis process. Various release and kinetic parameters were determined, such as initial rates and release plateau values. Based on the drug release results of this study, there was an attempt to correlate the ZOL release efficiency with the structural features of these CRSs. Full article
(This article belongs to the Special Issue Organophosphorus Chemistry: A New Perspective)
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20 pages, 2079 KiB  
Article
Design, Synthesis and Preliminary Evaluation of the Cytotoxicity and Antibacterial Activity of Novel Triphenylphosphonium Derivatives of Betulin
by Mirosława Grymel, Anna Lalik, Alicja Kazek-Kęsik, Marietta Szewczyk, Patrycja Grabiec and Karol Erfurt
Molecules 2022, 27(16), 5156; https://doi.org/10.3390/molecules27165156 - 12 Aug 2022
Cited by 9 | Viewed by 1677
Abstract
For several decades, natural products have been widely researched and their native scaffolds are the basis for the design and synthesis of new potential therapeutic agents. Betulin is an interesting biologically attractive natural parent molecule with a high safety profile and can easily [...] Read more.
For several decades, natural products have been widely researched and their native scaffolds are the basis for the design and synthesis of new potential therapeutic agents. Betulin is an interesting biologically attractive natural parent molecule with a high safety profile and can easily undergo a variety of structural modifications. Herein, we describe the synthesis of new molecular hybrids of betulin via covalent linkage with an alkyltriphenylphosphonium moiety. The proposed strategy enables the preparation of semi-synthetic derivatives (28-TPP BN and 3,28-bisTPP BN) from betulin through simple transformations in high yields. The obtained results showed that the presence of a lipophilic cation improved the solubility of the tested analogs compared to betulin, and increased their cytotoxicity. Among the triphenylphosphonium derivatives tested, analogs 7a (IC50 of 5.56 µM) and 7b (IC50 of 5.77 µM) demonstrated the highest cytotoxicity against the colorectal carcinoma cell line (HCT 116). TPP-conjugates with betulin showed antimicrobial properties against Gram-positive reference Staphylococcus aureus ATCC 25923 and Staphylococcus epidermidis ATCC 12228 bacteria, at a 200 µM concentration in water. Hence, the conjugation of betulin’s parent backbone with a triphenylphosphonium moiety promotes transport through the hydrophobic barriers of the mitochondrial membrane, making it a promising strategy to improve the bioavailability of natural substances. Full article
(This article belongs to the Special Issue Organophosphorus Chemistry: A New Perspective)
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23 pages, 3222 KiB  
Article
One-Pot and Catalyst-Free Transformation of N-Protected 1-Amino-1-Ethoxyalkylphosphonates into Bisphosphonic Analogs of Protein and Non-Protein α-Amino Acids
by Anna Kuźnik, Dominika Kozicka, Wioleta Hawranek, Karolina Socha and Karol Erfurt
Molecules 2022, 27(11), 3571; https://doi.org/10.3390/molecules27113571 - 2 Jun 2022
Cited by 4 | Viewed by 1687
Abstract
Herein, we describe the development of one-pot transformation of α-ethoxy derivatives of phosphorus analogs of protein and non-protein α-amino acids into biologically important N-protected 1-aminobisphosphonates. The proposed strategy, based on the three-component reaction of 1-(N-acylamino)-1-ethoxyphosphonates with triphenylphosphonium tetrafluoroborate and triethyl [...] Read more.
Herein, we describe the development of one-pot transformation of α-ethoxy derivatives of phosphorus analogs of protein and non-protein α-amino acids into biologically important N-protected 1-aminobisphosphonates. The proposed strategy, based on the three-component reaction of 1-(N-acylamino)-1-ethoxyphosphonates with triphenylphosphonium tetrafluoroborate and triethyl phosphite, facilitates good to excellent yields under mild reaction conditions. The course of the reaction was monitored by 31P NMR spectroscopy, allowing the identification of probable intermediate species, thus making it possible to propose a reaction mechanism. In most cases, there is no need to use a catalyst to provide transformation efficiency, which increases its attractiveness both in economic and ecological terms. Furthermore, we demonstrate that the one-pot procedure can be successfully applied for the synthesis of structurally diverse N-protected bisphosphonic analogs of α-amino acids. As shown, the indirect formation of the corresponding phosphonium salt as a reactive intermediate during the conversion of 1-(N-acylamino)-1-ethoxyphosphonate into a 1-aminobisphosphonate derivative is a crucial component of the developed methodology. Full article
(This article belongs to the Special Issue Organophosphorus Chemistry: A New Perspective)
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Review

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50 pages, 26329 KiB  
Review
Comprehensive Review on Synthesis, Properties, and Applications of Phosphorus (PIII, PIV, PV) Substituted Acenes with More Than Two Fused Benzene Rings
by Marek Koprowski, Krzysztof Owsianik, Łucja Knopik, Vivek Vivek, Adrian Romaniuk, Ewa Różycka-Sokołowska and Piotr Bałczewski
Molecules 2022, 27(19), 6611; https://doi.org/10.3390/molecules27196611 - 5 Oct 2022
Cited by 5 | Viewed by 2262
Abstract
This comprehensive review, covering the years 1968–2022, is not only a retrospective investigation of a certain group of linearly fused aromatics, called acenes, but also a presentation of the current state of the knowledge on the synthesis, reactions, and applications of these compounds. [...] Read more.
This comprehensive review, covering the years 1968–2022, is not only a retrospective investigation of a certain group of linearly fused aromatics, called acenes, but also a presentation of the current state of the knowledge on the synthesis, reactions, and applications of these compounds. Their characteristic feature is substitution of the aromatic system by one, two, or three organophosphorus groups, which determine their properties and applications. The (PIII, PIV, PV) phosphorus atom in organophosphorus groups is linked to the acene directly by a P-Csp2 bond or indirectly through an oxygen atom by a P-O-Csp2 bond. Full article
(This article belongs to the Special Issue Organophosphorus Chemistry: A New Perspective)
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28 pages, 2007 KiB  
Review
α-Aminophosphonates, -Phosphinates, and -Phosphine Oxides as Extraction and Precipitation Agents for Rare Earth Metals, Thorium, and Uranium: A Review
by Esa Kukkonen, Emilia Josefiina Virtanen and Jani Olavi Moilanen
Molecules 2022, 27(11), 3465; https://doi.org/10.3390/molecules27113465 - 27 May 2022
Cited by 16 | Viewed by 2883
Abstract
α-Aminophosphonates, -phosphinates, and -phosphine oxides are a group of organophosphorus compounds that were investigated as extraction agents for rare earth (RE) metals and actinoids for the first time in the 1960s. However, more systematic investigations of their extraction properties towards REs and actinoids [...] Read more.
α-Aminophosphonates, -phosphinates, and -phosphine oxides are a group of organophosphorus compounds that were investigated as extraction agents for rare earth (RE) metals and actinoids for the first time in the 1960s. However, more systematic investigations of their extraction properties towards REs and actinoids were not started until the 2010s. Indeed, recent studies have shown that these α-amino-functionalized compounds can outperform the commercial organophosphorus extraction agents in RE separations. They have also proven to be very efficient extraction and precipitation agents for recovering Th and U from RE concentrates. These actinoids coexist with REs in some of the commercially important RE-containing minerals. The efficient separation and purification of REs is becoming more and more important every year as these elements have a pivotal role in many existing technologies. If one also considers the facile synthesis of α-amino-functionalized organophosphorus extractants and precipitation agents, it is expected that they will be increasingly utilized in the extraction chemistry of REs and actinoids in the future. This review collates α-aminophosphonates, -phosphinates, and -phosphine oxides that have been utilized in the separation chemistry of REs and actinoids, including their most relevant synthetic routes and molecular properties. Their extraction and precipitation properties towards REs and actinoids are also discussed. Full article
(This article belongs to the Special Issue Organophosphorus Chemistry: A New Perspective)
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31 pages, 21235 KiB  
Review
1-Aminoalkylphosphonium Derivatives: Smart Synthetic Equivalents of N-Acyliminium-Type Cations, and Maybe Something More: A Review
by Jakub Adamek, Mirosława Grymel, Anna Kuźnik and Agnieszka Październiok-Holewa
Molecules 2022, 27(5), 1562; https://doi.org/10.3390/molecules27051562 - 26 Feb 2022
Cited by 3 | Viewed by 2134
Abstract
N-acyliminium-type cations are examples of highly reactive intermediates that are willingly used in organic synthesis in intra- or intermolecular α-amidoalkylation reactions. They are usually generated in situ from their corresponding precursors in the presence of acidic catalysts (Brønsted or Lewis acids). In [...] Read more.
N-acyliminium-type cations are examples of highly reactive intermediates that are willingly used in organic synthesis in intra- or intermolecular α-amidoalkylation reactions. They are usually generated in situ from their corresponding precursors in the presence of acidic catalysts (Brønsted or Lewis acids). In this context, 1-aminoalkyltriarylphosphonium derivatives deserve particular attention. The positively charged phosphonium moiety located in the immediate vicinity of the N-acyl group significantly facilitates Cα-P+ bond breaking, even without the use of catalyst. Moreover, minor structural modifications of 1-aminoalkyltriarylphosphonium derivatives make it possible to modulate their reactivity in a simple way. Therefore, these types of compounds can be considered as smart synthetic equivalents of N-acyliminium-type cations. This review intends to familiarize a wide audience with the unique properties of 1-aminoalkyltriarylphosphonium derivatives and encourage their wider use in organic synthesis. Hence, the most important methods for the preparation of 1-aminoalkyltriarylphosphonium salts, as well as the area of their potential synthetic utilization, are demonstrated. In particular, the structure–reactivity correlations for the phosphonium salts are discussed. It was shown that 1-aminoalkyltriarylphosphonium salts are not only an interesting alternative to other α-amidoalkylating agents but also can be used in such important transformations as the Wittig reaction or heterocyclizations. Finally, the prospects and limitations of their further applications in synthesis and medicinal chemistry were considered. Full article
(This article belongs to the Special Issue Organophosphorus Chemistry: A New Perspective)
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