Pauson–Khand Reaction
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The Pauson–Khand reaction (or PKR or PK-type reaction) is a
chemical reaction A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and break ...
described as a /nowiki>2+2+1/nowiki>
cycloaddition In organic chemistry, a cycloaddition is a chemical reaction in which "two or more unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity". ...
between an
alkyne \ce \ce Acetylene \ce \ce \ce Propyne \ce \ce \ce \ce 1-Butyne In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one triple bond and no ...
, an
alkene In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
and
carbon monoxide Carbon monoxide ( chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the si ...
to form a α,β-
cyclopentenone 2-Cyclopentenone is a ketone with chemical formula and CAS number 930-30-3. It is structurally similar to cyclopentanone, with the additional feature of α-β unsaturation in the ring system. 2-Cyclopentenone contains two functional groups, a ...
. Ihsan Ullah Khand (1935-1980) discovered the reaction around 1970, while working as a postdoctoral associate with
Peter Ludwig Pauson Prof Peter Ludwig Israel Pauson FRSE FRIC (1925–2013) was a German–Jewish emigrant who settled in Britain and who is remembered for his contributions to chemistry, most notably the Pauson–Khand reaction and as joint discoverer of ferrocene. ...
(1925–2013) at the
University of Strathclyde The University of Strathclyde ( gd, Oilthigh Shrath Chluaidh) is a public research university located in Glasgow, Scotland. Founded in 1796 as the Andersonian Institute, it is Glasgow's second-oldest university, having received its royal char ...
in Glasgow. Pauson and Khand's initial findings were intermolecular in nature, but starting a decade after the reaction's discovery, many intramolecular examples have been highlighted in both synthesis and methodology reports. This reaction was originally mediated by stoichiometric amounts of
dicobalt octacarbonyl Dicobalt octacarbonyl is an organocobalt compound with composition . This metal carbonyl is used as a reagent and catalyst in organometallic chemistry and organic synthesis, and is central to much known organocobalt chemistry. It is the parent me ...
, but newer versions are both more efficient, enhancing reactivity and yield via utilizing different
chiral auxiliaries In stereochemistry, a chiral auxiliary is a Stereogenic center, stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxil ...
for stereo induction, main group transition-metals (Ti, Mo, W, Fe, Co, Ni, Ru, Rh, Ir and Pd), and additives.


Mechanism

While the mechanism has not yet been fully elucidated, Magnus' 1985 explanation is widely accepted for both mono- and dinuclear catalysts, and was corroborated by computational studies published by Nakamura and Yamanaka in 2001. The reaction begins when an alkene, alkyne, and low-valent metal coordinate to form a metallacyclopentene complex. CO then migratorily inserts into an M-C bonds, followed by reductive elimination to deliver the
cyclopentenone 2-Cyclopentenone is a ketone with chemical formula and CAS number 930-30-3. It is structurally similar to cyclopentanone, with the additional feature of α-β unsaturation in the ring system. 2-Cyclopentenone contains two functional groups, a ...
. Typically, the dissociation of carbon monoxide from the organometallic complex is rate limiting.


Selectivity

With unsymmetrical alkenes or alkynes, the reaction is not very regioselective, a problem that is ameliorated in intramolecular reactions. The reaction works with both terminal and internal alkynes although internal alkynes tend to give lower yields. The order of reactivity for the alkene is \text>\text>\text>\text Unsuitable alkenes are tetrasubstituted alkenes and alkenes with strongly
electron withdrawing group In chemistry, an electron-withdrawing group (EWG) is a substituent that has some of the following kinetic and thermodynamic implications: *with regards to electron transfer, electron-withdrawing groups enhance the oxidizing power tendency of th ...
s. Mono-substituted alkenes are generally directed by the sterics of the alkyne. For intermolecular Pauson-Khand, the sterically larger group on the alkyne tends to go to the C2-position. Electron-withdrawing groups on the alkyne prefer the C3-position. Mono-substituted alkenes are difficult to discriminate between the C4- and C5-position, unless the C2-position is sterically congested or there is a chelating heteroatom on the alkene. Intramolecular Paulson-Khand has been widely exploited in total synthesis, and is amenable to the formation of bicyclic rings (specifically 5,5- and 6,5- fused bicyclic rings), as well as more general polycyclic ring structures. Generally, the reaction is highly syn selective about the bridgehead hydrogen and substituents on the cyclopentane.


Catalysis

The PKR can be rendered catalytic.
Buchwald Buchwald is a German and Jewish surname. Notable people with the surname include: * Art Buchwald (1925–2007), American humorist *Charles Buchwald (1880–1951), Danish amateur footballer *Dave Buchwald (born 1970), Computer hacker, filmmaker, art ...
showed that titanium and nickel complexes admit such a transformation. Additionally, Negishi found that zirconium worked as well. Other metals can also be employed in these transformations. Traditional catalytic aids such as phosphine ligands can make the cobalt complex too stable, but bulky phosphite ligands are operable. These reactions can be made enantioselective as well, with the addition of chiral ligands or auxiliaries. BINAP is commonly employed.


Additives

Typical PKR conditions are at elevated temperatures and pressures in aromatic/hydrocarbon (benzene, toluene) or etherate (tetrahydrofuran, 1,2-dichloroethane) based solvents. These harsh conditions, may be attenuated with the addition of various additives. Many different tactics have been exploited to ameliorate these harsh conditions, making it amenable for additional functional groups, granting higher yields, shorter reaction times, and typically greater stereocontrol. Some of the different approaches are:
adsorption Adsorption is the adhesion of atoms, ions or molecules from a gas, liquid or dissolved solid to a surface. This process creates a film of the ''adsorbate'' on the surface of the ''adsorbent''. This process differs from absorption, in which ...
, amine ''N''-oxides and hydrates, and the addition of
Lewis basic A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any spe ...
molecules.


Adsorption

Adsorbing the metallic complex onto silica or alumina can enhance the rate of decarbonylative ligand exchange as exhibited in the image below. This is because the donor posits itself on a solid surface (i.e. silica). Additionally using a solid support restricts conformational movement ( rotamer effect).


Amine ''N''-oxides and hydrates

The two most common amine ''N''-oxides are ''N''-methylmorpholine ''N''-oxide (NMO) and trimethylamine ''N''-oxide (TMANO). It is believed that these additives remove carbon monoxide ligands via nucleophilic attack of the ''N''-oxide onto the CO carbonyl, oxidizing the CO into CO2, and generating an unsaturated organometallic complex. As a result, this renders the first step of the mechanism irreversible, and allows for more mild conditions. Hydrates of the aforementioned amine ''N''-oxides have also been utilized. Schreiber utilized an amine ''N''-oxide additive for the total synthesis of epoxydictymene. The ''N''-oxide additive, while lower yielding, gave a d.r. of 11:1 in favor of the desired diastereomer (indicated at the red hydrogen), where as other conditions like thermal and ultrasonic were less effective.


Lewis basic additives

The most common Lewis basic additive is sulfur containing compounds like n-BuSMe. Lewis basic additives are believed to accelerate the decarbonylative ligand exchange process. However, an alternative view posited in 2005, claims that the Lewis basicity makes olefin insertion an irreversible step in the mechanistic pathway. However, these sulfur adducts are typically hard to handle and smelly, so recently, n-dodecyl methyl sulfide (DodSMe) has been utilized as an alternative Lewis basic source. Another example is with TMTU (tetramethylthiourea). Additionally, Chiral ''N''-oxides have been used for enantioinduction.


Miscellaneous


Gas Free PKR

Recently, several groups have published work avoiding the use of toxic carbon monoxide, and instead generate the cyclopentenone carbonyl motif from aldehydes, carboxylic acids, and formates. These examples typically employ Rhodium as the organometallic transition metal, as it is commonly used in decarbonylation reactions. The decarbonylation and PKR occur in the same reaction vessel.


Stable cobalt complexes

Canonical PKR utilizes low-valent cobalt, however, these complexes are typically unstable, and efforts have been focused on preparing low-valent cobalt from bench (and generally) more stable cobalt complexes. Chung reported a catalytic PKR utilizing Co(acac)2, where upon exposure to sodium borohydride (NaBH4), generates the active catalytic species.


Multinuclear cobalt catalysts

Generally, multinuclear cobalt catalysts like (Co)4(CO)12 and Co3(CO)93-CH) have been explored, however these complexes readily undergo oligomerization and often require harsh conditions. Takayama and co-workers used an intramolecular Pauson–Khand reaction to cyclise an enyne containing a ''tert''-butyldiphenylsilyl (TBDPS) protected primary alcohol. This was a key step in the
asymmetric Asymmetric may refer to: *Asymmetry in geometry, chemistry, and physics Computing * Asymmetric cryptography, in public-key cryptography *Asymmetric digital subscriber line, Internet connectivity * Asymmetric multiprocessing, in computer architect ...
total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes i ...
of the '' Lycopodium''
alkaloid Alkaloids are a class of basic BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Th ...
huperzine-Q. The inclusion of a cyclic
siloxane A siloxane is a functional group in organosilicon chemistry with the Si−O−Si linkage. The parent siloxanes include the oligomeric and polymeric hydrides with the formulae H(OSiH2)''n''OH and (OSiH2)n. Siloxanes also include branched compound ...
moiety Moiety may refer to: Chemistry * Moiety (chemistry), a part or functional group of a molecule ** Moiety conservation, conservation of a subgroup in a chemical species Anthropology * Moiety (kinship), either of two groups into which a society is ...
in the reagent ensures that the product is formed with the desired conformation – only a single
enantiomer In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
of the product was obtained in the Pauson–Khand reaction sequence.


Variations

Wilkinson's catalyst, based on the
transition metal In chemistry, a transition metal (or transition element) is a chemical element in the d-block of the periodic table (groups 3 to 12), though the elements of group 12 (and less often group 3) are sometimes excluded. They are the elements that c ...
rhodium Rhodium is a chemical element with the symbol Rh and atomic number 45. It is a very rare, silvery-white, hard, corrosion-resistant transition metal. It is a noble metal and a member of the platinum group. It has only one naturally occurring ...
, also effectively catalyses PK reactions but requires silver triflate as a co-catalyst. Molybdenum hexacarbonyl is a carbon monoxide donor in PK-type reactions between
allene In organic chemistry, allenes are organic compounds in which one carbon atom has double bonds with each of its two adjacent carbon centres (). Allenes are classified as cumulated dienes. The parent compound of this class is propadiene, which i ...
s and
alkyne \ce \ce Acetylene \ce \ce \ce Propyne \ce \ce \ce \ce 1-Butyne In organic chemistry, an alkyne is an unsaturated hydrocarbon containing at least one carbon—carbon triple bond. The simplest acyclic alkynes with only one triple bond and no ...
s with
dimethyl sulfoxide Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula ( CH3)2. This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds ...
in toluene. In general allenes can work in PKR. One example below is with molybdenum, however rhodium gives different regioselectivity. DFT investigations show the differences in selectivity are due to the different transition state metal geometries. The total synthesis of physostigmine by the Mukai group utilized the PKR on a carbodiimide. Cyclobutadiene also lends itself to a /nowiki>2+2+1/nowiki> cycloaddition although this reactant is generated in situ from decomplexation of stable cyclobutadiene iron tricarbonyl with ceric ammonium nitrate (CAN). An example of a newer version is the use of the chlorodicarbonylrhodium(I) dimer, CO)2RhClsub>2, in the synthesis of (+)-phorbol by Phil Baran. In addition to using a rhodium catalyst, this synthesis features an intramolecular cyclization that results in the normal 5-membered α,β-
cyclopentenone 2-Cyclopentenone is a ketone with chemical formula and CAS number 930-30-3. It is structurally similar to cyclopentanone, with the additional feature of α-β unsaturation in the ring system. 2-Cyclopentenone contains two functional groups, a ...
as well as 7-membered ring.


See also

* Nicholas reaction


References


Further reading

For Khand and Pauson's perspective on the reaction: * * * For a modern perspective: * * * On specifically catalytic versions of the reaction: * {{DEFAULTSORT:Pauson-Khand Reaction Cycloadditions Multiple component reactions Name reactions