![(3) Ladderane](https://upload.wikimedia.org/wikipedia/commons/1/18/%283%29_Ladderane.png)
In
chemistry
Chemistry is the science, scientific study of the properties and behavior of matter. It is a natural science that covers the Chemical element, elements that make up matter to the chemical compound, compounds made of atoms, molecules and ions ...
, a ladderane is an
organic molecule
In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The s ...
containing two or more fused
cyclobutane
Cyclobutane is a cycloalkane and organic compound with the formula (CH2)4. Cyclobutane is a colourless gas and commercially available as a liquefied gas. Derivatives of cyclobutane are called cyclobutanes. Cyclobutane itself is of no commercial ...
rings. The name arises from the resemblance of a series of fused cyclobutane rings to a
ladder
A ladder is a vertical or inclined set of rungs or steps used for climbing or descending. There are two types: rigid ladders that are self-supporting or that may be leaned against a vertical surface such as a wall, and rollable ladders, such a ...
. Numerous synthetic approaches have been developed for the
synthesis
Synthesis or synthesize may refer to:
Science Chemistry and biochemistry
*Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors
** Organic synthesis, the chemical synthesis of organ ...
of ladderane compounds of various lengths. The
mechanisms often involve
photocycloadditions"> + 2photocycloadditions, a useful reaction for creating strained 4-membered rings. Naturally occurring ladderanes have been identified as major components of the anammoxosome membrane of the
anammox
Anammox, an abbreviation for anaerobic ammonium oxidation, is a globally important microbial process of the nitrogen cycle that takes place in many natural environments. The bacteria mediating this process were identified in 1999, and were a grea ...
bacteria, phylum ''
Planctomycetota
The Planctomycetota are a phylum of widely distributed bacteria, occurring in both aquatic and terrestrial habitats. They play a considerable role in global carbon and nitrogen cycles, with many species of this phylum capable of anaerobic ammoniu ...
''.
Nomenclature
Chain length
![Ladderane Nomenclature](https://upload.wikimedia.org/wikipedia/commons/2/22/Ladderane_Nomenclature.png)
Synthetic approaches have yielded ladderanes of varying lengths. A classification system has been developed to describe ladderanes based on the number of consecutive rings.
The length of the ladderane is described by the number in brackets that precedes the word "ladderane". This is equal to the number of bonds shared by two cyclobutanes (''n'') plus 1.
A ladderane of 3 or more units can connect in a circle, forming a band, which can also be considered to be two interconnected parallel
cycloalkane
In organic chemistry, the cycloalkanes (also called naphthenes, but distinct from naphthalene) are the monocyclic saturated hydrocarbons. In other words, a cycloalkane consists only of hydrogen and carbon atoms arranged in a structure containing ...
rings. These are called
prismanes
The prismanes are a class of hydrocarbon compounds consisting of prism-like polyhedra of various numbers of sides on the polygonal base. Chemically, it is a series of fused cyclobutane rings (a ladderane, with all-cis/all- syn geometry) that wraps ...
.
Stereochemistry
![Ladderane stereochemistry](https://upload.wikimedia.org/wikipedia/commons/9/98/Ladderane_stereochemistry.png)
Ladderanes have two types of
stereochemical
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereois ...
relationships.
One describes the relative arrangement of
hydrogen atom
A hydrogen atom is an atom of the chemical element hydrogen. The electrically neutral atom contains a single positively charged proton and a single negatively charged electron bound to the nucleus by the Coulomb force. Atomic hydrogen consti ...
s at the
fusion
Fusion, or synthesis, is the process of combining two or more distinct entities into a new whole.
Fusion may also refer to:
Science and technology Physics
*Nuclear fusion, multiple atomic nuclei combining to form one or more different atomic nucl ...
between two cyclobutane rings. These hydrogen atoms can be in either the
cis- or trans- configuration. Trans-ladderanes have not been synthesized due to the
ring strain
In organic chemistry, ring strain is a type of instability that exists when bonds in a molecule form angles that are abnormal. Strain is most commonly discussed for small rings such as cyclopropanes and cyclobutanes, whose internal angles are su ...
in these compounds.
The second stereochemical relationship describes the orientation of three consecutive cyclobutane rings, and therefore is only relevant to ladderanes of ''n'' ≥ 2. The two outer rings can be on the same face (syn-) or on the opposite face (anti-) of the center ring.
Synthesis
Various synthetic methods have been used for the laboratory synthesis of ladderane compounds. The three major approaches are (1)
dimerization of
polyene
In organic chemistry, polyenes are poly- unsaturated, organic compounds that contain at least three alternating double () and single () carbon–carbon bonds. These carbon–carbon double bonds interact in a process known as conjugation, resultin ...
precursors, (2) the stepwise addition, one or two rings at a time, (3) and oligomerization.
Several examples of ladderane synthesis are outlined below.
Dimerization of cyclobutadiene
The dimerization of two
cyclobutadiene
Cyclobutadiene is an organic compound with the formula . It is very reactive owing to its tendency to dimerize. Although the parent compound has not been isolated, some substituted derivatives are robust and a single molecule of cyclobutadiene is ...
s can generate both the syn and anti ladderane products depending on the reaction conditions.
The first step in forming the syn product involves the generation of 1,3-cyclobutadiene by treatment of cis-3,4-dichlorocyclobutene with
sodium amalgam
Sodium amalgam, commonly denoted Na(Hg), is an alloy of mercury and sodium. The term amalgam is used for alloys, intermetallic compounds, and solutions (both solid solutions and liquid solutions) involving mercury as a major component. Sodium amal ...
. The reactant passes through a metalated
intermediate before forming 1,3-cyclobutadiene, which can then dimerize to form the syn-diene.
Hydrogenation
Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a Catalysis, catalyst such as nickel, palladium or platinum. The process is commonly employed to redox, reduce or S ...
of the
double bond
In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
s will form the
saturated
Saturation, saturated, unsaturation or unsaturated may refer to:
Chemistry
* Saturation, a property of organic compounds referring to carbon-carbon bonds
** Saturated and unsaturated compounds
**Degree of unsaturation
** Saturated fat or fatty ac ...
syn-
ladderane.
To generate the anti product, cis-3,4-dichlorocyclobutene is treated with
lithium
Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid el ...
amalgam
Amalgam most commonly refers to:
* Amalgam (chemistry), mercury alloy
* Amalgam (dentistry), material of silver tooth fillings
** Bonded amalgam, used in dentistry
Amalgam may also refer to:
* Amalgam Comics, a publisher
* Amalgam Digital
...
. The lithium derivative undergoes a C-C
coupling reaction A coupling reaction in organic chemistry is a general term for a variety of reactions where two fragments are joined together with the aid of a metal catalyst. In one important reaction type, a main group organometallic compound of the type R-M (R = ...
to produce the open dimeric structure. This intermediate reacts to form the anti-diene, which can be hydrogenated to form the final anti-
ladderane product.
Synthesis of a ladderdiene
A different synthetic approach developed by Martin and coworkers has allowed for the synthesis of
ladderanes.
The initial step involves the formation of a
ladderane from the addition of two equivalents of
maleic anhydride
Maleic anhydride is an organic compound with the formula C2H2(CO)2O. It is the acid anhydride of maleic acid. It is a colorless or white solid with an acrid odor. It is produced industrially on a large scale for applications in coatings and poly ...
with
acetylene
Acetylene (systematic name: ethyne) is the chemical compound with the formula and structure . It is a hydrocarbon and the simplest alkyne. This colorless gas is widely used as a fuel and a chemical building block. It is unstable in its pure ...
. The remaining two rings are formed from the
Ramberg–Bäcklund ring contraction.
Synthesis of long-chain ladderanes
Ladderanes with lengths up to 13 cyclobutane rings have been synthesized by Mehta and coworkers. This process involves the ''in situ'' generation of dicarbomethoxycyclobutadiene from its Fe(CO)
3 complex at low temperatures with the addition of
ceric(IV) ammonium nitrate (CAN). Generation of the
butadiene
1,3-Butadiene () is the organic compound with the formula (CH2=CH)2. It is a colorless gas that is easily condensed to a liquid. It is important industrially as a precursor to synthetic rubber. The molecule can be viewed as the union of two viny ...
rapidly forms a mixture of
'n''ladderanes of lengths up to ''n'' = 13 with an overall
yield of 55%. All of the ladderanes synthesized through this method have one cis,syn,cis structure. This may be a result of the initial dimerization of two cyclobutadienes which preferably forms the syn product, shown below. The further dimerization only produces the anti product due to steric factors.
Dimerization of polyene precursors
In these reactions, ladderanes are formed from multiple
+ 2photocycloadditions between the double bonds of two polyenes. A complication that arises from this approach is the reaction of the precursors through alternative, more favorable
photoexcitation
Photoexcitation is the production of an excited state of a quantum system by photon absorption. The excited state originates from the interaction between a photon and the quantum system. Photons carry energy that is determined by the wavelengths ...
routes. These side reactions are prevented by the addition of a chemical spacer unit that holds the two polyenes parallel to each other, only allowing
+ 2cycloadditions to occur.
A common spacer used in these reactions is the
aracyclophane">.2aracyclophane system. This is sufficiently rigid and can hold the polyene tails in close enough proximity for the cycloadditions to occur.
![Schmidt et al](https://upload.wikimedia.org/wikipedia/commons/1/10/Schmidt_et_al.png)
MacGillivray and colleagues have demonstrated that a supramolecular approach to covalent synthesis in the organized, solvent-free environment of the solid state can provide a solution to the problem of organizing two polyenes for an intramolecular reaction to give a ladderane. Specifically, by taking an approach to control reactivity in solids by using molecules that serve as linear templates, they have demonstrated the utility of cocrystallization of resorcinol (1,3-benzenediol), or a derivative, with an all-''trans''-bis(4-pyridyl)poly-''m''-ene (4-pyr-poly-''m''-ene) produces a four-component molecular assembly, 2(resorcinol)·2(4-pyr-poly-''m''-ene), in which each resorcinol preorganizes, through two O—H···N hydrogen-bonding interactions, two poly-''m''-enes for
+2photoaddition. The two polyenes are positioned by the templates such that the C=C bonds of the olefins lie parallel and separated by < 4.2 Å, a position suitable for the photoreaction. UV irradiation of the solid produces the targeted
'n''adderane, with the C=C bonds reacting to form the fused cyclobutane framework. Broadband UV-irradiation of two such hydrogen-bonded, four-component supramolecular assemblies furnishes the corresponding ladderanes stereospecifically and in quantitative yield in gram quantities.
Biological background
![Ladderane lipids of anammox bacteria](https://upload.wikimedia.org/wikipedia/commons/b/b6/Ladderane_lipids_of_anammox_bacteria.png)
Ladderanes were first identified in a rare group of anaerobic ammonium oxidizing (
anammox
Anammox, an abbreviation for anaerobic ammonium oxidation, is a globally important microbial process of the nitrogen cycle that takes place in many natural environments. The bacteria mediating this process were identified in 1999, and were a grea ...
)
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
belonging to the phylum
Planctomycetota
The Planctomycetota are a phylum of widely distributed bacteria, occurring in both aquatic and terrestrial habitats. They play a considerable role in global carbon and nitrogen cycles, with many species of this phylum capable of anaerobic ammoniu ...
. These bacteria sequester the catabolic anammox reactions to intracellular compartments called anammoxosomes.
The anammox process involves the
oxidation
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
of
ammonium
The ammonium cation is a positively-charged polyatomic ion with the chemical formula or . It is formed by the protonation of ammonia (). Ammonium is also a general name for positively charged or protonated substituted amines and quaternary a ...
to nitrogen gas with
nitrite
The nitrite polyatomic ion, ion has the chemical formula . Nitrite (mostly sodium nitrite) is widely used throughout chemical and pharmaceutical industries. The nitrite anion is a pervasive intermediate in the nitrogen cycle in nature. The name ...
as the final
electron acceptor
An electron acceptor is a chemical entity that accepts electrons transferred to it from another compound. It is an oxidizing agent that, by virtue of its accepting electrons, is itself reduced in the process. Electron acceptors are sometimes mista ...
. Intermediates in this process are two highly toxic compounds,
hydrazine
Hydrazine is an inorganic compound with the chemical formula . It is a simple pnictogen hydride, and is a colourless flammable liquid with an ammonia-like odour. Hydrazine is highly toxic unless handled in solution as, for example, hydrazine ...
(N
2H
4) and
hydroxylamine
Hydroxylamine is an inorganic compound with the formula . The material is a white crystalline, hygroscopic compound.Greenwood and Earnshaw. ''Chemistry of the Elements.'' 2nd Edition. Reed Educational and Professional Publishing Ltd. pp. 431–43 ...
(NH
2OH). The oxidation process involves the generation of a
proton gradient
An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts, the chemical gradient, or difference in solute concentration across a membrane, and th ...
on the intracytoplasmic face of the anammoxosome. Dissipation of the proton gradient is coupled to the phosphorylation of
ADP through membrane-bound
ATPase
ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...
s.
Anammoxosomes are enriched in the ladderane
lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include ...
s shown at right. Analysis of the anammoxosome membranes from the bacterial species ''
Brocadia anammoxidans
"''Candidatus'' Brocadia" is a ''candidatus'' genus of bacteria. Many of the species in this genus are capable of anammox.
Phylogeny
Phylogeny based on GTDB 07-RS207 by Genome Taxonomy Database
The Genome Taxonomy Database (GTDB) is an onl ...
'' and ''
Kuenenia stuttgartiensis'' has revealed that ladderanes constitute more than 50% of membrane lipids. The high abundance of ladderane lipids in the anammoxosome results in an exceptionally dense membrane with reduced permeability. The reduced permeability may decrease the
passive diffusion
Passive transport is a type of membrane transport that does not require energy to move substances across cell membranes. Instead of using cellular energy, like active transport, passive transport relies on the second law of thermodynamics to d ...
of protons across the membrane that would dissipate the electrochemical gradient. This would be especially detrimental to anammox bacteria, due to the relatively slow anammox metabolism. The decreased permeability has also been hypothesized to sequester the highly toxic and mutagenic intermediates, hydrazine and hydroxylamine, which can readily diffuse through biomembranes. The loss of these key intermediates would damage key cellular components such as
DNA, as well as reduce the catabolic efficiency of the cell.
Synthesis of ladderane lipids
A naturally occurring
ladderane lipid, named pentacycloanammoxic acid, has been synthesized by
Corey
Corey is a masculine given name and a surname. It is a masculine version of name Cora, which has Greek origins and is the maiden name of the goddess Persephone. The name also can have origins from the Gaelic word ''coire'', which means "in a caul ...
and coworkers. The first step in this reaction involves
bromination
In chemistry, halogenation is a chemical reaction that entails the introduction of one or more halogens into a compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polymers, ...
followed by cyclization of
cyclooctatetraene
1,3,5,7-Cyclooctatetraene (COT) is an unsaturated derivative of cyclooctane, with the formula C8H8. It is also known as nnulene. This polyunsaturated hydrocarbon is a colorless to light yellow flammable liquid at room temperature. Because of ...
to form a cyclohexadiene. This cyclohexadiene is trapped by dibenzyl azodicarboxylate.
Functional group
In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...
modifications are made to produce a cyclobutane which is elaborated through a
+2photocycloaddition with a cyclopentenone to produce a second cyclobutane ring. Protection of the
carbonyl group
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...
, followed by a N
2 extrusion reaction, yields two more fused cyclobutane rings. The final cyclobutane is formed by a
Wolff rearrangement
The Wolff rearrangement is a reaction in organic chemistry in which an α-diazocarbonyl compound is converted into a ketene by loss of dinitrogen with accompanying 1,2-rearrangement. The Wolff rearrangement yields a ketene as an intermediate produ ...
, and the alkyl chain is installed by a
Wittig olefination.
![Corey et a 2l](https://upload.wikimedia.org/wikipedia/commons/d/d7/Corey_et_a_2l.png)
In 2016, Burns and co-workers at Stanford University reported an enantioselective synthesis of both the
and
ladderane lipid tails and their incorporation into a full
phosphatidylcholine
Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup.
They are a major component of biological membranes and can be easily obtained from a variety of readily available sources, such as egg yolk or soyb ...
lipid.
Both routes leverage a small
ladderene building block bicyclo
.2.0exene prepared by a
Ramberg–Bäcklund reaction
The Ramberg–Bäcklund reaction is an organic reaction converting an α-halo sulfone into an alkene in presence of a base with extrusion of sulfur dioxide. The reaction is named after the two Swedish chemists Ludwig Ramberg and Birger Bäcklund ...
. The route to a
ladderane-containing fatty acid involves dimerization of this intermediate to form an all-''anti''
ladderane hydrocarbon.
C–H chlorination by a manganese
porphyrin
Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical com ...
catalyst and subsequent elimination introduces unsaturation to produce a
ladderene.
Hydroboration
In organic chemistry, hydroboration refers to the addition of a hydrogen-boron bond to certain double and triple bonds involving carbon (, , , and ). This chemical reaction is useful in the organic synthesis of organic compounds.
Hydroboration p ...
and a
Zweifel reaction install the linear alkyl group.
![5-ladderane 1-2](https://upload.wikimedia.org/wikipedia/commons/0/03/5-ladderane_1-2.svg)
The route to a
ladderane fatty alcohol begins with a
+2photocycloaddition between a brominated
benzoquinone Benzoquinone (C6H4O2) is a quinone with a single benzene ring. There are 2 (out of 3 hypothetical) benzoquinones:
* 1,4-Benzoquinone, most commonly, right image (also ''para''-benzoquinone, ''p''-benzoquinone, ''para''-quinone, or just quinone)
* 1 ...
and bicyclo
.2.0exene. Elimination of H–Br and addition of an
organozinc compound
Organozinc compounds in organic chemistry contain carbon (C) to zinc (Zn) chemical bonds. Organozinc chemistry is the science of organozinc compounds describing their physical properties, synthesis and reactions.The Chemistry of Organozinc Compoun ...
installs the alkyl alcohol. A
hydrazine
Hydrazine is an inorganic compound with the chemical formula . It is a simple pnictogen hydride, and is a colourless flammable liquid with an ammonia-like odour. Hydrazine is highly toxic unless handled in solution as, for example, hydrazine ...
-mediated deoxygenation reaction followed by hydrogenation with
effects reduction to the cyclohexane ring.
References
{{Reflist
Cyclobutanes
Polycyclic nonaromatic hydrocarbons