Cross-aldol Condensation Research Articles

Water‐Tolerant Superbase Polyoxometalate [H2(Nb6O19)]6− for Homogeneous Catalysis

AbstractHere, doubly protonated Lindqvist‐type niobium oxide cluster [H2(Nb6O19)]6–, fabricated by microwave‐assisted hydrothermal synthesis, exhibited superbase catalysis for Knoevenagel and crossed aldol condensation reactions accompanied by activating C−H bond with pKa >26 and proton abstraction from a base indicator with pKa=26.5. Surprisingly, [H2(Nb6O19)]6− exhibited water‐tolerant superbase properties for Knoevenagel and crossed aldol condensation reactions in the presence of water, although it is well known that the strong basicity of metal oxides and organic superbase is typically lost by the adsorption of water. Density functional theory calculation revealed that the basic surface oxygens that share the corner of NbO6 units in [H2(Nb6O19)]8− maintained the negative charges even after proton adsorption. This proton capacity and the presence of un‐protonated basic sites led to the water tolerance of the superbase catalysis.

Water-Tolerant Superbase Polyoxometalate [H2(Nb6O19)]6- for Homogeneous Catalysis.

Here, doubly protonated Lindqvist-type niobium oxide cluster [H2(Nb6O19)]6-, fabricated by microwave-assisted hydrothermal synthesis, exhibited superbase catalysis for Knoevenagel and crossed aldol condensation reactions accompanied by activating C-H bond with pKa >26 and proton abstraction from a base indicator with pKa=26.5. Surprisingly, [H2(Nb6O19)]6- exhibited water-tolerant superbase properties for Knoevenagel and crossed aldol condensation reactions in the presence of water, although it is well known that the strong basicity of metal oxides and organic superbase is typically lost by the adsorption of water. Density functional theory calculation revealed that the basic surface oxygens that share the corner of NbO6 units in [H2(Nb6O19)]8- maintained the negative charges even after proton adsorption. This proton capacity and the presence of un-protonated basic sites led to the water tolerance of the superbase catalysis.

Exploring helix structures of γ-peptides based on 2-(aminomethyl)cyclopentanecarboxylic acid.

Conformational search and density functional theory calculations were performed to explore the preferences of helical structures for chiro-specific oligo-γ-peptides of 2-(aminomethyl)cyclopentanecarboxylic acid (γAmc5) with a cyclopentyl constraint on the Cα-Cβ bond in solution. The dimer and tetramer of γAmc5 (1) with homochiral (1S, 2S) configurations exhibited a strong preference for the 9-membered helix foldamer in solution, except for the tetramer in water. However, the oligomers of γAmc5 (1) longer than tetramer preferentially adopted a right-handed (P)-2.614-helix (H1-14) as the peptide sequence becomes longer and as solvent polarity increases. The high stabilities for H1-14 foldamers of γAmc5 (1) in solution were ascribed to the favored solvation free energies. The calculated mean backbone torsion angles for H1-14 helix foldamers of γAmc5 (1) were similar to those calculated for oligomers of other γ-residues with cyclopentane or cyclohexane rings. However, the substitution of cyclopentane constraints on the Cα-Cβ bond of the γAmc5 (1) residue resulted in different conformational preferences and/or handedness of helix foldamers. In particular, the pyrrolidine-substituted analogs of the H1-14 foldamers of γAmc5 (1) with adjacent amine diads substituted at a proximal distance are expected to be potential catalysts for the crossed aldol condensation in nonpolar and polar solvents.

CuWO4 Reinforced Co‐doped HAp Nanocomposite: Improved Photocatalytic Activity Towards Degradation of Eosin Y and Catalytic Activity in Crossed Aldol Condensation Reaction

AbstractPreventing the recombination of photoinduced charge carriers in different semiconductor photocatalysts is crucial but high‐performance photocatalyst is still challenging. Herein, we report the synthesis of a novel heterojunction of cobalt‐doped hydroxyapatite with CuWO4 i. e. Co‐HAp@CuWO4 nanocomposite by simple and facile ultrasonication technique. The morphological and structural features of the composite was examined using PXRD, FTIR, SEM, EDS, TEM, UV‐DRS and XPS techniques. The optical analysis showed that the band gap of Co‐HAp@CuWO4 nanocomposite is 1.59 eV which is very much lower than pure HAp. The photocatalytic efficiency of Co‐HAp@CuWO4 was assessed in the degradation of Eosin Y dye under solar light irradiation. The result of degradation capacity is 94.5 % after 70 minutes of solar irradiation and it follows pseudo first‐order kinetics. The impact of different reaction parameters such as catalyst amount, initial concentration of the dye, and solution pH was also examined. The recyclability test showed that the synthesized material was highly stable in the visible‐light driven dye degradation. Heterogeneous catalytic efficacy of the prepared nanocomposite was examined in the crossed aldol condensation reaction of benzaldehyde and acetone and the outcomes confirmed that dibenzylideneacetone (DBA) was formed in the condensation reaction in outstanding yields under optimum conditions.

Development of ruthenium complexes with S-donor ligands for application in synthesis, catalytic acceptorless alcohol dehydrogenation and crossed-aldol condensation.

The reaction of [Ru(dmso)4Cl2] with a potassium salt of four xanthate (RO-C(S)S-; R = Me, Et, iPr and tBu) ligands (depicted as Ln; n = 1-4) in hot methanol afforded a group of mixed-ligand complexes of type [Ru(Ln)2(dmso)2]. The crystal structures of all the four complexes have been determined, which show that the xanthate ligands are bound to the metal center forming four-membered chelates and dmso is coordinated through sulfur and they are mutually cis. The relative thermodynamic stability of this cis and the other possible trans-isomers of these complexes has been assessed with the help of DFT calculations, which have revealed that the cis-isomer is the more stable isomer. The coordinated dmso in the [Ru(Ln)2(dmso)2] complexes could be easily displaced by chelating bidentate ligands (depicted as L') to furnish complexes of type [Ru(Ln)2(L')], as demonstrated through isolation of two such complexes, viz. [Ru(L3)2(bpy)] and [Ru(L2)2(phen)] (bpy = 2,2'-bipyridine and phen = 1,10-phenanthroline). The crystal structure of [Ru(L3)2(bpy)] has been determined and the structure of [Ru(L2)2(phen)] has been optimized by the DFT method. The electronic spectra of the four [Ru(Ln)2(dmso)2] complexes and the two derivatives ([Ru(Ln)2(L')]; n = 3, L' = bpy; n = 2, L' = phen), recorded in dichloromethane solutions, show intense absorptions spanning the visible and ultraviolet regions, which have been analyzed by the TDDFT method. The [Ru(Ln)2(dmso)2] complexes are found to serve as efficient catalyst precursors for the acceptorless dehydrogenation of 2-propanol followed by crossed-aldol condensation with substituted benzaldehydes (and related aldehydes), using tert-butoxide as the co-catalyst, producing dibenzylideneacetone derivatives in good yields.

Synthesis and catalytic activity of tetradentate β-diketiminato rare-earth metal monoalkyl complexes in tandem Oppenauer oxidation and cross-aldol condensation.

A series of unsymmetric tetradentate β-diketiminato rare-earth metal monoalkyl complexes were synthesized, and their catalytic behavior has been well developed. Indole-incorporated β-diketiminato proligands H2L (L = MeC(NDipp)CHC(Me)NCH2CH2-3-(1-R-C8H4N), R = CH2-(2-C4H7O), L1; R = (CH2)2OMe, L2; Dipp = 2,6-iPr2C6H3) were prepared by the reaction of an arylamino-enone with 1-substituted-tryptamine in good yields. Treatment of the proligands with the rare-earth metal trialkyl complexes RE(CH2SiMe3)3(THF)2 generated the corresponding unsymmetric N,N,C,O-tetradentate β-diketiminato rare-earth metal monoalkyl complexes LRE(CH2SiMe3) (L1, RE = Y (1a), Gd (1b), Yb (1c), Lu (1d); L2, RE = Y (2a), Gd (2b), Yb (2c), and Lu(2d)). During the process, the activation of the sp2 C-H bond at the 2-position of the indole ring led to the formation of an unprecedented β-diketiminato dianion L2-, bonding to the rare-earth metal ions in a chelating N,N,C,O-tetradentate manner. Further studies indicated that these tetradentate rare-earth metal complexes could initiate the Oppenauer oxidation of secondary alcohols into the corresponding ketones in high yields. In the case of primary alcohols, a tandem Oppenauer oxidation and cross-aldol condensation occurred unexpectedly. Various α-mono-substituted benzylidene acetones, α,α'-bis-substituted benzylidene acetones and cyclohexanones were obtained under mild conditions only by controlling the molar ratio of alcohols to ketones. Notably, all these alkenylation ketones exhibited exclusive E configuration.

Synthesis of Dibenzalacetone using Sonochemistry and Its Antibacterial Activity Against Escherichia coli

The synthesis of dibenzalacetone, a ketone compound with potential antibacterial properties, especially against <em>Escherichia coli</em>, has typically involved time-consuming methods. This study adopts sonochemistry, an increasingly popular technique recognized for its efficiency and quick yield. The aim is to synthesize dibenzalacetone using the sonochemical method and evaluate its antibacterial efficacy against <em>E. coli</em>. The synthesis process includes a cross-aldol condensation reaction between acetone and benzaldehyde, catalyzed by NaOH, conducted in an ultrasonic bath at 35 °C for 1-5 minutes. The optimal synthesis condition, achieved in 4 minutes, resulted in a 76.56% yield of dibenzalacetone, characterized as a bright yellow solid with a melting point of 111-114°C. Techniques such as FT-IR, GC-MS, 1H-NMR, and 13C-NMR spectrometry were employed for structural characterization. The FTIR analysis revealed various functional groups, including C=O ketone, C=C aromatic, and C-H aromatic. GC-MS data confirmed the molecular weight of dibenzalacetone at m/z 234.1. Furthermore, <sup>1</sup>H-NMR and <sup>13</sup>C-NMR analyses provided detailed insights into the compound's chemical shifts and structural groups, affirming the successful synthesis of dibenzalacetone. The antibacterial activity of dibenzalacetone against <em>E. coli</em> was tested at concentrations ranging from 5% to 20%. Notably, at a 15% concentration, dibenzalacetone exhibited antibacterial activity comparable to amoxicillin. These findings suggest that dibenzalacetone, efficiently synthesized via sonochemistry, not only achieves a high yield but also has potential as an antibacterial agent against <em>E. coli</em>. This research highlights the efficacy of sonochemistry for the rapid and effective synthesis of compounds with significant medical applications.

In‐Vitro Investigation of the α‐Amylase Inhibition Activity of Bare Bis‐Benzylidene‐Cyclohexanone Synthesized by a Highly Selective Solvent‐Free Route

AbstractCurrent work reports the highly selective, solvent‐free synthesis of an endorsed bioactive compound, Bis benzylidine cyclohexanone (BBC) through solid acid catalysed cross aldol condensation route and checks its in‐vitro bio activity. The catalytic support (Multiwalled carbon nanotube) employed was synthesized through the highly sophisticated catalytic chemical vapor deposition (CVD) method and simple mechanical grinding strategy was adopted to decorate sulfonic acid on the support. The C1s X‐ray photoelectron peak of at 290.3 eV confirms the effective interaction of sulfonic acid with MWCNT. The sharp and intense desorption peaks observed at approximately 528.7 °C and 655.15 °C in the TPD analysis unmistakably substantiate the strong acidity of the synthesized system. The alpha amylase inhibition activity of the synthesized compound was calculated to be around 88.5 %, which is in par with the commercial drug as it could inhibit only 96 %. Further, the in‐silico (Docking and Molecular Dynamic Simulation) investigations unveiled a new target site for the compound and this can further be studied in detail to advance the applications in drug design. Detailed scrutiny of various parameters was conducted to validate the bioactivity and pharmaceutical potential of the synthesized compound.

Synthesis of chiral functional polyhydroxylated arenes via Mukaiyama aldol reaction from Perlin aldehydes

Functionalized aryl polyhydroxylated compounds could be of great synthetic value for natural product synthesis. However, the synthesis of such compounds usually requires multi-step synthesis or the usage of sensitive reagents. We present here a practically simple route for the synthesis of such functionalized arylpolyols from glycal derived α,β-unsaturated 2,3-dideoxy aldehyde as well as α,β-saturated 2,3-dideoxy aldehyde (Perlin aldehydes) via Mukaiyama cross aldol condensation in the presence of silyl enol ether and TiCl4. It was observed that the nature of the electronic substitution of the silyl enol ether does not play any role in the yield of the desired products. Further functionalization of the products has also been shown.

Solvent-free cross aldol condensation of aldehydes and ketones over SrMo1-xNixO3-δ perovskite nanocrystals as heterogeneous catalysts

Aldol condensation is arguably one of the most fascinating reactions that leads to the formation of C–C bonds. Its use in the pharmaceutical industry to synthesis complex drugs from simple aldehydes and ketones has become of paramount importance. Although this is one reaction that has lured a lot of attention, not enough has been explored in heterogeneous catalysis. In this work we have successfully synthesized multicationic perovskites via the soft-template method and characterized them thoroughly. The synthesized perovskite nanocrystals were found to have small SBET however their catalytic application in the conversion of benzaldehyde (BAL) in the aldol condensation with diethyl ketone (DEK) was found to be astonishing. The synthesis was confirmed using many techniques, from determining the oxidation states of the materials using XPS. This gave access to determine the coordination of the metals in the perovskite lattice and also qualitatively assess the oxygen environments that exist. The oxygen vacancies and SBET were used to assess the activity of the perovskite catalysts in the cross-aldol condensation reaction. The optimal conditions for this aldol condensation were found to be 120 °C after 25 h with no solvent using SrMo0.5Ni0.5O3-δ inorganic perovskite which had the highest amount of oxygen vacant sites which gave a conversion of 88 % and an 82 % selectivity towards the desired cross-aldol condensation product. The use of dimethylformamide (DMF) for this reaction is discouraged as it reacts with BAL to produce a higher amide.

An Updated Review on Recent Advancements in the Diverse Biological Applications of Medicinally Privileged Scaffold: Chalcone and its derivatives

Fused heterocyclic compounds rank among the most significant systems in medicinal chemistry because of their wide-ranging biological effects. Among the various class of compounds, chalcones and their derivatives are found to be one of the important classes in the field of synthetic and pharmaceutical chemistry. These derivatives are mainly synthesized by means of Claisen-Schmidt condensation, Crossed Aldol condensation and Knoevenagel condensation reactions, which provides wider applications in the field of medicine. Due to the broader biological applications like antimicrobial, anticancer, antimalarial, antioxidant, anti-inflammatory, antitubercular, antidiabetic, antileishmanial, anti-vitiligo and neuroprotective properties, these derivatives extended their role in coordination chemistry and also act as intermediates for the synthesis of various organic derivatives containing isoxazole, pyrazole, pyrimidine, naphthalene, indole, polyamine and other moieties as hybrid molecules. The present review discusses the biological applications of various chalcone derivatives. Due to their easiest way of synthesis, nowadays, these types of derivatives were tried for various ailments and by means of implementing various greener chemistry approaches, novel and potent derivatives can be synthesized and applied for various applications. Thus, this review will be helpful for the design of potent chalcone derivatives for numerous applications in the future. Keywords: Chalcones, 1,3-diphenyl-2-propene-1-one, microbial properties, anticancer, antioxidant, neuroprotective and biological applications

Kinetics and optimization studies of modified VPO/γ-Al2O3 catalyst prepared in situ for cross-aldol condensation

Modified VPO/γ-Al2O3 catalysts were prepared in situ for the first time and applied to the aldol condensation reaction of acetic acid and formaldehyde. VPO/γ-Al2O3 exhibited excellent catalytic performance at a calcination temperature of 350 °C.

Novel Route to Produce Hydrocarbons from Woody Biomass Using Molten Salts.

The thermochemical decomposition of woody biomass has been widely identified as a promising route to produce renewable biofuels. More recently, the use of molten salts in combination with pyrolysis has gathered increased interest. The molten salts may act as a solvent, a heat transfer medium, and possibly also a catalyst. In this study, we report experimental studies on a process to convert woody biomass to a liquid hydrocarbon product with a very low oxygen content using molten salt pyrolysis (350–450 °C and atmospheric pressure) followed by subsequent catalytic conversions of the liquids obtained by pyrolysis. Pyrolysis of woody biomass in molten salt (ZnCl2/NaCl/KCl with a molar composition of 60:20:20) resulted in a liquid yield of 46 wt % at a temperature of 450 °C and a molten salt/biomass ratio of 10:1 (mass). The liquids are highly enriched in furfural (13 wt %) and acetic acid (14 wt %). To reduce complexity and experimental issues related to the production of sufficient amounts of pyrolysis oils for further catalytic upgrading, model studies were performed to convert both compounds to hydrocarbons using a three-step catalytic approach, viz., (i) ketonization of acetic acid to acetone, (ii) cross-aldol condensation between acetone and furfural to C8–C13 products, followed by (iii) a two-stage catalytic hydrotreatment of the latter to liquid hydrocarbons. Ketonization of acetic acid to acetone was studied in a continuous setup over a ceria–zirconia-based catalyst at 250 °C. The catalyst showed no signs of deactivation over a period of 230 h while also achieving high selectivity toward acetone. Furfural was shown to have a negative effect on the catalyst performance, and as such, a separation step is required after pyrolysis to obtain an acetic-acid-enriched fraction. The cross-aldol condensation reaction between acetone and furfural was studied in a batch using a commercial Mg/Al hydrotalcite as the catalyst. Furfural was quantitatively converted with over 90% molar selectivity toward condensed products with a carbon number between C8 and C13. The two-stage hydrotreatment of the condensed product consisted of a stabilization step using a Ni-based Picula catalyst and a further deep hydrotreatment over a NiMo catalyst, in both batch setups. The final product with a residual 1.5 wt % O is rich in (cyclo)alkanes and aromatic hydrocarbons. The overall carbon yield for the four-step approach, from pinewood biomass to middle distillates, is 21%, assuming that separation of furfural and acetic acid after the pyrolysis step can be performed without losses.

Polymer-Supported Poly(Ethylene Glycol) as a Phase-Transfer Catalyst for Cross-Aldol Condensation of Isobutyroaldehyde and Formaldehyde.

Immobilized poly(ethylene glycol) (PEG 600-PS) was used as an effective phase-transfer catalyst for the synthesis of hydroxypivaldehyde from isobutyraldehyde (IBA) and formaldehyde in the presence of an inorganic base. Studies on the influence of the parameters on the course of the reaction in a batch reactor showed that the use of the PEG 600-PS catalyst allowed one to obtain HPA with high efficiency (IBA conversion >96%, selectivity >98%) in a relatively short time and under mild conditions (2 h, 40 °C). The developed method enables easy separation of the post-reaction mixture by simple phase separation, and the immobilized catalyst can be separated by filtration and then used five times without a loss in its activity. The high activity and stability of the catalyst was also confirmed in a test carried out in a flow reactor.

Greener Synthesis of Jasminaldehyde via Cross Aldol Condensation Reaction Using Recyclable Phase Transfer Catalysis and its Cosmetic Application

Jasminaldehyde or alpha amyl cinnamic aldehyde is a commonly used aroma molecule in perfume formulationsThe aldol condensation of equimolar n-heptanal and benzaldehyde in NaOH using a surfactant catalyst cetyltrimethylammonium bromide to achieve high cross aldol product Jasminaldehyde selectivity was studied. The process is highly efficient due to the recyclability of the catalyst. The process was studied for four cycles of catalyst reusability. The selectivity of the cross product was dependent on the temperature, surfactant concentration, and mixing. The olfactive profile of Jasminaldehyde obtained with 0.1 M surfactant solution was identical to the standard. Jasminaldehyde formulation was created and applied to in-home care applications.

On the role of Zr to facilitate the synthesis of diesel and jet fuel range intermediates from biomass-derived carbonyl compounds over aluminum phosphate

Heterogeneous zeolite/zeotype catalysts are attractive for converting renewable biomass-derived chemicals into transportation fuels by aldol condensation reactions, which provide a simple strategy to improve carbon numbers. Herein, Zr-doped aluminum phosphate (ZrAPO-5) were applied for efficient syntheses of diesel and jet fuel range C11, C12 and C16 intermediates from biomass-derived furfural (FF) and cyclohexanone (CH). Incorporation of Zr in the APO-5 framework facilitated the adsorption of the CO groups of FF and CH and created more and stronger acid and base sites, which co-catalyzed the aldol condensation and facilitated the product yields. ZrAPO-5 (Zr/Al = 0.20) yielded up to 79.3% single aldol condensation product C11 or 80.7% double aldol condensation product C16 in the cross-aldol condensation of FF and CH under appropriate reaction conditions, and also realized 83.3% C12 yield in the self-aldol condensation of CH. In addition, the catalytic system displayed good to excellent yields of other value-added chemicals in aldol condensations of alternative carbonyl compounds.

AN EFFICIENT FRIENDLY PROCESS FOR SYNTHESIS OF (2E, 6E)-2, 6-BIS (4-NITROBENZYLIDENE) CYCLOHEXANONE A DRUG AGAINST DORMANT VERSION OF THE MYCOBACTERIUM TUBERCULOSIS H37RA

The objective of this study is the Synthesis of (2E, 6E)-2, 6-bis(4-nitrobenzylidene) cyclohexanone a drug against dormant version of the Mycobacterium tuberculosis H37Ra. The Cross-aldol condensation between 4-nitrobenzaldehyde and cyclopentanone catalyzed by modified fluorapatite Na/FAP catalyst in aqueous media is an important protocol for the synthesis of this product and the reaction conditions were optimized by the response surface methodology. The work-up procedure is simplified by simple filtration with high yield and by-products of usual undesirable reaction are not observed.

Dehydrogenation of ethanol over CuO–Mg–Y for cross-aldol condensation with aryl aldehydes

An economically viable approach for the synthesis of different α, β-unsaturated aldehydes through modified cross-aldol condensation reaction has been developed. In this synthetic process, acetaldehyde is generated in situ through the catalytic dehydrogenation of the ethanol. The dehydrogenation reaction is found to occur over copper oxide nanoparticles supported on magnesium exchanged zeolite-Y. The formation of acetaldehyde through dehydrogenation of ethanol is confirmed by the modified Hantzsch reaction. Different kinetic studies have been performed to predict the rate of acetaldehyde as well as cinnamaldehyde formation. The formation of α, β-unsaturated aldehydes through the dehydrogenative cross-aldol reaction of ethanol with various aldehydes are found to be dependent on different reaction parameters viz temperature, catalyst amount, time, and the nature of bases. The catalytic dehydrogenation process is found to occur within 80–100 °C. TDDFT calculations are used to correlate the electronic spectra of Hantzsch reaction product with the experimental one.

Nontraditional Aldol Condensation Performance of Highly Efficient and Reusable Cs+ Single Sites in β-Zeolite Channels.

Aldol reactions (self- and cross-aldol condensations) for conjugated enone synthesis were efficiently performed on large-sized Cs+ single sites (1 wt %) confined in β-zeolite channels in toluene, which showed the highest level of catalytic aldol condensation activity among reported zeolite catalysts. In general, aldol condensation reactions for C-C bond synthesis can proceed by acids (e.g., H+), bases (e.g., OH-), enolate species, and acidic or basic solid catalysts. However, the Cs+ single site/β sample without significant acid-base property showed unprecedented, efficient, and reusable catalysis for self-aldol and cross-aldol condensations. Intrinsically inactive Cs+ single sites due to the noble-gas electronic structure were transformed to active Cs+ single sites in β-zeolite channels. Cs+/β has many advantages such as broad substrate scope, eco-friendliness, high product selectivity and yield, and simple work-up procedure. Thus, the Cs+ single site/β provides an attractive and useful methodology for practical C-C bond synthesis. On the basis of the Cs+/β characterization by X-ray photoelectron spectroscopy (XPS), in situ X-ray absorption fine structure (XAFS) (X-ray absorption near edge structure (XANES) and extended X-ray absorption fine structure (EXAFS)), and temperature-programmed desorption (TPD), density functional theory (DFT) calculations of the self- and cross-aldol condensation reaction pathways involving the transition states on the Cs+ single site in β-zeolite channel revealed nontraditional concerted interligand bond rearrangement mechanisms.

Structural and evolutionary analysis unveil functional adaptations in the promiscuous behavior of serum albumins

Promiscuous activities have been related to the capacity to catalyze reactions different from those a protein has evolved to sustain. In this work, we rethought the serum albumin's promiscuous behavior using evolutionary and structural analysis. We found that the cross aldol condensation of acetone and p-formylbenzonitrile is a promiscuous reaction conserved in humans serum albumin and in closely related albumins from other mammals. Evolutionary analysis indicates that the residues involved in this promiscuous reaction are evolving under positive selection, an evolutionary pattern indicating a putative functional adaptation. Also, key residues are located in an evolutionary conserved cavity connected with the protein surface with an also conserved tunnel and mutations involving these residues are described in human diseases. Overall, our results suggest that albumin could have evolved to sustain a still unknown biological function among the many others it maintains. Our results could contribute to better characterize the serum albumin family and raise questions about the evolution of protein promiscuity and function.