3-Hydroxypropionic acid, also known as 3-hydroxypropanoic acid or hydracrylic acid, is a three-carbon β-hydroxy carboxylic acid with the molecular formula C₃H₆O₃ and a molecular weight of 90.08 g/mol. It appears as a colorless, viscous liquid that is highly soluble in water, exhibiting a density of 1.066 g/mL at 25°C and a refractive index of n/D 1.449.[1] Chemically, it features both a hydroxyl group at the beta position and a carboxyl group, making it a non-chiral compound with a pKa of approximately 4.5 for the carboxylic acid moiety.[2][1]As a versatile platform chemical, 3-hydroxypropionic acid serves as a key building block for the synthesis of high-value industrial products, including acrylic acid (a precursor to polymers and adhesives), 1,3-propanediol (used in polyesters and antifreeze), acrylonitrile, and biodegradable polymers such as poly(3-hydroxypropionate) (P3HP). Its global market potential is significant, with projections as of 2023 estimating potential demand exceeding 3.6 million tons per year and a potential value over USD 10 billion annually (for derivatives), driven by applications in sustainable materials, cleaning agents, fibers, and pharmaceuticals; updated direct market projections reach USD 1.3 billion by 2030.[3][4][5]Biologically, 3-hydroxypropionic acid functions as a human metabolite and microbial intermediate, primarily arising from the catabolism of branched-chain amino acids and gut-derived propionic acid via propionyl-CoA pathways. Elevated concentrations can act as a metabotoxin, contributing to acidosis (pH < 7.35) in conditions like propionic acidemia or biotinidase deficiency, leading to symptoms such as lethargy, seizures, and neurological issues. It is also produced by microorganisms like Escherichia coli and Klebsiella pneumoniae.[6]Industrial production of 3-hydroxypropionic acid predominantly relies on microbial fermentation using metabolically engineered strains of bacteria (e.g., E. coli, Klebsiella pneumoniae) or yeast (Saccharomyces cerevisiae) from renewable feedstocks such as glycerol, glucose, or lignocellulosic biomass. Key biosynthetic routes include the glycerol pathway (via 3-hydroxypropionaldehyde), malonyl-CoA pathway, and β-alanine pathway, with optimized fed-batch processes achieving titers up to 154 g/L. Challenges include toxicity to host cells, cofactor dependencies (e.g., coenzyme B12), and by-product formation, which ongoing genetic engineering aims to address for scalable, sustainable manufacturing.[3][5]
Properties
Physical properties
3-Hydroxypropionic acid, also known as 3-hydroxypropanoic acid, has the molecular formula C₃H₆O₃ and the structural formula HO-CH₂-CH₂-COOH, consisting of a three-carbon chain with a beta-hydroxy carboxylic acid functionality.[2][1] Its molar mass is 90.08 g/mol.[1]At room temperature, 3-hydroxypropionic acid appears as a viscous, colorless to almost colorless syrupy liquid.[1] It has a low melting point below 25 °C, remaining in the liquid state under standard ambient conditions.[7] The compound decomposes before reaching its boiling point under normal pressure, with a rough estimated boiling temperature of 212 °C; distillation is typically conducted under reduced pressure in the range of 200-250 °C to avoid decomposition.[1]It is miscible with water and soluble in ethanol, methanol, and diethyl ether. As a polar molecule, it is insoluble in non-polar solvents such as hexane.[1][8]The carboxylic acid group imparts weak acidity, with a pKa value of 4.51 at 25 °C.[1]
Chemical properties
3-Hydroxypropionic acid (3-HP), with the formula HOCH₂CH₂COOH, features both a primary hydroxyl group and a carboxylic acid group, conferring bifunctional reactivity that allows for reactions such as esterification of the carboxyl group with alcohols or dehydration involving the hydroxyl and carboxyl moieties.[2] This bifunctional nature distinguishes 3-HP from simple monofunctional acids, enabling it to participate in condensation reactions typical of both alcohol and carboxylic acid functionalities.[1]The acidity of 3-HP arises from its carboxylic acid group, with a dissociation constant (pKa) of 4.51 at 25 °C, indicating moderate acidity comparable to other short-chain carboxylic acids.[1] This property facilitates the formation of salts, such as sodium 3-hydroxypropionate, which exhibits a melting point of 131–135 °C and is utilized in various chemical processes due to its ionic character.[9]In terms of reactivity, 3-HP can undergo lactonization under acidic conditions to yield β-propiolactone, a strained four-membered ring lactone, through intramolecular dehydration of the hydroxyl and carboxyl groups.[10] The hydroxyl group is susceptible to oxidation, potentially forming 3-oxopropionic acid under appropriate oxidizing conditions, while reduction pathways, such as hydrogenation, can convert 3-HP to 1,3-propanediol by reducing the carboxyl group.[11]Regarding stability, 3-HP thermally decomposes above 200 °C via dehydration to produce acrylic acid and water, a process that can be catalyzed to enhance selectivity.[12] It is sensitive to strong bases, which may promote polymerization to form poly(3-hydroxypropionate) through condensation, but remains stable in neutral aqueous solutions at room temperature without significant degradation.[13]Spectroscopic characterization confirms the functional groups: infrared (IR) spectroscopy shows characteristic absorption bands at approximately 1710 cm⁻¹ for the C=O stretch of the carboxylic acid and 3400 cm⁻¹ for the broad O-H stretch.[14] In ¹H nuclear magnetic resonance (NMR) spectroscopy (in D₂O), the methylene protons adjacent to the carboxyl group appear around 2.6 ppm (triplet), while those next to the hydroxyl group resonate at about 3.8 ppm (triplet), spanning the 2.5–4.0 ppm range typical for such protons in β-hydroxy acids.[15]
Natural occurrence and biosynthesis
Biological sources
3-Hydroxypropionic acid (3-HP) serves as a metabolic intermediate in various bacterial species, particularly in autotrophic CO₂ fixation pathways. It is notably present in the phototrophic bacterium Chloroflexus aurantiacus, where it functions within the 3-hydroxypropionate cycle, and in the thermoacidophilic archaeon Metallosphaera sedula, which utilizes the 3-hydroxypropionate/4-hydroxybutyrate cycle for carbon assimilation.[16][17][18]In eukaryotic organisms, 3-HP has been detected in endophytic fungi isolated from plant organs, such as birch twigs and leaves of tropical trees, where it exhibits nematicidal properties. Additionally, it arises in the gut microbiota through the breakdown of branched-chain amino acids and propionic acid, contributing to microbial metabolic processes. It is also produced by common bacteria such as Escherichia coli and Klebsiella pneumoniae as a microbial intermediate.[7][19]Within mammalian systems, 3-HP occurs as a minor metabolite derived from propionate metabolism, with relevance to disorders of propionyl-CoA carboxylase deficiency. Its presence was first documented in scientific literature in the 1970s during investigations of propionate β-oxidation in rat liver and human urine.[20]Concentrations of 3-HP in natural environments, such as hot springs inhabited by thermophilic bacteria or soil microbial communities, are typically low, reflecting its role as a transient intermediate rather than an accumulated product.[16]
Metabolic pathways
The 3-hydroxypropionate bicycle operates in phototrophic bacteria such as Chloroflexus aurantiacus as a carbon fixation pathway that assimilates two molecules of CO₂ to produce glyoxylate from acetyl-CoA. The pathway commences with the carboxylation of acetyl-CoA to malonyl-CoA, catalyzed by acetyl-CoA/propionyl-CoA carboxylase. Malonyl-CoA is subsequently reduced to 3-hydroxypropionic acid (3-HP) by the bifunctional malonyl-CoA reductase (MCR), which performs a two-step NADPH-dependent reduction via the intermediate malonate semialdehyde, releasing CO₂ and CoA in the process.[21][22]The net reaction for the MCR-catalyzed reduction is:\text{Malonyl-CoA} + 2\text{NADPH} + 2\text{H}^{+} \rightarrow \text{3-HP} + \text{CoA} + \text{CO}_{2} + 2\text{NADP}^{+}This step establishes the C3 unit essential for further cycle progression, where 3-HP is activated to 3-hydroxypropionyl-CoA (3-HP-CoA) via CoA transferase (using succinyl-CoA as donor), dehydrated to acryloyl-CoA by 3-hydroxypropionyl-CoA dehydratase, and reduced to propionyl-CoA by acryloyl-CoA reductase using NADPH.[21][22]A related autotrophic pathway, the 3-hydroxypropionate/4-hydroxybutyrate (3-HP/4-HB) cycle, functions in chemolithoautotrophic and thermoacidophilic archaea including Metallosphaera sedula and Acidianus brierleyi. Here, acetyl-CoA carboxylation yields malonyl-CoA, which is reduced to 3-HP through sequential action of malonyl-CoA reductase (producing malonate semialdehyde) and malonate semialdehyde reductase, both NADPH-dependent. The 3-HP is then converted to 3-HP-CoA by 3-hydroxypropionyl-CoA synthetase (using ATP), dehydrated to acryloyl-CoA, and reduced to propionyl-CoA. In anaerobic conditions, this facilitates propionate fermentation by channeling the propionyl-CoA intermediate toward propionate production, supporting energy conservation and carbon assimilation.[18][23]
Synthesis
Chemical synthesis
One established chemical synthesis route for 3-hydroxypropionic acid (3-HP) involves the hydrolysis of β-propiolactone, which is first prepared from ketene and formaldehyde in the presence of a Friedel–Crafts catalyst such as zinc chloride-modified aluminum chloride.[24] The [2+2] cycloaddition between ketene and formaldehyde yields β-propiolactone as a strained four-membered ring lactone, which readily undergoes ring-opening hydrolysis in aqueous media, often under acidic or basic conditions, to produce 3-HP.[25] This method, while effective for laboratory-scale preparation, requires careful handling due to the reactivity and potential toxicity of β-propiolactone.[26]Another route proceeds from ethylene oxide via carbonylation with carbon monoxide in the presence of water and a transition metal catalyst, such as cobalt-based systems, under high pressure (typically 100–200 atm) and elevated temperatures (150–200°C). The reaction forms β-propiolactone as an intermediate, which is subsequently hydrolyzed to 3-HP, though direct incorporation of water can yield 3-HP or its esters alongside side products like ethylene glycol.[27] The overall process can be represented as:\text{Ethylene oxide} + \text{CO} + \text{H}_2\text{O} \xrightarrow{\text{catalyst}} \text{HO-CH}_2\text{-CH}_2\text{-COOH}This pathway is limited by side reactions and the need for high-energy conditions.[26]The Reformatsky reaction provides a classical laboratory method, involving the zinc-mediated addition of ethyl bromoacetate to formaldehyde to form ethyl 3-hydroxypropionate, followed by saponification and acidification to yield 3-HP.[28] This organozinc addition proceeds under mild conditions in solvents like benzene or ether, offering good selectivity for the β-hydroxy ester intermediate, though purification steps are required to isolate the final acid.Additional routes include the catalytic hydration of acrylic acid using acid catalysts such as ion-exchange resins (e.g., sulfonic acid resins) at moderate temperatures (60–100°C), achieving equilibrium conversions around 50–60% due to the reversibility of the addition.[29] Alternatively, hydroformylation of allyl alcohol with syngas (CO/H₂) over rhodium or cobalt catalysts produces 3-hydroxypropanal, which is then oxidized (e.g., with air or nitric acid) to 3-HP. These methods, while versatile, suffer from reliance on non-renewable petrochemical feedstocks like propylene-derived acrylic acid or allyl alcohol, alongside high energy demands for pressure and temperature control.[26]
Biotechnological production
Biotechnological production of 3-hydroxypropionic acid (3-HP) relies on engineered microbial fermentation processes that introduce heterologous pathways into suitable host organisms to convert renewable feedstocks into the target compound. Primary hosts include Escherichia coli, Saccharomyces cerevisiae, and Lactobacillus strains such as L. reuteri, which have been modified to express non-native enzymes for efficient 3-HP synthesis. These organisms are selected for their robust growth, genetic tractability, and ability to tolerate acidic conditions, enabling scalable fermentation. Additional hosts like Halomonas bluephagenesis have achieved the highest reported titer of 154 g/L from 1,3-propanediol via fed-batch fermentation.[30]Key strategies involve the malonyl-CoA pathway, where glucose is metabolized via glycolysis to pyruvate and subsequently to acetyl-CoA, which is carboxylated to malonyl-CoA by overexpressed acetyl-CoA carboxylase (ACC). Malonyl-CoA is then reduced to 3-HP through a multi-step enzymatic process catalyzed by malonyl-CoA reductase (MCR), often a bifunctional enzyme requiring NADPH. This pathway is implemented by heterologous expression of genes like acc and mcr from sources such as Chloroflexus aurantiacus, with additional optimizations like cofactor balancing to enhance flux. The simplified reaction sequence is:\text{Glucose} \rightarrow 2 \text{ Acetyl-CoA} \rightarrow \text{Malonyl-CoA} \rightarrow \text{3-HP (via multi-step enzymatic reduction)}[30]Fed-batch fermentation processes have achieved titers of 50–100 g/L in engineered E. coli and related hosts, with yields approaching 0.5 g/g glucose, as demonstrated in optimized E. coli strains reaching 76.2 g/L from glycerol at 0.45 g/g. Challenges such as 3-HP toxicity to cells, which inhibits growth at concentrations above 50 g/L, are mitigated through in situ extraction techniques like reactive extraction with amines or membrane contactors to continuously remove the product and maintain productivity. These methods prevent accumulation and allow prolonged fermentation runs, improving overall process economics.[30]Renewable feedstocks like sugars derived from corn starch (glucose) or lignocellulosic biomass (xylose and glucose mixtures) serve as carbon sources, supporting sustainable production. To address redox imbalances in the pathway, particularly NADPH demand, co-production with 1,3-propanediol (1,3-PDO) is employed in glycerol-based fermentations, as seen in L. reuteri and E. coli hybrids yielding 125.93 g/L 3-HP alongside 88.46 g/L 1,3-PDO at 0.95 g/g total yield. This strategy recycles cofactors and valorizes by-products from biodiesel industries.[30]Recent advances include CRISPR-edited pathways in cyanobacteria such as Synechocystis sp. PCC 6803 for direct CO₂ utilization, enabling photosynthetic 3-HP production at titers up to 0.83 g/L via the malonyl-CoA route under autotrophic conditions, as reported in studies up to 2023. These developments leverage solar energy for carbon fixation, reducing reliance on external sugars and offering a pathway toward carbon-neutral biomanufacturing.[30]
Applications
Platform chemical derivatives
3-Hydroxypropionic acid (3-HP) serves as a versatile platform chemical, enabling the synthesis of various industrial intermediates through targeted chemical transformations such as dehydration, oxidation, esterification, and hydrogenation. These derivatives leverage 3-HP's hydroxyl and carboxyl functionalities to produce high-value compounds used in polymers, pharmaceuticals, and solvents, contributing to sustainable chemical manufacturing from renewable feedstocks.[31]Dehydration of 3-HP to acrylic acid is a key process, typically conducted in the gas or liquid phase using acidic heterogeneous catalysts like silica gel, which provides weak Lewis acid sites for selective elimination of water. The reaction occurs at temperatures of 150–300 °C, achieving complete conversion of 3-HP with acrylic acid selectivity and yields exceeding 99%. In February 2025, LG Chem announced acceleration of commercial production of 100% plant-based acrylic acid derived from 3-HP produced by microbial fermentation of plant-based raw materials.[12][31][32][33]Acrylic acid, the primary product, is widely applied in the production of superabsorbent polymers for hygiene products and as a monomer in paints and coatings, with global demand surpassing 6 million metric tons annually.[12][31][32]Oxidation of 3-HP yields malonic acid through the conversion of the primary hydroxyl group to a carboxylic acid, performed via catalytic methods in aqueous media using noble metal catalysts such as palladium on activated carbon. Optimal conditions include temperatures of 20–60 °C, pH 7.5–9 maintained by alkali hydroxides, and oxygen as the oxidant, resulting in high yields of malonic acid or its salts. Malonic acid finds applications in the synthesis of pharmaceuticals, such as barbiturates, and in dyes and agrochemicals.[34][34]Esterification of 3-HP produces 3-hydroxypropyl esters by reaction with alcohols under acidic catalysis, yielding compounds suitable for use as solvents in coatings or as plasticizers in flexible materials. These esters maintain the hydroxyl group for further functionalization, enhancing their utility in industrial formulations.[35][36]Hydrogenation of 3-HP to 1,3-propanediol involves reduction of the carboxylic acid group in the liquid phase using ruthenium-based catalysts, often supported on titania or silica, under hydrogen pressure to achieve high selectivity. Yields approach 98% under optimized conditions, with the product serving as a monomer for polytrimethylene terephthalate (PTT) fibers, such as DuPont's Sorona brand used in textiles and carpets.[37][38]As of 2025, modeled minimum selling prices for bio-based 3-HP from industrial-scale production are approximately $2–5 per kg, positioning it as a cost-competitive precursor for bio-derived acrylic acid and enabling economic viability in large-scale production.[39]
Polymer production
3-Hydroxypropionic acid (3-HP) serves as a key monomer for producing poly(3-hydroxypropionate) (P3HP), a biodegradable thermoplastic belonging to the polyhydroxyalkanoate (PHA) family. P3HP is synthesized through bacterial fermentation where 3-HP is converted to 3-HP-CoA and polymerized intracellularly by PHA synthase enzymes, accumulating as granules within engineered microorganisms such as Escherichia coli or Halomonas bluephagenesis. This biological route mirrors the biosynthesis of other PHAs, utilizing substrates like glycerol or 1,3-propanediol to achieve high polymer content, up to 92 wt% of cell dry weight in optimized strains.[40][41]Industrial production of P3HP also includes chemical methods, such as ring-opening polymerization of β-propiolactone (the cyclic form of 3-HP) or direct polycondensation of 3-HP derived from acrylic acid hydration. These approaches enable scalable synthesis, with recent fed-batch fermentations yielding up to 80 g/L of P3HP homopolymer in recombinant E. coli within 45 hours. Direct fermentation to polymer granules remains predominant for biocompatibility, while chemical routes address limitations in biological yields.[42][43][44]P3HP exhibits a melting point of approximately 70–80 °C and a glass transition temperature of −20 °C, rendering it highly flexible with high tensile strength and elongation at break, alongside excellent biodegradability and biocompatibility. These properties suit applications in packaging films, injection-molded products, and thermoforming, where its ductility outperforms more brittle PHAs like poly(3-hydroxybutyrate). In biomedical devices, P3HP's non-toxicity supports uses in tissue engineering scaffolds. Compared to polylactic acid (PLA), P3HP demonstrates greater hydrophilicity due to its odd-numbered carbon chain and pendant hydroxyl groups, enhancing water permeability but potentially requiring blending for moisture-sensitive uses.[45][46][45]Copolymers of 3-HP with 4-hydroxybutyric acid (P(3HP-co-4HB)) expand material versatility, forming elastomers with tunable compositions from 12–82 mol% 4HB via recombinant E. coli fed mixtures of 1,3-propanediol and 1,4-butanediol. These copolymers display melting points from 35–78 °C and reduced tensile strength (0.64–33.8 MPa) with increasing 4HB content, achieving full transparency at higher 4HB fractions. Their biocompatibility and elasticity make them ideal for medical implants, such as resorbable sutures and vascular grafts, leveraging the elastomeric nature absent in P3HP homopolymer.[47][47][48]Early P3HP productions faced challenges with low molecular weights (around 10^5 Da), limiting mechanical integrity due to inefficient polymerization. Advances by 2025, including pathway engineering and cofactor optimization in halophilic bacteria, have overcome this, achieving polymer titers exceeding 50 g/L and higher molecular weights for robust thermoplastics.[49][44][41]
Research and development
Genetic engineering systems
Genetically encoded inducible systems for 3-hydroxypropionic acid (3-HP) production were characterized in the 2010s, leveraging 3-HP as a ligand for bacterial transcription factors to enable precise, dose-dependent gene expression in microbial hosts such as Escherichia coli. These systems, derived from bacteria like Pseudomonas denitrificans and Pseudomonas putida, utilize LysR-type transcriptional regulators (LTTRs) that respond specifically to 3-HP concentrations, facilitating orthogonal control in engineered strains without interfering with native metabolism.[50][51]The mechanism involves 3-HP binding to repressor proteins, such as C3-LysR or HpdR from propionate and 3-HP degradation pathways, which alters their conformation and derepresses target promoters like P_hpdH. This binding enhances RNA polymerase recruitment, leading to upregulation of downstream genes with fold inductions ranging from 23-fold in E. coli at 10 mM 3-HP to over 140-fold in native hosts at 25 mM. Applications include dynamic metabolic control, where 3-HP levels trigger expression of pathway enzymes only when toxicity thresholds are approached, thereby balancing production and cell viability during fermentation.[50][51]In synthetic biology, these 3-HP sensors have been integrated into genetic circuits for advanced pathway regulation, including coupling production to cell growth via antibiotic resistance markers for adaptive laboratory evolution. For instance, biosensor-driven selection in E. coli rewired central carbon flux toward 3-HP biosynthesis, with CRISPR-Cas9 used to introduce targeted mutations in genes like cyaA and crp for on/off pathway switches. This approach enabled combinatorial engineering, achieving yields up to 0.91 g/g glycerol (91% of theoretical maximum) in fed-batch fermentation.[52]Such systems offer advantages in tight regulation, with demonstrated titer and yield improvements of 37–48% over parental strains by minimizing acetate overflow and toxicity. Early demonstrations combined 3-HP sensors with acrylate pathways in E. coli, converting 3-HP to acrylate via enzymes like propionyl-CoA synthetase and acyl-CoA hydrolase, enabling real-time monitoring of intracellular levels up to 4.2 g/L. However, limitations include cross-reactivity with structurally similar acids like propionate, butyrate, and 3-hydroxybutyrate, which can reduce specificity in complex fermentations.[52][53][51]
Market and industrial advances
The global 3-hydroxypropionic acid (3-HP) market was estimated at USD 713.8 million in 2023 and is projected to reach USD 1.4 billion by 2030, expanding at a compound annual growth rate (CAGR) of 9.5% from 2024 to 2030, fueled by rising demand for sustainable bio-based chemicals in polymers and platform compounds.[4]Major industry players, including Cargill, BASF, Novozymes, and LG Chem, have invested heavily in fermentation technologies and facilities for bio-3-HP production; for instance, Cargill and Novozymes collaborated on microbial processes since 2008, while LG Chem initiated commercial-scale production of bio-acrylic acid derived from 3-HP in early 2025 using plant-based feedstocks.[4][33][54]Recent industrial advances encompass integrating 3-HP fermentation with biorefineries to utilize waste feedstocks such as brewer's spent grain, enhancing resource efficiency and reducing costs.[55] Engineered Escherichia coli strains have achieved titers up to 71.9 g/L through optimized metabolic pathways (as reported in 2015, with ongoing research). Recent advances include titers up to 154 g/L in fed-batch processes and 100 g/L in engineered yeast (Yarrowia lipolytica) as of 2025, paving the way for higher-yield commercial processes.[56][3][57]Bio-based 3-HP production offers sustainability benefits, including a reduced carbon footprint compared to petrochemical routes for derivatives like acrylic acid, with lifecycle analyses showing potential emissions reductions of 10-50% through renewable feedstocks.[31] Biobased polymers have gained regulatory approvals in the EU and US under frameworks like the USDA BioPreferred program and EU Circular Economy Action Plan, supporting their use in packaging and textiles.[58][59]Key challenges in commercialization include scaling downstream purification to achieve high purity at low cost and ensuring economic competitiveness against established propylene-based chemical routes.[31]Market projections indicate potential growth to approximately $1.4 billion by 2030, contingent on expanded applications in biopolymers and broader adoption of bio-based platforms.[4]