Table of Contents
Section 1: The Classification of Oxymorphone as a Semi-Synthetic Opioid
1.1 Direct Answer and Thesis Statement
Oxymorphone is unequivocally classified as a semi-synthetic opioid.
This designation is not a matter of ambiguity but is rooted in the specific industrial and chemical processes used for its manufacture.
It is synthesized in a laboratory through the chemical modification of a naturally occurring precursor, thebaine, which is an alkaloid extracted from the opium poppy plant, Papaver somniferum.
While its origins are tied to a natural product, the final molecule of oxymorphone does not exist in nature and is the result of deliberate chemical transformation.
This report will establish and defend the central thesis that an opioid’s classification as natural, semi-synthetic, or fully synthetic is determined by its starting material and manufacturing pathway.
This classification, in turn, has profound and predictable implications for its chemical structure, pharmacological properties, relative potency, metabolic fate, and ultimately, its public health impact and regulatory status.
The journey of oxymorphone, from a non-therapeutic plant alkaloid to a potent, legally prescribed analgesic with a history of significant abuse, serves as a quintessential case study in the complexities of the semi-synthetic opioid class.
1.2 Overview of the Opioid Landscape
To fully contextualize the classification of oxymorphone, it is essential to first understand the broader landscape of opioid pharmacology.
Opioids are a diverse class of drugs that exert their effects by acting on opioid receptors in the central and peripheral nervous systems.
They are broadly categorized into three distinct groups based on their origin and method of production: natural, semi-synthetic, and fully synthetic.
- Natural opioids, often called opiates, are compounds isolated directly from the opium poppy.
- Semi-synthetic opioids, the category to which oxymorphone belongs, are synthesized in laboratories using a natural opiate as the chemical starting point.
- Fully synthetic opioids are created entirely through chemical synthesis in a laboratory, without reliance on any poppy-derived precursors.
This tripartite classification provides a fundamental framework for understanding the chemical relationships, relative potencies, and distinct risks associated with each compound within this powerful class of medicines and substances of abuse.
Section 2: Defining the Opioid Spectrum: Natural, Semi-Synthetic, and Fully Synthetic Alkaloids
The precise classification of any opioid hinges on a clear understanding of the definitions that delineate the spectrum from naturally occurring compounds to entirely man-made substances.
The terminology itself reflects a history of scientific advancement; the term “opiate” historically referred strictly to the natural alkaloids derived from opium, such as morphine and codeine.
As chemists began to modify these natural structures and later create entirely new molecules with similar effects, the broader term “opioid” was adopted to encompass any substance, regardless of origin, that binds to opioid receptors.
This linguistic evolution mirrors the technological progression from simple plant extraction to the complex laboratory synthesis that defines the modern opioid landscape.
2.1 Natural Opiates
Natural opiates are pharmacologically active alkaloids that are biosynthesized by and extracted directly from the opium poppy, Papaver somniferum.
Their molecular structures are the product of the plant’s metabolic pathways, not human intervention in a laboratory.
The primary source material is either opium gum—the dried latex collected from incisions made in the unripe seed pods—or poppy straw, which refers to the mature, dried plant material (capsules, stems, and leaves) harvested for industrial processing.
The archetypal examples of natural opiates are morphine and codeine.
Morphine is the most abundant alkaloid in opium, typically constituting about 10% of its weight, and serves as the benchmark against which the potency of other opioids is measured.
Codeine is present in much smaller quantities and can be extracted directly or, more commonly, synthesized from morphine.
Thebaine is another important natural opiate, but it possesses stimulatory and convulsant properties at high doses and is not used therapeutically as an analgesic.
Its primary value lies in its unique chemical structure, which makes it an ideal starting material for the synthesis of other opioids.
The manufacturing process for natural opiates is one of extraction and purification.
In traditional methods, crude opium gum is dissolved in hot water and treated with calcium hydroxide (lime) to precipitate non-morphine alkaloids and impurities.
Ammonium chloride is then added to the filtered solution, causing the morphine base to precipitate out of the solution, after which it can be collected and purified.
The industrial poppy straw process involves mechanically crushing the dried plant matter and using a series of solvent and acid washes to extract the alkaloids in a large-scale factory setting, a method considered more secure and efficient for legal pharmaceutical production.
In either case, the fundamental molecule is pre-existing in the plant.
2.2 Semi-Synthetic Opioids
Semi-synthetic opioids are compounds created in a laboratory through the chemical modification of a naturally occurring opiate.
This process uses the complex molecular scaffold of a natural alkaloid as a starting point, and chemists then alter specific functional groups to create a new substance with different pharmacological properties, such as enhanced potency, altered duration of action, or different receptor binding affinity.
This class includes many of the most widely prescribed and abused opioid analgesics.
Prominent examples are heroin (diacetylmorphine), which is synthesized from morphine; hydrocodone and hydromorphone, which can be derived from codeine or morphine; and oxycodone and oxymorphone, which are most commonly synthesized from thebaine.
The defining characteristic of this class is its reliance on a naturally derived precursor molecule.
The core 4,5-epoxymorphinan ring structure is inherited from the plant, but the final product is the result of deliberate laboratory synthesis.
2.3 Fully Synthetic Opioids
Fully synthetic opioids are substances that are synthesized entirely in a laboratory from simple chemical precursors, a process known as de novo synthesis.
Their creation is completely independent of the opium poppy and its alkaloids.
The chemical structures of these compounds are often fundamentally different from the classic morphinan skeleton of natural and semi-synthetic opioids.
This class includes medically important drugs like fentanyl, methadone, and tramadol.
It also encompasses a growing number of novel synthetic opioids (NSOs) or “designer drugs” that are produced in clandestine laboratories for the illicit market, such as U-47700 and the highly potent nitazene family.
The synthesis of these compounds starts from basic, widely available chemical building blocks, which are assembled through a series of chemical reactions.
This method gives chemists the freedom to design molecules with highly specific properties, which has led to the creation of compounds with potencies far exceeding that of morphine.
For example, fentanyl is 50 to 100 times more potent than morphine, and its analogue carfentanil is approximately 10,000 times more potent.
The following table provides a consolidated overview of these classifications for common opioids, clarifying their origin and primary precursors.
| Drug Name | Chemical Class | Primary Precursor/Starting Material |
| Morphine | Natural | Opium / Poppy Straw (Papaver somniferum) |
| Codeine | Natural | Opium / Poppy Straw (Papaver somniferum) |
| Thebaine | Natural | Opium / Poppy Straw (Papaver somniferum, P. bracteatum) |
| Heroin | Semi-Synthetic | Morphine |
| Hydrocodone | Semi-Synthetic | Codeine or Thebaine |
| Hydromorphone | Semi-Synthetic | Morphine |
| Oxycodone | Semi-Synthetic | Thebaine |
| Oxymorphone | Semi-Synthetic | Thebaine (via Oxycodone) |
| Buprenorphine | Semi-Synthetic | Thebaine |
| Fentanyl | Fully Synthetic | Non-opioid chemical precursors (e.g., N-phenethyl-4-piperidone) |
| Methadone | Fully Synthetic | Non-opioid chemical precursors |
| Tramadol | Fully Synthetic | Non-opioid chemical precursors |
Section 3: The Chemical Genesis of Oxymorphone: From Poppy Alkaloid to Potent Analgesic
The story of oxymorphone’s creation is a prime example of the strategic chemical manipulation that defines the semi-synthetic class.
It begins not with a therapeutic drug, but with a non-analgesic plant alkaloid that possesses a uniquely suitable chemical structure for laboratory transformation.
3.1 The Strategic Starting Material: Thebaine
Thebaine, also known as paramorphine, is a natural opiate alkaloid found as a minor constituent in Papaver somniferum but in much greater abundance in other poppy species, such as Papaver bracteatum (the Iranian poppy).
Unlike its close chemical relatives morphine and codeine, thebaine does not produce depressant or analgesic effects.
Instead, it acts as a stimulant on the central nervous system, and at high doses, it can cause strychnine-like convulsions.
For this reason, thebaine itself has no therapeutic application as a pain reliever.
However, thebaine is the most valuable precursor for the industrial synthesis of a wide array of modern semi-synthetic opioids, including both potent agonists like oxycodone and oxymorphone, and crucial antagonists like naloxone and naltrexone.
Its utility stems from its unique chemical structure.
Thebaine possesses a conjugated diene system within its C-ring and a dienol ether functional group.
This arrangement provides chemists with a reactive “handle” that is absent in morphine and codeine, allowing for specific and high-yield chemical transformations.
Most importantly, it facilitates the introduction of a hydroxyl group at the C-14 position of the morphinan skeleton, a structural feature strongly associated with the high potency of analgesics like oxymorphone and oxycodone.
This industrial reliance on thebaine has spurred significant advancements in both agriculture and biotechnology.
Recognizing the value of a non-narcotic precursor, researchers and pharmaceutical companies have developed genetically modified strains of Papaver somniferum that are engineered to produce high concentrations of thebaine and oripavine while producing little to no morphine or codeine.
This deliberate cultivation strategy marks a fundamental shift in the global opioid supply chain.
It transforms poppy farming from the production of a psychoactive drug (opium) into the industrial farming of a chemical feedstock.
This “thebaine economy” allows for a more stable, controllable, and legally defensible supply chain that is less vulnerable to diversion at the agricultural level compared to traditional opium gum harvesting.
From this single, optimized, non-analgesic precursor, a diverse portfolio of high-value pharmaceutical products can be manufactured.
3.2 The Industrial Synthesis Pathway
The commercial production of oxymorphone is a multi-step process that begins with thebaine and proceeds through an oxycodone intermediate.
While specific industrial methods are proprietary, the general chemical pathway is well-established in the scientific and patent literature.
- Step 1: Oxidation of Thebaine to 14-Hydroxycodeinone. The synthesis begins with the oxidation of thebaine. This is typically achieved by reacting thebaine with a peroxyacid, such as peracetic acid or performic acid, or with hydrogen peroxide in the presence of an acid. This reaction targets the reactive diene system in thebaine, leading to the formation of 14-hydroxycodeinone. This step is critical as it installs the C-14 hydroxyl group (−OH) that is a hallmark of the oxycodone and oxymorphone family and is crucial for their high analgesic potency.
- Step 2: Catalytic Hydrogenation to Oxycodone. The intermediate, 14-hydroxycodeinone, is then subjected to catalytic hydrogenation. In this step, the molecule is reacted with hydrogen gas in the presence of a metal catalyst, typically a palladium catalyst (e.g., palladium on carbon, Pd/C). This reaction reduces the carbon-carbon double bond between the C-7 and C-8 positions in the C-ring of the morphinan structure. This conversion of the α,β-unsaturated ketone (enone) into a saturated ketone transforms 14-hydroxycodeinone into oxycodone.
- Step 3: O-Demethylation of Oxycodone to Oxymorphone. The final and most chemically challenging step is the conversion of oxycodone to oxymorphone. This requires the selective removal of the methyl group from the phenolic ether at the C-3 position (an O-demethylation) to convert the methoxy group (−OCH3) of oxycodone into a free hydroxyl group (−OH), which is characteristic of oxymorphone. Historically, this transformation has been accomplished using harsh and hazardous reagents, most notably boron tribromide (BBr3), which is toxic and corrosive.1 The reaction cleaves the ether bond, releasing the methyl group and forming the final oxymorphone molecule.
Reflecting the ongoing drive for more environmentally sound and safer industrial processes, significant research has been dedicated to developing “greener” methods for these demethylation steps.
Recent innovations include electrochemical approaches that can achieve both N- and O-demethylation under milder conditions, avoiding the use of large quantities of wasteful and dangerous reagents.
These advancements underscore the continuous evolution of semi-synthetic chemistry, aiming to improve the efficiency and sustainability of producing these vital medicines.
Section 4: Comparative Analysis I: Morphine as the Archetypal Natural Opiate
To fully appreciate why oxymorphone is classified as semi-synthetic, it is instructive to compare its origin and structure directly with that of morphine, the quintessential natural opiate.
This comparison highlights the fundamental difference between extracting a pre-existing molecule and creating a new one in a Lab.
4.1 From Plant to Powder: The Extraction of Morphine
The production of pharmaceutical-grade morphine is a process of extraction and purification, not chemical synthesis.
The morphine molecule itself is fully constructed by the biosynthetic machinery of the Papaver somniferum plant.
The human role is to isolate this molecule from the complex mixture of other alkaloids and plant materials.
As previously described, this can be done through two primary methods.
The traditional method involves collecting opium gum, a crude resin that is about 10% morphine by weight, and subjecting it to a series of precipitations using simple chemical reagents like water, lime, and ammonium chloride to isolate the morphine base.
The more modern industrial method, known as the poppy straw process, involves harvesting the entire dried poppy plant and using factory-based chemical processes to extract the alkaloids directly from the plant matter.
This latter method is more efficient and secure, but the underlying principle remains the same: the morphine molecule is harvested, not created.
4.2 A Tale of Two Structures: Morphine vs. Oxymorphone
A direct visual and chemical comparison of the morphine and oxymorphone molecules reveals the specific, deliberate alterations made in the laboratory to create the semi-synthetic compound.
While both share the same core 4,5-epoxymorphinan scaffold, there are three critical differences that fundamentally change the molecule’s properties:
- The C-6 Position: Morphine features a hydroxyl group (−OH) at the C-6 position. In oxymorphone, this is replaced with a ketone group (a carbonyl, C=O). This modification increases the lipophilicity (fat-solubility) of the molecule, which may allow it to cross the blood-brain barrier more readily than morphine.
- The C-7/C-8 Bond: The C-ring of morphine contains a double bond between the C-7 and C-8 atoms. During the synthesis of oxymorphone (via hydrogenation of 14-hydroxycodeinone), this bond is saturated, becoming a single bond.
- The C-14 Position: Morphine has a simple hydrogen atom at the C-14 position. Oxymorphone, by virtue of its synthesis from thebaine, has a hydroxyl group (−OH) at this position. This C-14 hydroxyl is a key structural feature strongly correlated with increased analgesic potency.
These three laboratory-induced modifications are directly responsible for the significant pharmacological differences between the two drugs.
Most notably, these changes result in oxymorphone being approximately 10 times more potent as an analgesic than morphine on a milligram-per-milligram basis.
This demonstrates how targeted semi-synthesis can dramatically enhance the properties of a natural product.
Section 5: Comparative Analysis II: Fentanyl as a Paradigm of Fully Synthetic Opioids
The distinction between semi-synthetic and fully synthetic opioids becomes starkly clear when oxymorphone is compared to fentanyl.
This comparison moves beyond simple modification of a natural template to the complete construction of a novel chemical entity, illustrating a profound leap in chemical intervention and a corresponding escalation in potency and risk.
5.1 Building from Scratch: The De Novo Synthesis of Fentanyl
Fentanyl’s synthesis is entirely a laboratory endeavor, beginning with simple, common chemical precursors that have no structural relationship to any alkaloid from the opium poppy.
This process of building a complex molecule from basic starting materials is known as de novo synthesis.
Several established synthetic routes for fentanyl exist, including the original Janssen method, the Siegfried method, and the more recent Gupta method, all of which are well-documented in the chemical literature and known to both legitimate pharmaceutical manufacturers and clandestine laboratory operators.
The U.S. Drug Enforcement Administration (DEA) closely monitors and regulates the chemical precursors used in these syntheses, such as N-phenethyl-4-piperidone (NPP), 4-anilino-N-phenethylpiperidine (4-ANPP), phenethyl bromide, and propionyl chloride.
The focus on controlling these non-opioid building blocks underscores the fact that fentanyl is constructed piece by piece, in stark contrast to the extraction of morphine or the modification of thebaine.
5.2 Unrelated Families: Morphinan vs. Phenylpiperidine Structures
The most compelling evidence of the different origins of oxymorphone and fentanyl lies in their fundamentally distinct molecular architectures.
- Oxymorphone, as a semi-synthetic opioid, is built upon the complex, rigid, multi-ring 4,5-epoxymorphinan scaffold. This entire intricate structure is inherited directly from its natural precursor, thebaine.
- Fentanyl, by contrast, belongs to the phenylpiperidine class of opioids. Its structure is far simpler, consisting of a central piperidine ring attached to aniline and phenethyl groups.
A visual comparison of the two structures immediately reveals that they are not chemical relatives.
They do not share a common core structure or a common precursor.
While both are potent agonists at the μ-opioid receptor, they achieve this effect through entirely different molecular shapes.
This structural divergence is the definitive proof of their separate classifications: one is a modification of a natural blueprint, while the other is a novel invention of synthetic chemistry.
This progression from natural to semi-synthetic to fully synthetic opioids illustrates a critical trend in pharmacology and public health.
The journey from morphine to oxymorphone to fentanyl represents an escalation ladder in human chemical intervention, which is directly mirrored by an escalation in potency and potential risk.
Morphine’s potency is set by the plant.
The semi-synthesis of oxymorphone allows for a deliberate “tuning” of the natural molecule to achieve a roughly tenfold increase in potency.
The de novo synthesis of fentanyl breaks free from the natural template entirely, allowing for the design of a novel structure with a 50- to 100-fold increase in potency over morphine.
This trend continues with fentanyl analogues like carfentanil (10,000 times more potent than morphine) and certain nitazenes (up to 4,300 times more potent than morphine), which are also fully synthetic.
This synthesis-potency-risk ladder is not merely an academic observation; it is the central dynamic driving the modern overdose crisis.
The ability to produce hyper-potent opioids in clandestine labs using readily available, non-poppy-derived precursors is the primary engine of the crisis’s lethality.
Therefore, an opioid’s classification is a direct indicator of its place on this ladder and its potential public health threat.
Section 6: Structural Relationships and Pharmacological Implications
The chemical classification and structure of an opioid are inextricably linked to its biological activity, its clinical utility, and the regulatory measures required to control its use.
The case of oxymorphone and its relatives within the morphinan family provides a clear illustration of how subtle structural differences translate into significant pharmacological and public health consequences.
6.1 The Morphinan Family: A Study in Subtle Differences
Oxymorphone is part of a closely related family of semi-synthetic morphinan opioids, and understanding these relationships is key to appreciating its clinical profile.
- Oxymorphone and Oxycodone: The relationship between these two drugs is particularly intimate. As established, oxymorphone is the C-3 O-demethylated analogue of oxycodone. This is not just a laboratory transformation; it is also a key metabolic pathway in the human body. Oxymorphone is a primary active metabolite of oxycodone, formed when oxycodone is metabolized by the cytochrome P450 enzyme CYP2D6. This metabolic link has profound clinical implications. The analgesic effect of oxycodone is believed to be mediated, in part, by its conversion to the more potent oxymorphone. Consequently, a patient’s genetic makeup can significantly influence their response to oxycodone. Individuals who are “poor metabolizers” due to genetic variations in the CYP2D6 enzyme cannot efficiently convert oxycodone to oxymorphone, which may result in reduced analgesic efficacy.
- Metabolic Consequences: Conversely, oxymorphone itself is not significantly metabolized by the CYP450 enzyme system. Its primary metabolic pathway is glucuronidation (conjugation with glucuronic acid) in the liver to form metabolites like oxymorphone-3-glucuronide. This gives oxymorphone a more predictable metabolic profile and a lower potential for drug-drug interactions compared to opioids like oxycodone or fentanyl, which are heavily reliant on the highly variable and easily inhibited or induced CYP enzyme system.
- Oxymorphone and Hydromorphone: Oxymorphone and hydromorphone share a very close structural resemblance. Both are 6-keto opioids with a saturated C-7/C-8 bond, making them structurally more similar to each other than to morphine. The primary difference is the C-14 hydroxyl group present on oxymorphone. This close structural relationship accounts for their similar pharmacological profiles as potent analgesics.
6.2 Potency, Abuse Liability, and Regulatory Scrutiny
All opioids that act as agonists at the μ-opioid receptor, including natural, semi-synthetic, and fully synthetic variants, carry a high potential for abuse, misuse, and addiction.
The euphoria, anxiolysis, and feelings of relaxation they produce are powerful reinforcing effects.
However, factors like increased potency and rapid onset of action, often achieved through semi-synthesis or full synthesis, can heighten the abuse liability and the risk of fatal overdose.
Oxymorphone, with its high potency and abuse potential, is strictly regulated worldwide.
In the United States, it is classified as a Schedule II controlled substance under the Controlled Substances Act, the same category as morphine, oxycodone, and fentanyl.
This classification indicates a high potential for abuse which may lead to severe psychological or physical dependence, while also having a currently accepted medical use.
To further mitigate its risks, oxymorphone is subject to the FDA’s Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) program.
This program requires manufacturers to provide education to healthcare providers on safe prescribing practices, pain management, and the diagnosis and treatment of opioid use disorder.
The history of oxymorphone’s extended-release formulation, Opana ER, serves as a critical case study in the intersection of pharmaceutical formulation, abuse, and regulation.
The paradox of semi-synthesis is vividly demonstrated here.
The chemical sophistication that produced a potent and long-acting analgesic also created a new and dangerous vector for abuse.
Opana ER was designed with a crush-resistant formulation intended to deter abuse.
However, determined users discovered that the tablet could be manipulated for intravenous injection, bypassing the extended-release mechanism to achieve a rapid and powerful high.
This practice led directly to severe public health consequences, including localized outbreaks of HIV and hepatitis C among clusters of people who injected the drug.
In response to this public health crisis, the FDA took the unprecedented step in June 2017 of requesting that the manufacturer voluntarily remove Opana ER from the market, concluding that the benefits of the drug no longer outweighed its risks in the context of its widespread abuse.
This event highlights a crucial point: the therapeutic intent and advanced formulation of a semi-synthetic opioid do not guarantee safety.
The inherent properties of the molecule itself, combined with human behavior, can create risks so severe that they necessitate drastic regulatory action.
Section 7: Conclusion: Synthesis, Structure, and Significance in the Opioid Landscape
7.1 Recapitulation of Key Findings
This analysis has definitively established that oxymorphone is a semi-synthetic opioid.
This classification is a direct consequence of its manufacturing process, which involves the laboratory-based chemical modification of thebaine, a naturally occurring alkaloid isolated from the opium poppy.
This places it in a distinct category, separate from both natural opiates like morphine, which are merely extracted and purified from the plant, and fully synthetic opioids like fentanyl, which are constructed de novo from simple chemical precursors unrelated to the poppy.
The key distinctions can be summarized as follows:
- Origin: Oxymorphone originates from a natural product (thebaine) but is finalized in a lab. Morphine is entirely a product of nature. Fentanyl is entirely a product of the laboratory.
- Structure: Oxymorphone retains the core 4,5-epoxymorphinan skeleton of its natural precursor but features key modifications at the C-6, C-7/C-8, and C-14 positions. This structure is fundamentally different from fentanyl’s phenylpiperidine architecture but clearly related to morphine’s.
- Synthesis: The creation of oxymorphone is a process of targeted chemical transformation. This contrasts with the extraction of morphine and the ground-up construction of fentanyl.
7.2 The Broader Significance
The classification of an opioid as natural, semi-synthetic, or fully synthetic is far more than an academic distinction.
It provides a crucial framework for understanding the evolution of analgesic pharmacology and the escalating dynamics of the opioid crisis.
The journey from morphine to oxymorphone to fentanyl is a narrative of increasing human intervention in molecular design, which has led to a parallel and dramatic escalation in potency and public health risk.
Understanding that oxymorphone is semi-synthetic is essential for appreciating its unique clinical profile—its high potency relative to morphine, its predictable metabolism compared to oxycodone, and its history as a valuable therapeutic agent that also carries a significant and proven risk of abuse.
The story of oxymorphone, and particularly the fate of its extended-release formulation, underscores the complex interplay between chemical innovation, therapeutic benefit, human behavior, and regulatory oversight.
Ultimately, an opioid’s origin story is inextricably linked to its power, its peril, and its place in the complex and challenging landscape of modern medicine and public health.
The following table provides a final, consolidated comparison of the three representative opioids discussed throughout this report, distilling the core findings into a clear, comparative summary.
| Feature | Morphine (Natural) | Oxymorphone (Semi-Synthetic) | Fentanyl (Fully Synthetic) |
| Chemical Class | Natural Opiate | Semi-Synthetic Opioid | Fully Synthetic Opioid |
| Primary Precursor | Opium / Poppy Straw | Thebaine (from Poppy) | Non-opioid chemical precursors |
| Core Chemical Structure | 4,5-Epoxymorphinan | 4,5-Epoxymorphinan | Phenylpiperidine |
| Relative Potency (vs. Morphine=1) | 1x | ~10x (parenteral), ~3x (oral) | ~50-100x |
| Primary Metabolic Pathway | Glucuronidation | Glucuronidation | CYP3A4 Oxidation |
| DEA Schedule (US) | Schedule II | Schedule II | Schedule II |
Works cited
- Sustainable Synthesis of Noroxymorphone via a Key …, accessed on August 12, 2025, https://pubs.acs.org/doi/10.1021/acssuschemeng.2c02824
