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Neotame
View on Wikipediafrom Wikipedia
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| Names | |
|---|---|
| Systematic IUPAC name
(3S)-3-[(3,3-Dimethylbutyl)amino]-4-{[(2S)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino}-4-oxobutanoic acid | |
| Other names
E961; N-(N-(3,3-Dimethylbutyl)-L-α-aspartyl)-L-phenylalanine 1-methyl ester
| |
| Identifiers | |
3D model (JSmol)
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| ChEBI | |
| ChemSpider | |
| ECHA InfoCard | 100.109.344 |
| E number | E961 (glazing agents, ...) |
PubChem CID
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|
| UNII | |
CompTox Dashboard (EPA)
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|
| |
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| Properties | |
| C20H30N2O5 | |
| Molar mass | 378.469 g·mol−1 |
| Appearance | white powder[1] |
| Melting point | 80.9–83.4 °C (177.6–182.1 °F; 354.0–356.5 K)[1] |
| 12.6 g/kg at 25 °C[2] | |
| Hazards | |
| NFPA 704 (fire diamond) | |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
| |
Neotame, also known by the brand name Newtame,[3] is a non-caloric artificial sweetener and aspartame analog.[2] By mass, it is 7,000 to 13,000 times sweeter than sucrose.[3] It has no notable off-flavors when compared to sucrose. It enhances original food flavors. It can be used alone, but is often mixed with other sweeteners to increase their individual sweetness (i.e. synergistic effect) and decrease their off-flavors (e.g. saccharin). It is chemically somewhat more stable than aspartame. Its use can be cost effective in comparison to other sweeteners as smaller amounts of neotame are needed.[2]
It is suitable for use in carbonated soft drinks, yogurts, cakes, drink powders, and bubble gums among other foods. It can be used as a table top sweetener for hot drinks like coffee. It covers bitter tastes (e.g. caffeine).[2]
In 2002, FDA approved it as a non-nutritive sweetener and flavor enhancer within the United States in foods generally, except meat and poultry.[3] In 2010, it was approved for use in foods within the European Union with the E number E961.[4] It has also been approved as an additive in many other countries outside US and EU.[2]
Its metabolism is fast and is not retained in the body. Methanol forms in its metabolism. Only trace amounts of neotame are added to foods, so the amount of methanol is insignificant for health. It is safe for type 2 diabetics and those with phenylketonuria.[5][1]
French scientists Claude Nofre and Jean-Marie Tinti invented neotame.[2] In 1992, they filed a United States patent, which was granted in 1996.[6]
Safety
[edit]In US and EU, the acceptable daily intake (ADI) of neotame for humans is 0.3 and 2 mg per kg of bodyweight (mg/kg bw), respectively. NOAEL for humans is 200 mg/kg bw per day within EU.[3][1] Estimated possible daily intakes from foods are well below ADI levels. Ingested neotame can form phenylalanine, but in normal use of neotame, this is not significant to those with phenylketonuria. It also has no adverse effects in type 2 diabetics. It is not considered to be carcinogenic or mutagenic.[5][1] The Center for Science in the Public Interest has ranked neotame as safe.[7]
Sweetness
[edit]Water solutions of neotame that are equivalent in sweetness to sucrose water solutions increase logarithmically in relative sweetness as the sucrose concentration of a comparably sweet sucrose solution increases until a plateau is reached. Maximum sweetness is reached at neotame solution concentrations that are relatively as sweet as a water solution that is 15.1 percentage sucrose by weight, i.e., at 15.1 sucrose equivalence % (SE%). For comparison, acesulfame K, cyclamate and saccharin reach their maximum sweetness at 11.6 SE%, 11.3 SE% and 9 SE%, respectively.[2]
Neotame is a high-potency sweetener, and it is 7,000 to 13,000 times sweeter than table sugar.[3] Neotame contains flavor-enhancing properties, and compared to sucrose or aspartame, it has a relatively lower cost per sweetness factor.[8]
Chemistry
[edit]Structure
[edit]Neotame is formally a secondary amine of 3,3-dimethylbutanal and aspartame. The latter is a dipeptide of phenylalanine and aspartic acid. Neotame has 2 stereocenters and 4 stereoisomers. Sweetness is due to the (2S),(3S)-stereoisomer.[9]
Spectroscopy
[edit]Neotame NMR spectroscopy identifies its structure with a peak at 0.84 ppm indicating the three methyl groups on the carbon chain bonded to the nitrogen.[10]
Synthesis
[edit]Neotame is synthesized from aspartame through a reductive alkylation with 3,3-dimethylbutyraldehyde in a palladium catalyst with methanol.[11] The stereochemistry of aspartame is conserved during the synthesis and therefore, neotame and aspartame have the same stereochemistry. (2S),(3S)-stereoisomer of aspartame is needed to synthesize the (2S),(3S)-stereoisomer of neotame.[11]
Properties and reactivity
[edit]
Neotame has similar stability as aspartame, but has greater stability especially in heated and dairy foods.[3] Increased temperature, moisture or pH increase losses, and are the main relevant properties of a food when considering the stability of neotame. For example, about 90% of original neotame remains after 8 weeks of storage in pH 3.2 beverages. Neotame is especially stable as a dry powder at room temperature and humidity even if mixed with glucose or maltodextrin, and is relatively inert in foods with reducing sugars like fructose.[2]
Unlike aspartame, neotame doesn't form diketopiperazines via intra-molecular cyclization due to its N-alkyl substitution with 3,3-dimethylbutyl. This increases its heat stability.[3]
Over 1000 g of neotame dissolves in 1 kg of ethanol at 15 °C. At 15 °C the solubility of neotame is 10.6 g/kg in water and 43.6 g/kg in ethyl acetate. At 25 °C the solubilities are 12.6 g/kg and 77.0 g/kg, respectively. At 40 °C the solubilities are 18.0 g/kg and 238 g/kg, respectively. At 50 °C the solubilities are 25.2 g/kg and 872 g/kg, respectively.[2] Neotame is acidic and its 0.5 wt% solution has a pH of 5.80.[1]
Manufacture
[edit]Industrially neotame is made from 3,3-dimethylbutanal and aspartame via reductive amination.[2] They are dissolved in methanol, palladium on carbon catalyst is added, air is replaced with hydrogen and the reaction is carried out in room temperature under pressure for a few hours. Catalyst is filtered out. This can be aided with diatomaceous earth. Methanol is distilled followed by addition of water. The mixture is cooled for a few hours, neotame is isolated via centrifugation, washed with water and vacuum dried. Neotame is milled to suitable size.[1]
Metabolism
[edit]
In humans and many other animals like dogs, rats and rabbits, neotame is rapidly but incompletely absorbed. Its metabolites are not retained or concentrated in specific tissues.[1]
In humans at oral doses of about 0.25 mg per kg of bodyweight (mg/kg bw), about 34% is absorbed into blood. Pharmacokinetics of oral doses of 0.1–0.5 mg/kg bw are somewhat linear, and at such doses, maximum neotame concentration in blood plasma is reached after about 0.5 hours with a half-life of about 0.75 hours. In blood and in body in general, non-specific esterases degrade neotame to de-esterified neotame and methanol, which is the main metabolic pathway in humans. De-esterified neotame has a plasma half-life of about 2 hours, and is the main metabolite in plasma.[1]
In humans, over 80% of the original oral dose is excreted in feces and urine within 48 hours and the rest later. About 64% of the original dose is excreted in feces mostly as metabolites. Major metabolite in feces is the de-esterified neotame. Over 1% of the original dose is excreted in feces as N-(3,3-dimethylbutyl)-L-aspartyl - L - phenylalanine. Over 1% is excreted in urine as carnitine conjugate of 3,3-dimethylbutyric acid. Other minor metabolites form.[1]
The major metabolic pathway leads to N-(3,3-dimethylbutyl)-L-aspartyl - L - phenylalanine with a side product of methanol, and the minor pathway happens when the N-(3,3-dimethylbutyl)-L-aspartyl - L - phenylalanine is oxidized into 3,3-dimethylbutyric acid. The side products for the minor pathway is methanol, aspartic acid and phenylalanine.[12]
Methanol from neotame metabolism is insignificant at regulated levels used in foods and in comparison to methanol naturally found in foods.[1]
Patent
[edit]The patent covering the neotame molecule in the US, 5,480,668,[6] was originally set to expire 7 November 2012, but was extended for 973 days by the U.S. Patent and Trademark Office. The patent expired on 8 July 2015.[13]
References
[edit]- ^ a b c d e f g h i j k "Neotame as a sweetener and flavour enhancer - Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in Contact with Food". EFSA Journal. 5 (11): 581. 2007. doi:10.2903/j.efsa.2007.581. ISSN 1831-4732.
- ^ a b c d e f g h i j Nabors LO (2011). Alternative sweeteners (4th ed.). CRC Press. pp. 133–150. ISBN 978-1439846155. OCLC 760056415.
- ^ a b c d e f g "Aspartame and Other Sweeteners in Food". US Food and Drug Administration. 14 July 2023. Archived from the original on June 1, 2023. Retrieved 30 June 2024.
- ^ Halliday, Jess (8 January 2010). "Neotame wins approval in Europe". foodnavigator.com. Retrieved 2019-09-15.
- ^ a b "Food additives permitted for direct addition to food for human consumption; neotame" (PDF). Federal Register. 67 (131): 45300–45310. 2002.
- ^ a b "US 5,480,668". Archived from the original on 2017-05-10. Retrieved 2019-09-15.
- ^ "Chemical Cuisine | Center for Science in the Public Interest". cspinet.org. 25 February 2016. Retrieved 2019-09-15.
- ^ Nofre, C; Tinti, Jean-Marie (15 May 2000). "Neotame: discovery, properties, utility". Food Chemistry. 69 (3): 245–257. doi:10.1016/S0308-8146(99)00254-X. Retrieved 12 November 2021.
- ^ Bathinapatla A, et al. (2014). "Determination of Neotame by High-Performance Capillary Electrophoresis Using β-cyclodextrin as a Chiral Selector". Analytical Letters. 47 (17): 2795–2812. doi:10.1080/00032719.2014.924008. ISSN 0003-2719. S2CID 93160173.
- ^ a b Garbow, Joel R.; Likos, John J.; Schroeder, Stephen A. (1 April 2001). "Structure, dynamics, and stability of β-cyclodextrin inclusion complexes of aspartame and neotame". Journal of Agricultural and Food Chemistry. 49 (4): 2053–2060. Bibcode:2001JAFC...49.2053G. doi:10.1021/jf001122d. PMID 11308366. Retrieved 12 November 2021.
- ^ a b Prakash, Indra; Bishay, Ihab; Schroeder, Steve (1 December 1999). "Neotame: Synthesis, Stereochemistry and Sweetness". Synthetic Communications. 29 (24): 4461-4467. doi:10.1080/00397919908086610. Retrieved 12 November 2021.
- ^ Nofre, C; Tinti, Jean-Marie (15 May 2000). "Neotame: discovery, properties, utility". Food Chemistry. 69 (3): 245–257. doi:10.1016/S0308-8146(99)00254-X. Retrieved 12 November 2021.
- ^ "USPTO extension of 5,480,668". Retrieved 2012-09-21.
External links
[edit]
Media related to Neotame at Wikimedia Commons
Neotame
View on Grokipediafrom Grokipedia
Neotame is a non-nutritive artificial sweetener, chemically derived from aspartame, that is approximately 7,000 to 13,000 times sweeter than sucrose and approved by the U.S. Food and Drug Administration (FDA) in 2002 for use as a general-purpose sweetener and flavor enhancer in a wide variety of foods, excluding meat and poultry.[1]
Developed in the 1990s by the NutraSweet Company through collaboration with French chemists Claude Nofre and Jean-Marie Tinti, neotame was designed to address limitations of aspartame, such as instability in heat, by incorporating an additional 3,3-dimethylbutyl group on its aspartyl residue, resulting in a dipeptide structure (N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester) that enhances its potency and thermal stability.[2][3]
Sold under the brand name Newtame®, it is about 30 to 40 times sweeter than aspartame itself and is metabolized differently in the body, producing minimal phenylalanine, which makes it safe for individuals with phenylketonuria (PKU).[4][1]
Neotame's high intensity allows for use in very small quantities in products such as soft drinks, baked goods, dairy items, frozen desserts, chewing gum, and sauces, where it provides sweetness without contributing calories and can mask off-flavors when blended with other sweeteners like sugar or acesulfame potassium.[4][2]
Its heat stability enables applications in cooking and baking, unlike aspartame, and it has been approved in the European Union since 2010 following safety evaluations by the European Food Safety Authority (EFSA).[4][5]
Safety assessments, including over 110 studies reviewed by the FDA, have established neotame as safe for the general population, including children, pregnant women, and those with diabetes, with an acceptable daily intake (ADI) of 0.3 mg/kg body weight per day; the FDA's review found no adverse effects. In 2025, EFSA re-evaluated neotame, reaffirming its safety and increasing the ADI to 10 mg/kg body weight per day for use in the EU. It received a "safe" rating from the Center for Science in the Public Interest (CSPI) due to its low metabolic impact and lack of adverse effects in toxicological tests.[1][4][6]
Despite its approvals, neotame remains less commonly used than other sweeteners. A 2024 study suggested potential adverse effects on the gut epithelium and microbiome, raising questions about long-term gastrointestinal impacts. Additionally, recent studies have identified its presence in disposable e-cigarettes, raising questions about inhalation exposure.[7][8][2]
Neotame exhibits limited solubility in water, approximately 12.6 g/L at 25 °C, though this increases to about 47.5 g/L at 60 °C; solubility is pH-dependent, remaining moderate under neutral conditions.[6] It is highly soluble in ethanol, exceeding 1000 g/L at 15–25 °C, and soluble in ethyl acetate (around 77 g/L at 25 °C), but insoluble in most oils due to its polar nature.[11][6]
Neotame demonstrates good thermal stability in dry form, resisting degradation up to 120 °C, which supports its use in baking applications.[15] In aqueous solutions, it remains stable across pH 3–7, with optimal stability near pH 4.5, where half-life exceeds 30 weeks at 25 °C; hydrolysis occurs slowly in strong acids or bases, proceeding more gradually than in aspartame.[11] Under typical beverage storage (pH 3.2, 20 °C), only about 7–10% degrades after 8 weeks.[6]
The compound is non-hygroscopic, facilitating easy handling and storage.[11] It shows minimal reactivity in Maillard reactions with reducing sugars at pH ≤ 6 and during thermal processing, producing negligible degradation products.[6] Neotame is generally compatible with food ingredients but may react with strong oxidants.[15]
Neotame possesses pKa values of approximately 3.0 for the carboxylic acid group and 8.0 for the amine group, reflecting its amphoteric character.[30]
The ¹H NMR spectrum of neotame, typically recorded in deuterated solvents like DMSO-d₆ or CD₃OD, reveals key proton environments aligned with its chemical structure. Notable signals include a singlet at δ 0.9 ppm (9H, t-butyl group), a multiplet at δ 1.3 ppm (2H, CH₂ in the side chain), a multiplet at δ 2.8–3.0 ppm (aspartyl CH₂), a singlet at δ 3.7 ppm (3H, OCH₃), and a multiplet at δ 7.2 ppm (5H, phenyl ring). These assignments confirm the presence of the N-(3,3-dimethylbutyl) substituent and the phenylalanine moiety.[31] ¹³C NMR Spectroscopy
In the ¹³C NMR spectrum, neotame exhibits carbonyl carbons from the amide and ester functionalities at approximately 170–175 ppm, reflecting their electron-withdrawing environments. The quaternary carbon of the dimethylbutyl side chain appears around 30 ppm, distinguishing it from other aliphatic carbons and aiding in polymorphism studies of solid forms.[32] Infrared (IR) Spectroscopy
Fourier-transform infrared (FTIR) spectroscopy of neotame highlights functional group vibrations, with characteristic peaks at 3300 cm⁻¹ (N-H stretch from the amide and amine), 1730 cm⁻¹ (C=O stretch of the ester), and 1650 cm⁻¹ (amide C=O stretch). These bands are used to verify the integrity of the peptide and ester linkages, with shifts observed in complexed forms for chelation studies.[33] Mass Spectrometry (MS)
Electrospray ionization mass spectrometry (ESI-MS) of neotame displays a prominent protonated molecular ion [M+H]⁺ at m/z 379, consistent with its formula C₂₀H₃₀N₂O₅. Fragmentation patterns include ions at m/z 319 (loss of methanol), m/z 172 (phenylalanine-related), and others confirming the peptide bond and side chain, enabling sensitive detection in complex matrices.[25] UV-Vis Spectroscopy
Neotame exhibits weak UV absorption at 257 nm, attributed to the π-π* transition of the phenylalanine chromophore. This wavelength is commonly employed in HPLC-UV detection methods for quantification, offering specificity in food analysis without interference from the aliphatic side chain.[28] These spectroscopic properties are routinely applied in quality control during neotame synthesis to monitor reaction completion and purity, as well as in analytical protocols for detecting trace levels in food products via techniques like HPLC-MS or FTIR.[34]
Introduction
Overview
Neotame is a non-caloric artificial sweetener derived from aspartame, chemically known as N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester.[9] It provides intense sweetness without contributing calories, making it suitable for low- and no-calorie food and beverage formulations.[1] By mass, neotame is 7,000 to 13,000 times sweeter than sucrose, allowing for minimal usage levels in products.[1] This high potency contributes to its cost-effectiveness compared to other sweeteners, as smaller quantities achieve equivalent sweetness.[10] Neotame offers key advantages including improved heat stability compared to aspartame (stable during processing at around 88°C), conditions across pH 3–7, and in dairy products, enabling its use in baked goods, beverages, and processed foods without significant degradation.[11] Additionally, it possesses flavor-enhancing properties that improve the taste profile of certain foods, such as extending mint flavors.[11] The U.S. Food and Drug Administration approved neotame in 2002 as a general-purpose sweetener for use in a wide range of foods.[1] In the European Union, it received approval as E 961 in 2010.[4] As of 2025, neotame is approved in more than 60 countries worldwide, reflecting its broad regulatory acceptance.[12] A 2024 study suggested potential damage to gut cells at concentrations near the acceptable daily intake, though overall safety assessments by regulatory bodies remain positive.[2]History and development
Neotame was invented in the early 1990s by French chemists Claude Nofre and Jean-Marie Tinti at Claude Bernard University in Lyon, as part of their research into high-potency sweeteners derived from aspartame structures.[13][14] This compound emerged from systematic modifications to aspartame, aiming for enhanced stability while maintaining intense sweetness, and was detailed in their seminal 2000 publication on its properties and utility.[13] The rights to neotame were licensed to NutraSweet, a subsidiary of Monsanto Company, which drove its commercial development throughout the 1990s.[15] Initial patent filings for the compound by Nofre and Tinti occurred in the early 1990s, with U.S. Patent No. 5,480,668 granted in 1996, covering its use as a sweetening agent.[16] During this period, NutraSweet conducted key preclinical research phases, including evaluations of neotame's sweetness potency and stability in various food matrices, to support regulatory submissions.[17] NutraSweet submitted a food additive petition to the U.S. Food and Drug Administration (FDA) in late 1997, with formal review commencing in 1998, leading to approval on July 23, 2002, following an extensive evaluation of over 110 studies.[15][1] In parallel, international assessments advanced: the Joint FAO/WHO Expert Committee on Food Additives (JECFA) evaluated neotame in 2003–2004, establishing its safety profile, while the European Food Safety Authority (EFSA) issued a positive scientific opinion in 2007, culminating in EU authorization as a sweetener and flavor enhancer on January 19, 2010.[18][5][19] In July 2025, EFSA re-evaluated neotame and established a higher acceptable daily intake of 10 mg/kg body weight per day.[9] Post-approval expansions included China's Ministry of Health granting permission for use in foods and beverages on March 10, 2003,[20] and Japan's Ministry of Health, Labour and Welfare approving it in 2010,[21] with additional authorizations in over 30 countries, such as Australia, Mexico, and Russia, by 2015.[22] More recently, by 2023–2025, neotame has been identified in unauthorized e-cigarette formulations, particularly flavored disposable vapes targeted at youth, prompting increased regulatory scrutiny from bodies like the FDA over its unapproved presence in tobacco products.[23][24]Chemistry
Structure and nomenclature
Neotame is an artificial sweetener with the molecular formula .[25] It is a dipeptide composed of L-aspartic acid and L-phenylalanine methyl ester connected via a peptide bond, featuring a 3,3-dimethylbutyl group attached to the amino terminus of the aspartic acid residue through reductive amination.[26] The systematic IUPAC name for neotame is -(N-(3,3-dimethylbutyl)-L-α-aspartyl)-L-phenylalanine 1-methyl ester, also expressed more formally as (3S)-3-(3,3-dimethylbutylamino)-4-[[(2S)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino]-4-oxobutanoic acid.[25][15] The core structure of neotame can be textually represented as -(3,3-dimethylbutyl)-Asp-Phe-OMe, where Asp denotes the L-aspartyl residue with its side-chain carboxylic acid, Phe-OMe is the L-phenylalanyl methyl ester, and the 3,3-dimethylbutyl () moiety provides a hydrophobic extension at the N-terminus.[25] This modification distinguishes neotame from its parent compound, aspartame (Asp-Phe-OMe), by introducing the bulky, nonpolar 3,3-dimethylbutyl group, which sterically hinders peptidases and stabilizes the peptide linkage against enzymatic hydrolysis, thereby preventing the release of free phenylalanine.[26][15] Neotame retains the (S) configuration—equivalent to the L-form—at both chiral centers (the α-carbons of aspartic acid and phenylalanine), a stereochemical feature conserved from aspartame and critical for eliciting the sweet taste response.[25][27] This specific L,L-stereochemistry ensures high sweetness potency, as alterations to the configuration diminish or eliminate the sweet sensation.[27]Synthesis
Neotame is primarily synthesized through the reductive alkylation of aspartame with 3,3-dimethylbutanal, employing sodium cyanoborohydride as the reducing agent.[16] This one-step process involves dissolving aspartame and the aldehyde in a solvent such as methanol or aqueous methanol, followed by selective reduction of the intermediate imine under mild conditions to yield neotame with high efficiency.[16] The reaction scheme can be represented as: Typical conditions include a pH range of 6-8, maintained with a buffer like acetic acid, and room temperature (approximately 20-25°C), which favor the formation of the desired product while minimizing side reactions; yields often exceed 90% based on optimized protocols.[16] The process proceeds via initial imine formation between the N-terminal amino group of aspartame and the aldehyde, followed by hydride reduction to install the 3,3-dimethylbutyl substituent without affecting the ester or carboxylic acid functionalities.[16] Alternative synthetic routes include protecting the amino group of aspartame, such as with a benzyloxycarbonyl (Z) group to form Z-aspartame, followed by alkylation with 3,3-dimethylbutanal under reductive conditions (e.g., catalytic hydrogenation with Pd/C), and subsequent deprotection via hydrogenolysis.[28] This protected approach, conducted in methanol or methanol-methyl isobutyl ketone mixtures at 25-65°C and atmospheric pressure, achieves yields up to 95% and is particularly suited for industrial production due to its compatibility with enzymatic preparation of the protected precursor.[28] Enzymatic variants utilize engineered C-N lyases, such as an EDDS lyase mutant, to perform asymmetric hydroamination on fumarate derivatives, yielding stereoselective N-substituted L-aspartic acid precursors for neotame with >99% enantiomeric excess and no racemization.[29] Key challenges in these syntheses involve preventing racemization at the chiral α-carbon centers of the aspartyl and phenylalanyl residues, which can occur under acidic or basic conditions during imine formation or reduction; mild pH control and low temperatures mitigate this risk.[16] Purification typically employs chromatography on silica gel for small-scale laboratory preparations or crystallization from ethanol-water or aqueous methanol for larger batches, ensuring high purity (>98%) by removing dialkylated byproducts and unreacted starting materials.[16][28] For industrial scalability, processes transition from batch reductive alkylations to continuous flow hydrogenation systems using fixed-bed Pd/C catalysts, enabling higher throughput, reduced solvent use, and consistent yields while leveraging aspartame as the key precursor from established dipeptide manufacturing.[28]Physical and chemical properties
Neotame appears as a white to off-white crystalline powder.[6] Its molecular formula is C20H30N2O5, with a molecular weight of 378.47 g/mol.[25] The compound has a melting point range of 81–84 °C.[6]| Property | Value |
|---|---|
| Appearance | White to off-white crystalline powder |
| Molecular weight | 378.47 g/mol |
| Melting point | 81–84 °C |
Spectroscopic properties
Neotame's molecular structure and purity are characterized through a range of spectroscopic techniques, providing essential data for structural confirmation, impurity detection, and regulatory compliance in its production and application as a sweetener. These methods leverage the compound's functional groups, including the dipeptide backbone, ester, amide, and hydrophobic side chain, to generate distinct spectral signatures. ¹H NMR SpectroscopyThe ¹H NMR spectrum of neotame, typically recorded in deuterated solvents like DMSO-d₆ or CD₃OD, reveals key proton environments aligned with its chemical structure. Notable signals include a singlet at δ 0.9 ppm (9H, t-butyl group), a multiplet at δ 1.3 ppm (2H, CH₂ in the side chain), a multiplet at δ 2.8–3.0 ppm (aspartyl CH₂), a singlet at δ 3.7 ppm (3H, OCH₃), and a multiplet at δ 7.2 ppm (5H, phenyl ring). These assignments confirm the presence of the N-(3,3-dimethylbutyl) substituent and the phenylalanine moiety.[31] ¹³C NMR Spectroscopy
In the ¹³C NMR spectrum, neotame exhibits carbonyl carbons from the amide and ester functionalities at approximately 170–175 ppm, reflecting their electron-withdrawing environments. The quaternary carbon of the dimethylbutyl side chain appears around 30 ppm, distinguishing it from other aliphatic carbons and aiding in polymorphism studies of solid forms.[32] Infrared (IR) Spectroscopy
Fourier-transform infrared (FTIR) spectroscopy of neotame highlights functional group vibrations, with characteristic peaks at 3300 cm⁻¹ (N-H stretch from the amide and amine), 1730 cm⁻¹ (C=O stretch of the ester), and 1650 cm⁻¹ (amide C=O stretch). These bands are used to verify the integrity of the peptide and ester linkages, with shifts observed in complexed forms for chelation studies.[33] Mass Spectrometry (MS)
Electrospray ionization mass spectrometry (ESI-MS) of neotame displays a prominent protonated molecular ion [M+H]⁺ at m/z 379, consistent with its formula C₂₀H₃₀N₂O₅. Fragmentation patterns include ions at m/z 319 (loss of methanol), m/z 172 (phenylalanine-related), and others confirming the peptide bond and side chain, enabling sensitive detection in complex matrices.[25] UV-Vis Spectroscopy
Neotame exhibits weak UV absorption at 257 nm, attributed to the π-π* transition of the phenylalanine chromophore. This wavelength is commonly employed in HPLC-UV detection methods for quantification, offering specificity in food analysis without interference from the aliphatic side chain.[28] These spectroscopic properties are routinely applied in quality control during neotame synthesis to monitor reaction completion and purity, as well as in analytical protocols for detecting trace levels in food products via techniques like HPLC-MS or FTIR.[34]