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DXM is Not Converted to DXO with Citric Acid or HCl
A Technical Correction to the DXM FAQ
by Noiyzmaker
v1.0, Aug 2003; v2.0, Mar 2005
edited & published by Erowid
Citation:   Noiyzmaker. "DXM is Not Converted to DXO with Citric Acid or HCl"., v1.0, Aug 2003; v2.0, Mar 2005:
  • Mar 2005: Update of Discussion and References.
  • Aug 2003: Document created.

    Preliminary Note
    This document was created mostly as a response to assertions found online that any excess of citric acid combined with DXM will produce DXO. It was also created in response to assertions that excess HCl with DXM will produce DXO. The two documents supporting the erroneous claim about citric acid can be found in various "Agent Lemon" preparation techniques.

    Citric acid alone will not convert DXM to DXO. Converting DXM (dextromethorphan) to DXO (dextrorphan), involves the cleavage of an aryl-alkyl ether to produce a phenol (and another product). A review done in 1954 on ether cleavage by Robert L. Burwell, Jr. (Burwell, p. 634) simply states that organic carboxylic acids "are, in general, ineffective. Anisole is not cleaved by formic acid or acetic acid or even by trichloroacetic acid."

    Ethers are generally unreactive, and phenyl-alkyl ethers (like DXM) are even less reactive. Wade says that "ethers are not commonly used as synthetic intermediates because they do not undergo many reactions" (Wade 1999, p. 624). Generally this is correct, though there are a variety of methods used to cleave ethers. Most of these methods involve reagents more exotic than HBr or HI, such as halosilane reagents, or sulfur and selenium anions. These methods will not be discussed here as they are not relevant to the claim about citric acid, nor would they be of much use to someone who is not willing to find the information on their own. For comprehensive reviews of ether cleavage in general see Burwell (1954) and Bhatt MV. & Kulkarni (1983). For a review of aryl-alkyl ether cleavage, see Tiecco (1988).

    "Ethers are cleaved by heating HBr or HI to give alkyl bromides or alkyl iodides." (Wade 1999, p. 624) To give an idea of the conditions required for aryl-alkyl ether cleavage, consider that anisole (methoxybenzene) was heated to 130 celcius with 47% aqueous HBr for two hours to give phenol (Bhatt and Kulkarni).

    "Phenyl ethers (one of the groups bonded to oxygen is a benzene ring) react with HBr or HI to give alkyl halides and phenols." (Wade 1999, p. 625) For clarification, in 1983 Bhatt and Kulkarnia stated that ether cleavage using concentrated hydrohalic acids do not cleave diarylethers and that "cleavage of alkyl aryl ethers always involves alkyl-oxygen fission."

    In the DXM FAQ version 4, in section 11.6.1, William White mentions using HCl to produce DXO, and the following reference is given: [ Newman AH, Bevan K, et al. Synthesis and Evaluation of 3-Substituted 17- Methylmorphinan Analogs as Potential Anticonvulsant Agents. J. Med. Chem.. 1992; 35: 4135-4142. ]

    The reference makes no mention of HCl to synthesize DXO from DXM. It states:
      "Synthesis of the target compounds 5-9 began with 2 [Dextrorphan], which was prepared by a standard O-demethylation of 1 [Dextromethorphan] (Sigma Chemical Co.) with 48% HBr, in quantitative yield." (Newman et al., 1992)
    So both citric acid, which is a relatively weak acid, and HCl which is a strong acid fail to cleave the ether to produce DXO from DXM. As Bhatt and Kulkarni reported in 1983, "hydrochloric acid cleaves only special types of ethers." Aryl-alkyl ethers are not among them.

    The immediate result of cleaving the phenyl ether in DXM with Hbr or HI to produce DXO may present a problem. The product of such a cleavage would be DXO and a methyl halide (either methyl bromide or methyl iodide). The conditions required for the ether cleavage are acidic. In the presence of methyl halides, tertiary amines may react to produce a quaternary ammonium ion. [see endnote about quaternary ammonium products]

    It is not likely that a quaternary ammonium ion would result in a strongly acidic solution. In strongly acidic conditions the tertiary amine would be protonated and thus lose its nucleophilicity due to the positive charge. It would therefore be unable to react with a methyl halide to produce a quaternary ammonium ion. Also, methyl bromide and methyl iodide, the two possible methyl halides, are not very soluble in water, so they may not remain in high enough concentrations to react to any material extent with DXM or DXO. Methyl bromide is listed as soluble to 1.5g/100 mL at 25C (the same as DXM HBr's solubility) and methyl iodide is listed as soluble to 2g/100 mL at 25C.

    Whether or not the exhaustive alkylation will occur is an open question, as far as I'm concerned. The data that is lacking to answer this question is both thermodynamic data and kinetic data.

    In a nutshell, the extent of exhaustive alkylation will depend on the pH of the solution and the rate at which it occurs, as well as thermodynamic factors. A very low pH will almost certainly not cause exhaustive alkylation to occur and should produce only DXO and methyl halide. Presumably, higher pH (but pH < 7) will produce less DXO and leave more unreacted DXM behind. At some pH essentially no reaction will occur, leaving only DXM and acid. The exhaustive alkylation of DXO (and unreacted DXM) threatens to be a problem at a pH low enough to allow the cleavage of DXM's phenyl ether to proceed but high enough (pH < 7, ether cleavage will not occur in base) so that the concentration of neutral amines is sufficient enough to allow for a significant reaction with the methyl halide product. One way to ensure that exhaustive alkylation will not occur is to make sure the pH is extremely low. (Note that the reference given in the DXM FAQ uses 48% HBr.)

    I would like to thank those with whom I corresponded for lending me their expertise in chemistry. Thanks!

    References #
    1. Bhatt MV, Kulkarni SU. "Cleavage of Ethers." Synthesis. 1983; 249.
    2. Burwell RL. "The Cleavage of Ethers." Chemical Reviews. 1954; 54(4):615-685.
    3. Delgado JN, Remers WA. (editors). Wilson and Gisvold's Textbooks of Organic Medicinal and Pharmaceutical Chemistry (Tenth Edition). Lippincott-Raven Publishers. New York, N.Y. 1998.
    4. Newman AH, Bevan K, et al. "Synthesis and Evaluation of 3-Substituted 17-Methylmorphinan Analogs as Potential Anticonvulsant Agents" J Med Chem. 1992; 35:4135-4142.
    5. Tiecco M. "Selective Dealkylations of Aryl Alkyl Ethers, Thioethers, and Selenoethers" Synthesis. 1988; 749.
    6. Wade LG Jr. Organic Chemistry (Fourth Edition). Prentice-Hall Inc., Upper Saddle River, N.J. 1999.
    Notes #
    1. Since, DXM and DXO are tertiary amines, the product of over-alkylation, would be the N,N-dimethyl derivatives of DXO (and possibly also of DXM, depending on the reaction kinetics of the ether cleavage and the amount of hydrohalic acid used). Both of these derivatives would be quaternary ammonium salts. Morphine relatives with a quaternary nitrogen are noted for having "strong curare action" [see below] with about 100 times less potency in terms of analgesic activity (Delgado and Remers 1998, p690). Presumably the "strong curare action" would be true for morphinans. I am not willing to speculate on potency.
    2. Curare : "Originally "curare" was a term used to describe collectively the very potent arrow poisons used since early times by the South American Indians." (Delgado and Remers 1998, p546)

      The characteristic action of "curare" is skeletal muscle relaxation. Drugs with curare-like effects are typically used to produce skeletal muscle relaxation for anesthesia.