Br2 and Electorphilic Br+ reagents

Mechanism + Description

Br2 and Br+ equivalents are electrophilic reagents normally used to add to unsaturated C-C bonds, take part in electrophilic substitution reactions with aromatics/heteroaromatics, or react with acidic C-H bonds. The attacking species is often written as Br2 or Br+, but maybe more complex than these simple species. Br2 and aqueous chlorine can produce HOBr, Br2O, BrCl and BrOCl.

General comments

Environ. Sci. Technol., 2013, 47, 1330−1338 - Reactivity of BrCl, Br2, BrOCl, Br2O, and HOBr Toward Dimethenamid in Solutions of Bromide + Aqueous Free Chlorine

Br2 is a moderate electrophile, and will react with unsaturated bonds and some (hetero)aromatics, carbanions and enols. It is often activated by strong acids, Lewis acids and oxidants. Oxidants can boost the electrophilic power of the reagent and can also generate Br2 / Br+ in situ from simple bromide salts or HBr. Oxidants can also reoxidise any Br- produced and maximise the use of bromide.

(Re)-Oxidants used in bromination
H2O2 or urea H2O2 complex
O2
CAN
Selectfluor
Chloramine-T
m-CPBA
Oxone® (KHSO5 0.5KHSO4 0.5K2SO4)
NaIO4
H5IO6
KClO3
PhI(OAc)2
Acids used to promote bromination
HOAc
HNO3
Oleum
H2SO4
NH4OAc

Bromination using Br2 or Br2 generated in situ  is normally the most atom efficient and sustainable bromination chemistry. Other common reagents can be classified as below :

  1. N-Br compounds
    NBS, DBDMH, TBCA – these can act as either sources of electrophilic bromine or radical bromine.
  2. Br2 complexes – typically Br3 - salts with amine cations. If used as a stoichiometric source of Br+, these salts are quite wasteful in bromine. A combination of NBS and n-Bu4NBr shows similar reactivity to n-Bu4NBr3
  3. High-valent bromine compounds (such as bromates).

Key references

Org. Lett., 2012, 14, 1858–1861 - Organocatalysis as a Safe Practical Method for the Stereospecific Dibromination of Unsaturated Compounds

Tetrahedron Lett. 2012, 53, 191 - Oxidative bromination of ketones using ammonium bromide and oxone

Synlett., 2008, 8, 1267-1268 KX/H2O2 – An Efficient and Non-Polluting Halogenating Reagent

Tetrahedron, 2009, 65, 4429-4439 - Environmentally benign electrophilic and radical bromination ‘on water’: H2O2–HBr system versus N-bromosuccinimide

Green Chem., 2007, 9, 1212-1218 - Bromination of ketones with H2O2-HBr in water

Tetrahedron Lett., 2014, 55, 5855–5858 - A green bromination process for synthesis of a novel drug candidate (KBr/ NaOCl/NaBrO3)

Current Green Chem., 2014, 1(2), 94-107 - Tribromoisocyanuric Acid: A Green and Versatile Reagent

Org. Process Res. Dev., 1998, 2,  261–269 Catalytic Processes of Oxidation by Hydrogen Peroxide in the Presence of Br2 or HBr. Mechanism and Synthetic Applications

Tetrahedron Lett., 1993, 34, 931 - N-Bromosuccinimide/Dibromodimethylhydantoin in aqueous base: A practical method for the bromination of activated benzoic acids

Tetrahedron Lett., 2007, 48, 877–881 - Chemoselective mono halogenation of β-keto-sulfones using potassium halide and hydrogen peroxide; synthesis of halomethyl sulfones and dihalomethyl sulfones

Org. Process Res. Dev., 2000, 4, 270–274 - Vanadium-Catalysed Oxidative Bromination Using Dilute Mineral Acids and Hydrogen Peroxide:  An Option for Recycling Waste Acid Streams

Synthesis, 2007, 1471-1474 - A New Chemoselective Synthesis of Brombuterol (PhMe3NBr3)

Org. Process Res. Dev., 2003, 7, 74–81 –  A New Route for Manufacture of 3-Cyano-1-naphthalenecarboxylic Acid - Example of bromination with pyridinium bromide perbromide

J. Med. Chem., 2011, 54,  8616–8631 - Identification of Benzoxazin-3-one Derivatives as Novel, Potent, and Selective Nonsteroidal Mineralocorticoid Receptor Antagonists - Example of bromination with pyridinium bromide perbromide

Canadian Journal of Chemistry, 2013, 91 679-683 - Green halogenation of aromatic heterocycles using ammonium halide and hydrogen peroxide in acetic acid solvent

Synthesis, 2004, 2641-2644 - A Convenient Halogenation of α,β-Unsaturated Carbonyl Compounds with Oxone® and Hydrohalic Acid (HBr, HCl)

Ind. Eng. Chem. Res., 2011, 50, 12271–12275 - Environment-Friendly Bromination of Aromatic Heterocycles Using a Bromide–Bromate Couple in an Aqueous Medium

J. Org. Chem., 2003, 68, 3695–3698 - An Improved Preparation of 3,5-Bis(trifluoromethyl)acetophenone and Safety Considerations in the Preparation of 3,5-Bis(trifluoromethyl)phenyl Grignard Reagent - Aromatic bromination with DBDMH

Tetrahedron Lett., 2007, 48, 6401–6404 - A practical highly selective oxybromination of phenols with dioxygen

Chem. Commun., 2009, 6460-6462 - Regioselective copper-catalyzed chlorination and bromination of arenes with O2 as the oxidant

Adv. Synth & Catal., 2011, 353,  3187-3195 - In situ Acidic Carbon Dioxide/Ethanol System for Selective Oxybromination of Aromatic Ethers Catalyzed by Copper Chloride

Green Chem., 2010, 12, 2124-2126  - An efficient copper-catalysed aerobic oxybromination of arenes in water

Synthesis, 2006, 0221–0223 - A New RegioselectiveBromination of Activated Aromatic Rings TCBA

Tetrahedron, 2009, 65, 9513–9526 - Recent advances in the application of bromodimethylsulfonium bromide (BDMS) in organic synthesis

J. Org. Chem. 2015, 80, 3701-3707 - Bromination of Olefins with HBr and DMSO

Green Chem., 2015, 17, 3285-3289 -  Efficient bromination of olefins, alkynes, and ketones with dimethyl sulfoxide and hydrobromic acid

ChemSusChem., 2013, 6(8), 1337-1340 -  A Sustainable Process for Catalytic Oxidative Bromination with Molecular Oxygen

Current Green Chemistry, 2014, 1, 94-107 - Tribromoisocyanuric Acid: A Green and Versatile Reagent

J. Am. Chem. Soc., 2012, 134, 8298-8301 - High-Yielding, Versatile, and Practical [Rh(III)Cp*]-Catalyzedortho-Bromination and Iodination of Arenes

J. Am. Chem. Soc., 2012, 134, 14760-14761 - Ruthenium-Catalyzed Transformation of Aryl and Alkenyl Triflates to Halides

Adv. Synth & Catal., 2008, 350,  2052–2058 - Copper-CatalyzedOxybromination and Oxychlorination of Primary Aromatic Amines Using LiBr or LiCl and Molecular Oxygen

 

Green Review

  1. Atom efficiency (by-products Mwt)
    HBr, Na/KBr salts and Br2 with activators/(re)-oxidants are the most atom efficient and maximize the use of bromine. The use of other Br+ reagents are less atom efficient
  2. Safety Concerns
    Bromination reactions can be very exothermic especially when activators and oxidants are added. Radical brominations can suffer from delayed exothermic events. Care should be taken with solvent compatibility – (see solvents section). The operational hazards associated with electrophilic and radical bromination can be somewhat mitigated by using flow chemistry. High valent Bromine compounds and N-Br compounds can cause fire, and may be explosive in combination with other materials.

    Org. Process Res. Dev., 2009, 13,  698–705 -  Facile, Fast and Safe Process Development of Nitration and Bromination Reactions Using Continuous Flow Reactors

    Org. Process Res. Dev., 2013, 17, 145−151 - Application of Flow Photochemical Bromination in the Synthesis of a 5-Bromomethylpyrimidine Precursor of Rosuvastatin: Improvement of Productivity and Product Purity

    Chemical radical sources used for radical bromination are often radical polymerisation initiators. The hazardous Dibenzoylperoxide has largely been replaced by AIBN, although this initiator can leave toxic residues. VAZO-52 represents a good compromise.



    Environ Health Perspect., 1990 (Jul), 87, 309–335 - Toxicity and carcinogenicity of potassium bromate -a new renal carcinogen

  3. Toxicity and environmental/aquatic impact
    High concentrations of Br2 and Br+ reagents will be extremely toxic to aquatic organisms though are probably too reactive to be persistent in the environment. Longer term environmental effects will reflect organic materials associated with the reagent. Higher MW organic cations can be inhibitory or toxic to certain aquatic life forms, so caution needs to be exercised with aqueous waste streams. In addition, Polybrominated organics can be persistent and bioaccumulate.

    The quaternary salts mentioned are generally tetra n-butyl, given the alkyl substituent is not directly involved it may be assumed that this could alter. Care should be taken if substitution to lower order groups particularly the tetra-methyl (Me4N+) moiety given high reported toxicity. The cation is a neurotoxin akin to paraquat and banned in the EU since 2007, recent publication; Lin CC1, Yang CC, Ger J, Deng JF, Hung DZ ClinToxicol (Phila). 201048(3):213-7
  4. Cost, availability & sustainable feedstocks
    Most bromination reagents are available at scale with varying degrees of cost – the most economical being reagents based on Br2, HBr or simple salts like NaBr.
  5. Sustainable implications
    No real sustainability issues with bromine.

 

Relevant scale up example


Org. Process Res. Dev., 2003, 7, 692-695
Experimental
77 kg scale


Org. Process Res. Dev., 2004, 8, 624-627
Experimental
10 kg scale


Org. Process Res. Dev., 1998, 2, 71-77
Experimental
40 kg scale


Org. Process Res. Dev., 2000, 4, 30-33
Experimental
124 g scale


Org. Process Res. Dev., 2006, 10, 354-360
Experimental
20 g scale


Org. Process Res. Dev., 2007, 11, 378-388
Experimental
650 g scale


Org. Process Res. Dev., 2002, 6, 591-596
Experimental
200 g scale


Org. Lett., 2015, 17, 2886-2889
Experimental
1 kg scale


Org. Process Res. Dev., 2006, 10, 36-45
Experimental
4 kg scale


Org. Process Res. Dev., 2009, 13, 67–72
Experimental
5.4 kg scale


Org. Process Res. Dev., 2012, 16, 2025−2030
Experimental
150 kg scale


Org. Process Res. Dev., 2011, 15, 1185-1191
Experimental
1.2 kg scale


Org. Process Res. Dev., 2012, 16, 1897−1904
Experimental
6.5 kg scale


Org. Process Res. Dev., 2011, 15, 1018–1026
Experimental
43 kg scale


Org. Process Res. Dev., 2012, 16, 1069−1081
Experimental
8 kg scale


Org. Process Res. Dev., 2012, 16, 1818−1826
Experimental
29 kg scale

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