Science of Synthesis

Science of Synthesis is the authoritative and comprehensive reference work for the entire field of organic and organometallic synthesis.

Science of Synthesis presents the important synthetic methods for all classes of compounds and includes:

Methods critically evaluated by leading scientists

Background information and detailed experimental procedures

Schemes and tables which illustrate the reaction scope

Preface

As our understanding of the natural world increases, we begin to understand complex phenomena at molecular levels. This level of understanding allows for the design of molecular entities for functions ranging from material science to biology. Such design requires synthesis and, as the structures increase in complexity as a necessity for specificity, puts increasing demands on the level of sophistication of the synthetic methods. Such needs stimulate the improvement of existing methods and, more importantly, the development of new methods. As scientists confront the synthetic problems posed by the molecular targets, they require access to a source of reliable synthetic information. Thus, the need for a new, comprehensive, and critical treatment of synthetic chemistry has become apparent. To meet this challenge, an entirely new edition of the esteemed reference work Houben–Weyl Methods of Organic Chemistry will be published starting in the year 2000.

To reflect the new broader need and focus, this new edition has a new title, Science of Synthesis, Houben–Weyl Methods of Molecular Transformations. Science of Synthesis will benefit from more than 90 years of experience and will continue the tradition of excellence in publishing synthetic chemistry reference works. Science of Synthesis will be a balanced and critical reference work produced by the collaborative efforts of chemists, from both industry and academia, selected by the editorial board. All published results from journals, books, and patent literature from the early 1800s until the year of publication will be considered by our authors, who are among the leading experts in their field. The 48 volumes of Science of Synthesis will provide chemists with the most reliable methods to solve their synthesis problems. Science of Synthesis will be updated periodically and will become a prime source of information for chemists in the 21st century.

Science of Synthesis will be organized in a logical hierarchical system based on the target molecule to be synthesized. The critical coverage of methods will be supported by information intended to help the user choose the most suitable method for their application, thus providing a strong foundation from which to develop a successful synthetic route. Within each category of product, illuminating background information such as history, nomenclature, structure, stability, reactivity, properties, safety, and environmental aspects will be discussed along with a detailed selection of reliable methods. Each method and variation will be accompanied by reaction schemes, tables of examples, experimental procedures, and a background discussion of the scope and limitations of the reaction described.

The policy of the editorial board is to make Science of Synthesis the ultimate tool for the synthetic chemist in the 21st century.

We would like to thank all of our authors for submitting contributions of such outstanding quality, and, also for the dedication and commitment they have shown throughout the entire editorial process.

October 2000

The Editorial Board

D. Bellus (Basel, Switzerland)

E. N. Jacobsen (Cambridge, USA)

S. V. Ley (Cambridge, UK)

R. Noyori (Nagoya, Japan)

M. Regitz (Kaiserslautern, Germany)

P. J. Reider (New Jersey, USA)

E. Schaumann (Clausthal-Zellerfeld, Germany)

I. Shinkai (Tsukuba, Japan)

E. J. Thomas (Manchester, UK)

B. M. Trost (Stanford, USA)

Volume Editor’s Preface

Shortly after the publication of Science of Synthesis, Vol. 34 (Fluorine), this volume now adds the synthesis of chloroalkanes, bromoalkanes, and iodoalkanes and so completes the coverage of the haloorganics. This is an important class of intermediates, especially for nucleophilic displacement reactions and elimination reactions. Moreover, there are important applications of haloalkanes in organic materials such as PVC. In addition, halogen substitution is used quite often to achieve biological activity, as in some biocides, or to fine-tune the performance of a drug.

The chemistry presented in this volume is extensively reviewed in Houben–Weyl, Vols. 5/3 (1962) and 5/4 (1960). The authors of Vol. 35 have done an excellent job in extracting still-valuable information from the old sources and adding to it new developments, including improved methods or introduction of novel reagent systems. So today we have a flexible arsenal to secure haloalkane synthesis avoiding rearrangement, premature elimination, or other secondary reactions. Moreover, in most cases high stereoselectivity can be achieved. Authors and editor are glad to include all these methods in this volume.

Throughout the development of this volume it was a pleasure to cooperate with the publishing house in Stuttgart. I gratefully acknowledge the support from Dr. Joe Richmond in the early stages of the planning of the volume and in particular from Dr. M. Fiona Shortt de Hernandez and her team, especially Dr. Matthew Weston, Dr. Marcus White, Dr. Mark Smith, Dr. Karen Muirhead, and production assistant Michaela Frey, who were always ready to help and have done a great job in securing the quality of this volume.

Volume Editor

Ernst Schaumann

Clausthal-Zellerfeld, Germany, December 2006

Introduction

E. Schaumann

The focus of this volume is on single-bond formation between an sp³-hybridized carbon atom and a chlorine, bromine, or iodine substituent. The synthesis of each type of haloalkane is treated separately and is subdivided in each case by a general treatise of the synthesis of the haloalkane (including halocycloalkanes) in question, followed by additional sections on special types of haloalkanes for which special synthetic methods are available or where special care must be taken to secure the synthetic success. Finally, the synthesis of compounds is discussed where the introduction of the halogen in question occurs simultaneously with the generation of another heterofunctionality in a vicinal arrangement or with larger distance between the two functionalities (▶ Table 1).

▶ Table 1 Classes of Halo(cyclo)alkanes Covered in Volume 35

Product Subclass or Method | Structural Formula | Section
|  | Hal = Cl | Hal = Br | Hal = I
haloalkanes | missing link | 35.1.1 | 35.2.1 | 35.3.1
by substitution of hydrogen |  | 35.1.1.1 | 35.2.1.1 | 35.3.1.1
by substitution of metals |  | 35.1.1.2 | 35.2.1.2 | 35.3.1.2
by substitution of carbon functionalities |  | 35.1.1.3 | 35.2.1.3 | 35.3.1.3
by substitution of other halogens |  | 35.1.1.4 | 35.2.1.4 | 35.3.1.4
by substitution of oxygen functionalties |  | 35.1.1.5 | 35.2.1.5 | 35.3.1.5
by substitution of sulfur, selenium, or tellurium functionalities |  | 35.1.1.6 | 35.2.1.6 | 35.3.1.6
by substitution of nitrogen functionalities |  | 35.1.1.7 | 35.2.1.7 | 35.3.1.7
by addition to π-type C—C bonds |  | 35.1.1.8 | 35.2.1.8 | 35.3.1.8
from other halo compounds |  | 35.1.1.9 | 35.2.1.9 | 35.3.1.9
propargylic halides | missing link | 35.1.2 | 35.2.2 | 35.3.2
benzylic halides | missing link | 35.1.3 | 35.2.3 | 35.3.3
allylic halides | missing link | 35.1.4 | 35.2.4 | 35.3.4
1-halo-n-heteroatom-functionalized alkanes (n ≥2) | missing link | 35.1.5 | 35.2.5 | 35.3.5

The organization of Volume 35 as shown in ▶ Table 1 implies that reactions leading to bond formation between a halogen and an sp²- or sp-hybridized carbon atom are excluded; however, because of the hierarchy of functional groups within Science of Synthesis, carbon—halogen bond formation next to another functional group of higher priority is covered in other volumes. Thus, although arguably the most important aspects of organochloro, -bromo, or -iodo chemistry are discussed in this volume, many other types of functional groups with a carbon—halogen unit are not covered, but are dealt with elsewhere within Science of Synthesis. ▶ Table 2 gives an overview on where to find the various types of organohalogen compounds within published volumes of Science of Synthesis. In addition, syntheses of halohetarenes and (1-haloalkyl)hetarenes are covered in the volumes of Category 2 (Vols. 9–17), typically under the “Synthesis by Substituent Modification” headings. The following volumes of Science of Synthesis will also discuss synthesis of halogencontaining compounds: Vol. 29 [Acetals: Hal/X and O/O, S, Se, Te] will include n-halo-n-heteroatom-functionalized alkanes. Vol. 31a [Arene—X (X = Hal, O, S, Se, Te)] will include haloarenes. Various sections of Vol. 32 [X—Ene—X (X = F, Cl, Br, I, O, S, Se, Te, N, P)] will include haloallenes, halocumulenes, 1,2-dihaloalkenes, 1-halo-2-heteroatom-functionalized alkenes, haloalkenes, and (halooxy)alkenes. Finally, Vol. 38 [Peroxides, Inorganic Esters (RO—X, X = Hal, S, Se, Se, Te, N)] will include discussion of organic hypohalites, chlorites, chlorates, and perchlorates.

It should be noted that, irrespective of the rigid basic system, reactions in this volume may lead to product mixtures including compounds that would be a topic of another volume, and sometimes reactions of other volumes are discussed in the present volume for comparison. Thus, to get the full information, a substructure search in the Science of Synthesis database is advised.

▶ Table 2 Location of Halogen-Containing Structural Units within Published Volumes of Science of Synthesis

Name
Structural Unita
Vol.
Section

trihalomethyllithium compounds
Hal₃CLi
8a [Compounds of Group 1 (Li…Cs)]
8.1.24.2

cyanogen halides
HalCN
18 (Four Carbon-Heteroatom Bonds:
X—C≡X, X=C=X, X₂C=X, CX₄)
18.1.1

carbonic acid halides
missing link

18.3

thiocarbonyl dihalides
missing link

18.10.1.1,18.10.1.2

halothioformate esters
missing link

18.10.3,18.10.4

haloselenoformate and halotelluroformate esters
missing link

18.11

tetrahalomethanes
CHal₄

18.15.1

alkoxytrihalomethanes and trihalomethyl hypohalites
CHal4–n(OR¹)n,
CHal4–n(OHal)n

18.15.2

trihalomethanethiols and trihalomethyl sulfides
CHal4–n(SR¹)n

18.15.3

trihalomethaneselenols and trihalomethyl selenides
CHal4–n(SeR¹)n

18.15.4

trihalomethyl tellurides
CHal4–n(TeR¹)n

18.15.5

(trihalomethyl)amines
CHal4–n(NR¹₂)n

18.15.6

(trihalomethyl)phosphines
CHal4–n(PR¹₂)n

18.15.7

acyl halides
R¹C(=O)Hal
20a (Three Carbon—Heteroatom Bonds: Acid Halides; Carboxylic Acids and Acid Salts)
20.1

2-halo-2-heteroatom-functionalized alkanoic acids
missing link

20.2.6

2-heteroatom-functionalized alkanoic acids
missing link

20.2.8.1.1

3-heteroatom-functionalized alkanoic acids
missing link

20.2.13.1.1

2-halo-2-heteroatom-functionalized alkanoic acid esters
missing link
20b [Three Carbon—Heteroatom Bonds: Esters and Lactones; Peroxy Acids and R(CO)OX Compounds; R(CO)X, X = S, Se, Te]
20.5.9.1

2-heteroatom-functionalized alkanoic acid esters
missing link

20.5.11.1.1

3-halo-3-heteroatom-functionalized alkanoic acid esters
missing link

20.5.15.1.2

3-heteroatom-functionalized alkanoic acid esters
missing link

20.5.16.1.1

N-(α-haloalkyl)alkanamides
missing link
21 (Three Carbon—Heteroatom Bonds: Amides and Derivatives; Peptides; Lactams)
21.3.1

α-haloalkanamides
missing link

21.5.1.1

β-haloalkanamides
missing link

21.7.1.1

N-haloamides
missing link

21.13.8

halosulfonium ylides and halosulfoxonium ylides
missing link
22 (Three Carbon—Heteroatom Bonds: Thio-, Seleno-, and Tellurocarboxylic Acids and Derivatives; Imidic Acids and Derivatives; Ortho Acid Derivatives)
22.1.1.2

thioacyl halides
R¹C(=S)Hal

22.1.2

C-chloronitrones and n-chloro-n-nitrosoalkanes
R¹HalC=N(O)R²

22.4.2.1.1

imidoyl halides
R¹C(=NR²)Hal

22.4.3

N-haloamidines
R¹C(=NHal)NR²R³

22.4.9.1.4.1

halophosphaalkenes
missing link

22.5.1

haloarsaalkenes
missing link

22.6.1

trihalomethyl compounds
R¹CHal₃

22.7.1

α,α-dihalo ethers and α-halo acetals
missing link
missing link
22.7.2.1.1

thioortho ester halides
missing link
missing link
22.7.3.1.1

selenoortho ester halides
missing link
missing link
22.7.4.1

telluroortho ester halides
missing link

22.7.5.1

haloketenes
missing link
23 (Three Carbon—Heteroatom Bonds: Ketenes and Derivatives)
23.3

1,1-dihaloallenes
missing link
24 (Three Carbon—Heteroatom Bonds: Ketene Acetals and Yne-X Compounds)
24.1.1

1-halo-1-heteroatom-functionalized allenes
missing link

24.1.2–24.1.5

1,1-dihaloalkenes
missing link

24.2.1

1-halo-1-heteroatom-functionalized alkenes
missing link

24.2.2–24.2.5

dihaloacetylenes
missing link

24.3.1

1-halo-2-heteroatom-functionalized acetylenes
missing link

24.3.2

1-haloaalk-1-ynes
missing link

24.4.1

2,2-dihalo-substituted aldehydes
missing link
25 (Aldehydes)
25.3

2-halo-substituted aldehydes
missing link

25.4

3-halo-substituted aldehydes
missing link

25.9.4

2,2-dihalo-substituted ketones R¹
missing link
26 (Ketones)
26.5

2-halo-substituted ketones
missing link

26.6

3- (or higher) halo-substituted ketones
missing link

26.11.1

N-haloimines
missing link
27 (Heteroatom Analogues of Aldehydes and Ketones)
27.12

halogen-substituted benzo-1,4-quinones
missing link
28 (Quinones and Heteroatom Analogues)
28.1.2

dihalogen-substituted benzo-1,4-quinones
missing link

28.1.6.1

(1-haloalkyl)-substituted benzo-1,4-quinones
missing link

28.1.7.1

fluoro(cyclo)alkanes
missing link
34 (Fluorine)
34.1–34.10

chloro-, bromo-, iodo(cyclo)alkanes
missing link
35 (Chlorine, Bromine, and Iodine)
–b

a X = heterofunctionality; Hal = Cl, Br, or I.

b See ▶ Table 1.

The halogen elements (including the radioactive astatine) form group 17 (formerly VIIb) of the periodic table. Consequently, there is a gradual change in physical and, to some extent, in chemical properties on passing from one element to another.[1] The main common feature is that the atoms are only one electron short of the perfect electron configuration of a noble gas. This makes the halogens typical nonmetals with high electron affinities (▶ Table 3).[2–5] As usual, the biggest difference is in the step between the first two elements, i.e. here the transition from fluorine to chlorine. This justifies the separate treatment of fluoroalkane synthesis in Science of Synthesis, Vol. 34 (Fluorine). However, within the remaining three elements chlorine, bromine, and iodine there is a close resemblance (▶ Table 3).

Gradual changes are also seen for the covalent radii of the four common halogens (▶ Table 3). When compared with the value for carbon (77.2 pm)[4] the best-matched bondforming orbital interaction is obviously with fluorine. This is reflected in the high stability of the C—F bond, as shown by the carbon—halogen bond dissociation energies, whereas the other halogens form much weaker bonds with carbon (▶ Table 3).

▶ Table 3 Physical Properties of the Halogens[3–5]

Physical Feature | F | Cl | Br | I | Ref
Electron Affinity for Hal₂ (eV) | 3.08 | 2.38 | 2.51 | 2.58 | [3]
Covalent Radius (pm) | 68.1 | 99.4 | 114.2 | 133.3 | [4]
H₃C—Hal Bond Dissociation Energy (kJ • mol⁻¹) | 452 | 351 | 293 | 234 | [5]

The electronegativity of an element correlates electron affinities, ionization energies, and bond energies. Even though the values differ depending on the method of calculation used, again the special role of fluorine is obvious, and all halogens are more electronegative than carbon (▶ Table 4). In the Sanderson scale of electronegativities, the polarizability of an element is emphasized.[4] Thus, fluorine must be considered as a “hard” atom, while iodine as a particularly “soft” atom marks the other extreme. This is also demonstrated in the polarizability values for fluoride (1.04 × 10⁻²⁴ mL), chloride (3.86 × 10⁻²⁴ mL), bromide (4.77 × 10⁻²⁴ mL), and iodide (7.1 × 10⁻²⁴ mL).[6] In addition, the contribution of d-orbitals in the heavy elements should be seen as polarization functions rather than as coordination sites for hypervalent interactions.[7]

▶ Table 4 Electronegativities of Fluorine, Chlorine, Bromine, Iodine, and, for Comparison, Carbon on Different Scales[2,4]

Method of Calculation | C | F | Cl | Br | I | Ref
Allred and Rochow | 2.50 | 4.10 | 2.83 | 2.74 | 2.21 | [2]
Pauling | 2.50 | 3.98 | 3.16 | 2.96 | 2.66 | [2]
Mulliken | 2.63 | 3.91 | 3.00 | 2.76 | 2.56 | [2]
Sanderson | 2.746 | 4.000 | 3.475 | 3.217 | 2.778 | [4]

Houben–Weyl, Vols. 5/3 and 5/4 provide a comprehensive review of the synthesis and of synthetic applications of chloro-, bromo-, and iodoalkanes, respectively, up to around 1960. Subsequently, haloalkane chemistry was reviewed in Comprehensive Organic Chemistry[8] and in the more specialized offsprings Comprehensive Organic Synthesis[9] and Comprehensive Organic Functional Group Transformations;[10] the latter series was updated in 2005.[11] In the The Chemistry of Functional Groups series an updated volume of The Chemistry of the Carbon—Halogen Bond is available, which includes a chapter on synthesis.[12] In addition, Rodd’s Chemistry of Carbon Compounds gives detailed information on many aspects of haloalkane chemistry.[13] Many of the methods that were reported in the Houben–Weyl volumes are still in use and are therefore covered in this volume, including experimental procedures. However, there has been a slow but constant development of improved or novel synthetic methods, which are also included here. Although Science of Synthesis does not claim to be comprehensive in the coverage of methods, the authors have carefully selected the important and reliable methods of haloalkane synthesis.

Quite often, haloalkanes are used as synthetic intermediates. This relies mainly on the high polarizability (▶ Table 4) making chloride, bromide, and iodide good nucleophiles as well as good leaving groups. This is also the reason why haloalkanes played an important role in the development of the mechanistic concepts of nucleophilic displacement reactions.[14] Based on the polarizability, the nucleophilicity increases in the series chlorine < bromine < iodine. The following is a more comprehensive series that shows the position of the halogens within a selection of the common nucleophiles, the order based on the reaction of the nucleophile with iodomethane:[15]

F⁻ < SO₄²⁻ < Cl⁻ < pyridine < NO₂⁻ < NH₃ < N₃⁻ < Br⁻ < OMe⁻ < CN⁻ < piperidine < I⁻ < SH⁻ < SPh⁻

It should be noted that the order of nucleophilicities of the halogens is inverse to that of the basicities. The latter may also be crucial under special conditions, e.g. if dimethylformamide is used as solvent in displacement reactions.[16] Another external influence on relative reactions rates of the halogens may be the catalyst. Thus, in the boron trifluoride catalyzed Friedel–Crafts alkylation of arenes by chloro-, bromo, or iodoalkyl fluorides, the C—F bond is cleaved to give an aryl(halo)alkane (▶ Scheme 1).[17] To account for this unusual selectivity, the high polarity of the C—F bond (cf. ▶ Table 3) as well as the high bond energy of the B—F bond to be formed by the interaction with the Lewis acid catalyst, together with an obviously small steric hindrance, are invoked to account for the high reactivity of the C—F bond.

▶ Scheme 1 Friedel–Crafts Alkylation Using Chloro-, Bromo-, or Iodoalkyl Fluorides[7]

There are ample technical uses of haloalkanes, with 15000 chlorinated compounds in commerce in the United States (1994).[18] In the high-polymer field, poly(tetrafluoroethylene) (PTFE, Teflon), polychloroprene, and poly(vinyl chloride) (PVC) are organic materials that are familiar to almost everybody. Polychloroprene has a chloroalkane structure if the compound polymerizes via the chlorine-free C=C bond. However, this is only a minor polymerization pathway (cf. Houben–Weyl, Vol. 14/1, p 736; ▶ Scheme 2). Poly(vinyl chloride) is within the scope of this volume (cf. ▶ Section 35.1.1.9).

▶ Scheme 2 Polymerization of Chloroprene[19]

Mixtures of chlorinated alkanes with a chlorine-content of 15–70% are used as flame-retarding agents.[20] Standard uses of halogenated compounds are as solvents for reactions, extractions, dry cleaning, or solvent dyeing.

Many drugs contain chlorine, though mostly bound to an sp²-hybridized carbon atom. It appears, however, that the biological activity is not related to the presence of the halogen substituent; the halogen rather seems to assist in resorption or to direct metabolism. Examples where the chlorine is on an sp³-hybridized carbon atom include the chiral anesthetics enflurane (1), isoflurane (2), and halothane (3), the bactericides chloramphenicol (4) and clindamycin (7-chlorolincomycin, 5), the anticonvulsive clomethiazole (6), and the analgesic chlorthenoxazine (7). Then, there is a group of chlorine-containing compounds with cytostatic activity that are derived from N-lost (8); in ▶ Scheme 3 the derivatives melphalan (9), cyclophosphamide (10), trofosfamide (11), ifosfamide (12), carmustine (13), lomustine (14), nimustine (15), and chlorambucile (16) are shown.[21] Pharmacological applications of organoiodine compounds are mainly in the area of X-ray contrast media, but it appears that here iodine is always bound to an aromatic ring system.

▶ Scheme 3 Haloalkanes with Pharmacological Activity[21]

In the field of pesticides, there are several examples of haloalkanes, again mainly chloro derivatives, such as the insecticide DDT (17), the insecti- and nematocide cloethocarb (18), and, from the family of biologically active thiophosphates, chlormephos (19) (▶ Scheme 4). Moreover, the insecticidal cycloaliphatics chlordane (20), aldrin (21), dieldrin (22), chlorodecone (Kepone, 23), and the hexachlorocyclohexanes [e.g., lindane (24)] should be mentioned. One of the few examples of a bromine-containing fungicide is bromuconazole (25).

▶ Scheme 4 Halogen-Containing Pesticides

Chloroalkanes[22] as well as most of the compounds in ▶ Scheme 4 have been widely criticized as being harmful for the environment as, due to their high lipophilicity, they are readily taken up by tissue in man and animals where they are only slowly metabolized with half-lives of weeks or months.[23,24] There is special concern about the possibility of causing liver cancer;[18,23] adverse effects on wildlife have been proven.[18,25] In response, there have been calls for a phase-out of chlorinated organics, culminating in chlorine’s labeling as “the devil’s element”.[26] There is an ongoing debate, where one side emphasizes the health risks, particularly of dioxins and polychlorinated biphenyls, and the opponents demand to differentiate between different classes of chloroorganic compounds and point out the advantages of chlorine and chloroorganics for hygiene, organic materials, and organic synthesis.[27] A crucial test of industrial production with “responsible care” can be seen in chlorine chemistry.

The scientific and public interest in the fate of chloralkanes in the environment has led to the development of sophisticated analytical methods that now allow high-quality trace analysis.[13,28]

Not only when working with chloroalkanes, but also with bromo- or iodoalkanes, special care should be taken to protect staff and the environment against any adverse effects. In principle, haloalkanes are alkylating agents and therefore possible carcinogens. This is particularly important with highly volatile haloalkanes. For the frequently used representatives, a vast body of biological tests and epidemiological studies have led to compound-specific risk assessment. On this basis, regulations have been issued which should be obeyed scrupulously. ▶ Table 5 shows the assessment of risks from the German perspective.[29]

▶ Table 5 Health Risks of Industrially Used Haloalkanes[29]

Haloalkane | Vapor Pressure (kPa) at 20°C | Maximum Workplace Concentration | Carcinogenic Effecta | Resorption or Sensitization Propertiesb | Ref
bromoethane | 50.7 | − | 2 | SR | [29]
bromomethane | − | 12 ppm | 3B | − | [29]
chlordane (20) | − | 0.5 mg•m⁻³ | 3B | SR | [29]
chlordecone (23) | − | − | 3B | − | [29]
1-chloro-2,3-epoxypropane (epichlorohydrin) | − | − | 2 | SR, SS | [29]
chloroethane | − | − | 3B | SR | [29]
2-chloroethanol | − | 1 ppm; 3.3 mg•m⁻³ | − | − | [29]
chloromethane | − | 50 ppm; 100 mg•m⁻³ | 3B | SR | [29]
chloroalkanes | − | − | 3B | − | [29]
3-chloroprop-1-ene | − | − | 3B | SR | [29]
benzyl chloride | − | − | 3B | − | [29]
bis(2-chloroethyl) ether | − | 10 ppm; 59 mg•m⁻³ | − | SR | [29]
bis(2-chloroethyl) sulfide | − | − | 1 | SR | [29]
1,2-dibromoethane | 1.5 | − | 2 | SR | [29]
1,4-dichlorobut-2-ene | − | − | 2 | − | [29]
1,2-dichloroethane | − | 100 ppm; 410 mg•m⁻³ | − | − | [29]
1,2-dichloropropane | 5.1 | − | 3B | − | [29]
1,3-dichloropropan-2-ol | − | − | 2 | SR | [29]
dieldrin (22) | − | 0.25 mg•m⁻³ | − | SR | [29]
1,2,3,4,5,6-hexachlorocyclohexane (diastereomeric mixture) | − | 0.5 mg•m⁻³ | − | SR | [29]
iodomethane | 43.8 | − | 2 | SR | [29]
1,2,3-trichloropropane | 0.45 | − | 2 | − | [29]
a Category 1: positive evidence based on epidemiological studies; category 2: positive experimental evidence from animal tests; category 3B: animal tests indicate a possible positive effect; more evidence is required.
b SR = skin resorption; SS = skin sensitization.

In the debate on environmental effects of chloroorganics, one issue has been the question of whether there are chlorine-containing natural products. Here, there has been a dramatic development. In 1973 it was stated that only “a few dozen really natural organic halogen compounds are known”.[28] However, in a 2006 count, some 4500 halogenated natural products were identified, many with promising medicinal properties, especially from marine origins, and with exciting structural features.[30] ▶ Scheme 5 displays a number of examples, including halomon,[31,32] prefuroplocamioid,[33] a-synderol,[34] aplysiaterpenoid A,[35] laurencin,[36]12-chloroillifunone C,[37] phoyoside II,[38] and chloroscoparin.[39] Most of the compounds are terpenes, but astin I[40] is an example of a cyclic peptide with the unusual amino acid 4-chloro-3-hydroxyproline[35] showing antitumor activity. 1-Chloro-3-methylbut-2-ene has been identified in the compound mix of a bat pheromone.[41] It now appears that nature often turns to halogenation to fine-tune a natural product’s biological properties. This has a parallel in that halogenation has always been and will continue to be a popular tool for tweaking a drug candidate’s biological properties in the pharmaceutical industry.

▶ Scheme 5 Examples of Natural Haloalkanes[31–41]

References

[1] Wagnière, G. H., In The Chemistry of the Carbon—Halogen Bond, Patai, S., Ed.; Wiley: Chichester, UK, (1973); p 1.

[2] Cotton, F. A.; Wilkinson, G., Anorganische Chemie, VCH: Weinheim, Germany, (1967).

[3] Chupka, W. A.; Berkowitz, J., J. Chem. Phys., (1971) 55, 2724.

[4] Sanderson, R. T., J. Am. Chem. Soc., (1983) 105, 2259.

[5] Benson, S. W., J. Chem. Educ., (1965) 42, 502.

[6] Hardt, H.-D., Die periodischen Eigenschaften der chemischen Elemente, 2nd ed., Thieme: Stuttgart, (1987); pp 165,166.

[7] Kutzelnigg, W., Angew. Chem., (1984) 96, 262; Angew. Chem. Int. Ed. Engl., (1984) 23, 272.

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Volume 35: Chlorine, Bromine, and Iodine

Preface

Volume Editor’s Preface

Table of Contents

Introduction

E. Schaumann

35.1 Product Class 1: One Saturated Carbon—Chlorine Bond

35.1.1 Product Subclass 1: Chloroalkanes

E. Schaumann

35.1.1.1 Synthesis by Substitution of Hydrogen

J. Hartung

35.1.1.2 Synthesis by Substitution of Metals

P. Margaretha

35.1.1.3 Synthesis by Substitution of Carbon Functionalities

P. Margaretha

35.1.1.4 Synthesis by Substitution of Other Halogens

P. Margaretha

35.1.1.5 Synthesis by Substitution of Oxygen Functionalities

P. Margaretha

35.1.1.6 Synthesis by Substitution of Sulfur, Selenium, or Tellurium Functionalities

P. Margaretha

35.1.1.7 Synthesis by Substitution of Nitrogen Functionalities

P. Margaretha

35.1.1.8 Synthesis by Addition to π-Type C—C Bonds

K.-M. Roy

35.1.1.9 Synthesis from Other Chlorine Compounds

H. Ulrich

35.1.2 Product Subclass 2: Propargylic Chlorides

P. Margaretha

35.1.3 Product Subclass 3: Benzylic Chlorides

35.1.3.1 Synthesis by Substitution of Hydrogen

W. D. Pfeiffer

35.1.3.2 Synthesis by Substitution of Carbonyl Oxygen

W. D. Pfeiffer

35.1.3.3 Synthesis by Substitution of σ-Bonded Heteroatoms

P. Margaretha

35.1.4 Product Subclass 4: Allylic Chlorides

35.1.4.1 Synthesis by Substitution of Hydrogen α to a C=C Bond

W. D. Pfeiffer

35.1.4.2 Synthesis by Substitution of σ-Bonded Heteroatoms

P. Margaretha

35.1.5 Product Subclass 5:1-Chloro-n-Heteroatom-Functionalized Alkanes (n ≥ 2) with Both Functions Formed Simultaneously

35.1.5.1 Synthesis by Addition across C=C Bonds

R. Göttlich

35.1.5.2 Synthesis by Addition across C—O Bonds

K. Rück-Braun and T. Freysoldt

35.1.5.3 Synthesis by Addition across C—S Bonds

K. Rück-Braun and T. Freysoldt

35.1.5.4 Synthesis by Addition across C—N Bonds

K. Rück-Braun and T. Freysoldt

35.1.5.5 Synthesis by Addition across C—C Bonds

K. Rück-Braun and T. Freysoldt

35.2 Product Class 2: One Saturated Carbon—Bromine Bond

35.2.1 Product Subclass 1: Bromoalkanes

E. Schaumann

35.2.1.1 Synthesis by Substitution of Hydrogen

J. Hartung

35.2.1.2 Synthesis by Substitution of Metals

P. Margaretha

35.2.1.3 Substitution of Carbon Functionalities

P. Margaretha

35.2.1.4 Synthesis by Substitution of Other Halogens

M. Braun

35.2.1.5 Synthesis by Substitution of Oxygen Functionalities

M. Braun

35.2.1.6 Synthesis by Substitution of Sulfur, Selenium, or Tellurium Functionalities

M. Braun

35.2.1.7 Synthesis by Substitution of Nitrogen Functionalities

M. Braun

35.2.1.8 Synthesis by Addition to π-Type C—C Bonds

K.-M. Roy

35.2.1.9 Synthesis from Other Bromo Compounds

H. Ulrich

35.2.2 Product Subclass 2: Propargylic Bromides

M. Braun

35.2.3 Product Subclass 3: Benzylic Bromides

35.2.3.1 Synthesis by Substitution of Hydrogen

W. D. Pfeiffer

35.2.3.2 Synthesis by Substitution of Carbonyl Oxygen

W. D. Pfeiffer

35.2.3.3 Synthesis by Substitution of σ-Bonded Heteroatoms

M. Braun

35.2.4 Product Subclass 4: Allylic Bromides

35.2.4.1 Synthesis by Substitution of Hydrogen a to a C=C Bond

W. D. Pfeiffer

35.2.4.2 Synthesis by Substitution of σ-Bonded Heteroatoms

M. Braun

35.2.5 Product Subclass 5:1-Bromo-n-Heteroatom-Functionalized Alkanes (n ≥ 2) with Both Functions Formed Simultaneously

35.2.5.1 Synthesis by Addition across C=C Bonds

T. Troll

35.2.5.2 Synthesis by Addition across C—O Bonds

K. Rück-Braun and T. Freysoldt

35.2.5.3 Synthesis by Addition across C—S Bonds

K. Rück-Braun and T. Freysoldt

35.2.5.4 Synthesis by Addition across C—N Bonds

K. Rück-Braun and T. Freysoldt

35.2.5.5 Synthesis by Addition across C—C Bonds

K. Rück-Braun and T. Freysoldt

35.3 Product Class 3: One Saturated Carbon—Iodine Bond

35.3.1 Product Subclass 1: Iodoalkanes

E. Schaumann

35.3.1.1 Synthesis by Substitution of Hydrogen

J. Hartung

35.3.1.2 Synthesis by Substitution of Metals

S. Härtinger and M. Härtinger

35.3.1.3 Synthesis by Substitution of Carbon Functionalities

S. Härtinger and M. Härtinger

35.3.1.4 Synthesis by Substitution of Other Halogens

S. Härtinger and M. Härtinger

35.3.1.5 Synthesis by Substitution of Oxygen Functionalities

S. Härtinger

35.3.1.6 Synthesis by Substitution of Sulfur, Selenium, or Tellurium Functionalities

S. Härtinger and M. Härtinger

35.3.1.7 Synthesis by Substitution of Nitrogen Functionalities

S. Härtinger and M. Härtinger

35.3.1.8 Synthesis by Addition to π-Type C—C Bonds

K.-M. Roy

35.3.1.9 Synthesis from Other Iodo Compounds

H. Ulrich

35.3.2. Product Subclass 2: Propargylic Iodides

S. Härtinger

35.3.3 Product Subclass 3: Benzylic Iodides

35.3.3.1 Synthesis by Substitution of Carbonyl Oxygen

W. D. Pfeiffer

35.3.3.2 Substitution of σ-Bonded Heteroatoms

S. Härtinger and M. Härtinger

35.3.4 Product Subclass 4: Allylic Iodides

S. Härtinger

35.3.5 Product Subclass 5:1-Iodo-n-Heteroatom-Functionalized Alkanes (n ≥ 2) with Both Functions Formed Simultaneously

35.3.5.1 Synthesis by Addition across C=C Bonds

T. Troll lil

35.3.5.2 Synthesis by Addition across C—O Bonds

K. Rück-Braun and T. Freysoldt

35.3.5.3 Synthesis by Addition across C—S Bonds

K. Rück-Braun and T. Freysoldt

35.3.5.4 Synthesis by Addition across C—N Bonds

K. Rück-Braun and T. Freysoldt

35.3.5.5 Synthesis by Addition across C—C Bonds

K. Rück-Braun and T. Freysoldt

Keyword Index

Author Index

Abbreviations

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