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Reaction-Map of Organic Chemistry
The article on the Reaction-Map of Organic Chemistry was originally published in the Journal of Chemical Education (Murov, S. J. Chem. Ed ., 2007 , 84 (7), 1224). The supporting information including the Reaction-Map were published online only. This web site includes only the supporting information and is published with permission from J. Chem. Ed. 2007 , 84 (7), 1224. Copyright 2007 American Chemical Society. The following web sites are available to J. Chem. Ed. subscribers. http://pubs.acs.org/doi/pdf/10.1021/ed084p http://pubs.acs.org/doi/suppl/10.1021/ed084p1224/suppl_file/jce2007p1224w.pdf
The Reaction -Map of Organic Chemistry has been designed to give organic chemistry students an overview of most of the reactions needed for the organic chemistry course. The chart has been partially organized according to the periodic table on the horizontal axis and according to carbon oxidation level on the vertical axis. In addition the carboxyls are grouped vertically according to decreasing reactivity and carbon - carbon bond forming reactions are emphasized with bold arrows. The chart provides a study aide for students and should help students develop synthetic routes from one functional group to another. The chart should be especially useful for students studying for the final examination for the two semester organic chemistry course. In addition to the chart, three keys are available that organize the reactions according to mechanism, functional group preparations and functional group reactions. These keys are included on this site. Chemistry can be thought of a search for order in matter and this chart attempts to provide some insight into the order that exists in organic chemistry.
General Organization
Left to right, compounds in the shaded regions are arranged according to the periodic table. Organolithium and Grignard reagents are under lithium and magnesium but these reagents are used elsewhere on several bold arrows for the synthesis of C-C bonds. Carbon compounds that do not contain other elements are under carbon, carbon - nitrogen (and C, N, O) compounds are under nitrogen, carbon - oxygen compounds are under oxygen and carbon - halogen (and C, O, X) compounds are under fluorine and the halogens. From top to bottom, within groups, the compounds are arranged according to the oxidation level of the compound.
The oxidation level of organic compounds is somewhat of a complex concept. Even for propane, the carbons technically have different oxidation states. For the purposes of grouping compounds by oxidation level for this chart, the general guideline used has been that oxidation involves a decrease in the number of bonds to carbon from an atom less electronegative than carbon (most frequently hydrogen) and/or an increase in the number of bonds from carbon to atoms more electronegative than carbon (most frequently N, O, X). Reduction is the reverse. If two carbons change, then the sum of the changes must be considered. When water is added to a double bond, one carbon gains a hydrogen and the other an oxygen and the net oxidation level of the molecule does not change. The increase in oxidation level is indicated by the degree of darkness on the next page and in color in the online version.
This organization results in five groups including: 1. alkanes (and organometallics), 2. alkenes (and alkene addition products such as alcohols, ethers and halides), aromatics and amines, 3. alkynes (and alkyne addition products such as carbonyls), 4. carboxyls and 5. carbon dioxide and tetrahalomethane.
The two crosshatched areas to the left and right of the shaded region contain products of carbon - carbon bond forming reactions. These reactions are also emphasized by bold arrows.
For the purposes of organizing the numbering of the reactions for this key, the reactions have been grouped according to mechanism of the first step of the reaction. Many reactions fall into more than one group. The addition of hydrogen to π bonds is usually discussed in texts along with electrophilic additions to π bonds but here the hydrogen additions have been placed in the reduction category. Reductions with hydrides such as LiAlH 4 are often grouped with nucleophilic additions but here have also been included in the reduction category. The reactions are listed in the order substitution, addition, elimination, addition- elimination, oxidation, reduction, concerted and miscellaneous. To facilitate the finding of reactions from any of the keys that follow, a roadmap grid has been included. For example, the addition of HX to an alkene is represented by reaction 30 which is in grid position B.
A B C D E F G H I J K L M
A B C D E F G H I J K L M
25,41,44,69,70,
10
81
81
similar to butmore reactivethan RMgX
R-Q
100
RX
30
73
82
83
85
46
17
98
CH
=CH 2
2
18
22
31
32
23
: CH
2
99
20
87
47
19
21
48
ROH
ROR’
76
84
33
88
89
77
26
49
50
89
75
25
41
78
101
24
42
86
45
designed by Steve MurovModesto Junior Collegehttp://murov.info
90
27
51
80
102
43
74
91
96
68
52
92
94
97
69
60
93
95
37
58
79
39
38
54
55
57
65
70
71
40
13
59
14
56
62
66
72
106
15
53
63
103
29
28
61
67
CHX
3
16
104
107
12
64
105
Cl Cl
44
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
O||
RC
-^ OR’
RC
N
OH
OH
|^
|
CH
CH
2
O||
RC
-^ OH
O||
RC
-^ X
O||
RC
-^ NH
2
O|| 2 RCH(R’)
OH
O
|^
||
RCHCH
CR 2
O||
RCH=CHCR
O
O
||^
||
RCOCR
O
O
||^
||
RCCH
COR 2
CH
CH
O||
RCH(R’)
O|| RCCHR’R”
O|| RCCH
R’ 2
2
RC
CH
PhSO
H 3
PhNO
2
PhX
PhR
PhCOR
PhNH
2
R^2
C=CHR
(^12)
3
4
5
6
7
8
9
11
34,
36
RCH
NH 2
2
oxidation level(increases blueto red)
carboxylreactivityexcludingRCN
PhCH
X 2
PhCOOH
PhXPhOHPhI PhF PhH
RNH
2
2
CH
XCH 2
X 2
CH
CHX 3
2
R^2
CHOH or R
COH 3 RCOR’
RCOR’R^3
COH
PhN
+^ X 2
PhCN
PhH
PhN=NPhY
RCOOH
R-R’RCN
RC(OH)
R’ 2
OH| RCR
| OR RC(OR)
R’ 2
OH| RC(CN)R
RCH=NR
H 1
REACTION-MAP OF ORGANIC CHEMISTRY
He 2
Li 3
Be 4
B 5
C 6
N 7
O 8
F 9
10
Ne
11
Na
12
Mg
13
Al
14
Si
15
P
16
S
17
Cl
35
Br
53
126.90I
18
Ar
RLi
RMgX
CH
CH 3
3
H 2
(when R’ = CH
) 3
CO
2
(+ RH)
CX
4
R(CH
)^22 OH
Keys for
Reaction-Map of Organic Chemistry
Reaction-Map as a Study Aid At the end of a two semester course in organic chemistry, a student should be able to perform the exercises below. (Note: In addition to the exercises below, a student of organic chemistry should be able to demonstrate competency with spectroscopic, stereochemical and multistep synthetic challenges.) By performing the exercises below should result in the preparation of three keys for the Reaction-Map of Organic Chemistry.
- For each numbered reaction, classify the reaction by mechanism (e.g., substitution, nucleophilic) and list the reagents, conditions, regioselectivity, stereoselectivity and restrictions associated with the reaction.
- List all methods of preparing each functional group.
- List all reactions of each functional group.
- Write mechanisms for reactions: 3 (D2) , 10 (B13) , 19 (C13) , 32 (C11) , 33 (E14) , 39 (J3) +28 (K2) , 42 (G7) , 46 (B13) , 47 (C11) , 62 (K13) , 72 (J17) , 106 (K19).
The problems above should be attempted without reference to the keys but the keys can be used to help check for the correctness of answers for 1-3. The keys are available below and to subscribers of the Journal of Chemical Education at: http://pubs.acs.org/doi/suppl/10.1021/ed084p1224/suppl_file/jce2007p1224w.pdf For the answers to question #4, reference to an organic chemistry textbook may be required.
This organization results in five groups including: 1. alkanes (and organometallics), 2. alkenes (and alkene addition products such as alcohols, ethers and halides), aromatics and amines, 3. alkynes (and alkyne addition products such as carbonyls), 4. carboxyls and 5. carbon dioxide and tetrahalomethane.
For the purposes of organizing the numbering of the reactions for this key, the reactions have been grouped according to mechanism of the first step of the reaction. Many reactions fall into more than one group. The addition of hydrogen to π bonds is usually discussed in texts along with electrophilic additions to π bonds but here the hydrogen additions have been placed in the reduction category. Reductions with hydrides such as LiAlH 4 are often grouped with nucleophilic additions but here have also been included in the reduction category. The reactions are listed in the order substitution, addition, elimination, addition-elimination, oxidation, reduction, concerted and miscellaneous. To facilitate the finding of reactions from any of the keys that follow, a roadmap grid has been included. For example, the addition of HX to an alkene is represented by reaction 30 which is in grid position B.
Three keys are have been designed to accompany the map. The keys are arranged according to mechanism, functional group preparations and functional group reactions. Reactions in the three keys contain the reaction numbers and grid locators.
Outside of the main region, bold arrows indicate reactions that form C-C bonds. In the online version, products that result from carbon - carbon bond formation are in the grey areas. In Appendix C , these products are in the area with a graph grid. Dotted arrows represent reactions that result in the breaking of C-C bonds. Also included outside the main region are the reactions of aromatics and miscellaneous reactions.
Reaction-Map as a Study Aid At the end of a two semester course in organic chemistry, a student should be able to perform the exercises below. In addition to the exercises below, a student of organic chemistry should be able to demonstrate competency with spectroscopic, stereochemical and multistep synthetic challenges.
- For each numbered reaction, classify the reaction by mechanism (e.g., substitution, nucleophilic) and list the reagents, conditions, regioselectivity, stereoselectivity and restrictions associated with the reaction.
- List all methods of preparing each functional group.
- List all reactions of each functional group.
- Write mechanisms for reactions: 3 (D2) , 10 (B13) , 19 (C13) , 32 (C11) , 33 (E14) , 39 (J3) +28 (K2) , 42 (G7) , 46 (B13) , 47 (C11) , 62 (K13) , 72 (J17) , 106 (K19). The problems above should be attempted without reference to the keys but the keys can be used to help check for the correctness of answers. For the answers to question #4, reference to an organic chemistry textbook may be required.
O
|| RC- X
O O
|| ||
RCOCR
Reaction Mechanism (Listed in the order substitution, addition, elimination, addition- elimination, oxidation, reduction, concerted, miscellaneous) SUBSTITUTION Electrophilic (for electrophilic aromatic substitution, ortho-para directors with rate increase compared to benzene in decreasing order of reactivity are (2, p. 632):
The halides are deactivating ortho-para directors. Meta directors arranged approximately in order of decreasing reactivity are:
1 (D1) H 2 SO 4 (can be reversed, see # 2 (E1) ), aromatic J aromatic derivatives. 2 (E1) H 3 O+/D, aromatic J aromatic derivatives. 3 (D2) HNO 3 /H 2 SO 4 produces NO 2 +, aromatic J aromatic derivatives. 4 (D3) X 2 /FeX 3 (or AlX 3 ), aromatic J aromatic derivatives. 5 (D4) RX/AlCl 3 , aromatic J aromatic derivatives, Friedel-Crafts alkylation, can rearrange and undergo multiple substitution, does not work when ring is deactivated or contains an amino group. 6 (D5)
/AlCl 3 or /AlCl 3 , aromatic J aromatic derivatives, Friedel-Crafts acylation, no rearrangement or multiple substitution, does not work when ring is deactivated or contains an amino group, carbonyl can be reduced to CH 2 (see #87 (C9) ).
7 (L2) PhY where Y is a strong activator, aromatic J aromatic derivatives (e.g., OH or NH 2 ) for electrophilic aromatic substitution. 8 (A5) H 2 O or any good proton donor, organometallic J alkane. Free Radical 9 (E3) NBS (N-bromosuccinimide), aromatics J aromatic derivatives, good for benzylic and allylic bromination. 10 (B13) X 2 /hν or Δ, alkane J alkyl halide, free radical chain reaction, multiple substitution, because of limited selectivity, useful primarily when there is only one type of hydrogen or for more reactive hydrogens (e.g., benzylic and allylic). 11 (I1) CuCl or CuBr, aromatics J aromatic halides, Sandmeyer reaction. 12 (L4) CuCN, aromatics J aromatic nitriles, Sandmeyer reaction. Nucleophilic 13 (J1) H 3 O+/Δ, aromatics J aromatic phenols. 14 (J1) KI, aromatics J aromatic iodides. 15 (K1) HBF 4 /Δ, aromatics J aromatic fluorides. 16 (L1) H 3 PO 2 , aromatics J aromatic derivatives. 17 (B18) CN-^ , alkyl halide J nitrile. 18a (C14) NH 3 , alkyl halide J amine. The direct synthesis of amines from halides is subject to many problems including multiple substitution. Generally, alternatives (e.g., 18b, 18c) should be used.
O O
-NH 2 -OH -OR -NHCR -OCR -R -Ar -vinyl
(^1) Although the orientation of the water in the product is anti-Markovnikov, since boron is more electropositive
than hydrogen, the intermediate orientation is consistent with Markovnikov’s rule (1, p 163).
ADDITION
Electrophilic (except 30b) 30a (B11) HX, alkene J alkyl halide, electrophilic Markovnikov addition. b (B11) HBr/peroxides, alkene J alkyl halide, free radical mechanism yields anti- Markovnikov orientation. 31a (C12) H+^ (H 2 SO 4 or H 3 PO 4 )/ROH, alkene J ether, electrophilic Markovnikov addition with possible rearrangement and competing reactions. b (C12) 1. Hg(O 2 CCF 3 ) 2 , ROH 2. NaBH 4 , alkene J ether, alkoxymercuration reaction, Markovnikov addition without rearrangement. 32a (C11) H+^ (H 2 SO 4 or H 3 PO 4 )/H 2 O, alkene J alcohol, electrophilic Markovnikov addition with possible rearrangement and competing reactions. b (C11) 1. Hg(OAc) 2 , THF, H 2 O 2. NaBH 4 , alkene J alcohol, Markovnikov without rearrangement. c (C11) 1. BH 3 2. OH -^ , H 2 O 2 , H 2 O, alkene J alcohol, anti-Markovnikov 1 orientation without rearrangement. 33 (E14) X 2 , alkene J dihalide, anti-addition, only practical for X = Cl or Br. 34 (F10) 1. H 2 /Lindlar’s catalyst 2. X 2 , alkyne J dihalide (vicinal). 35 (F10) HX, 2 moles, alkyne J dihalide (geminal). 36a (E6) H 2 O/H 2 SO 4 for disubstituted alkynes, H 2 O/H 2 SO 4 /HgSO 4 for terminal alkynes, alkynes J ketones (except ethylene J acetaldehyde), Markovnikov orientation. b (E6) 1. BH 3 2. H 2 O 2 /OH -^ for disubstituted alkynes, substitute disiamylborane for borane for terminal alkynes, alkynes J aldehydes and ketones, anti-Markovnikov orientation. 37,38 (I4) H+/H 2 O or OH -^ /H 2 O reversible formation of hydrate, aldehyde and ketones ' hydrates. Equilibrium strongly favors carbonyl for ketones but is very structure dependent for aldehydes (formaldehyde - 99.99% hydrate and acetaldehyde - 58% hydrate). 39,40 (J3) H+/ROH reversible formation of hemiacetal and hemiketal, aldehyde and ketones ' hemiacetals and hemiketals, hemiacetals and hemiketals are generally unstable and, except for sugars, not isolated. Sugars usually exist in cyclic hemiacetal or hemiketal form. Addition of second molecule of alcohol (28 (K2) , 29 (K3) ) to hemiacetals and hemiketals in reversible substitution reaction yields acetal or ketal. Especially important as blocking or protecting group when ethylene glycol is used to form cyclic acetal or ketal. Nucleophilic 41 (F7, A2) 1. RMgX 2. H+/H 2 O, aldehyde or ketone J alcohol, Grignard reaction. 42 (G7) H+^ or OH -^ , aldehyde or ketone J β-hydroxycarbonyl compound (aldol), aldol addition of conjugate base of carbonyl to carbonyl. If R’s present are aromatic, addition product eliminates to give enone. If R’s are not aromatic, elimination will occur with heating. If elimination occurs, the reaction is called an aldol condensation. Useful primarily when only one kind of α hydrogen is present. 43 (H7) NaCN/HCl, aldehyde or ketone J cyanohydrin, forms cyanohydrin that can be hydrolyzed to α-hydroxycarboxylic acid. 44 (M7, A2) 1. RMgX + CO 2 2. H+/H 2 O, carbon dioxide J carboxylic acid, Grignard Rxn.
ELIMINATION
45 (G4) see #42 (G7) , alcohol J alkene. 46a (B13) strong base, strong nucleophile such as OH -^ /ROH, alkyl halide J alkene, Zaitsev product unless R is bulky such as t -butyl or X is fluorine, E2 for 1 o^ halide competes with S (^) N2, E2 for 3 o^ halide, anti elimination, thermodynamic alkene favored but decreases as base strength increases due to earlier TS. b (B13) poor base, poor nucleophile such as H 2 O, alkyl halide J alkene, Zaitsev product with thermodynamically favored stereochemistry dominant, doesn’t work for 1 o halides, competition between E1 and S (^) N1 for 2 o^ and 3 o^ halides. 47a (C11) H 2 SO 4 or H 3 PO 4 , alcohol J alkene, Zaitsev product with thermodynamically favored stereochemistry dominant, E2 for 1 o^ halides, E1 for 2 o^ and 3 o^ halides, rearrangement possible. b (C11) POCl 3 /pyridine/O o^ C, alcohol J alkene, milder conditions than 47a, use of this catalyst avoids rearrangements, Zaitsev product with thermodynamically favored stereochemistry dominant, E2 reaction. 48 (D8) 1. CH 3 I (excess) 2.Ag 2 O/H 2 O 3. Δ , amine J alkene, Hofmann (least substituted) product. 49 (E8) NaNH 2 /NH 3 or K t-butoxide/DMSO, (di)halide J alkyne. ADDITION-ELIMINATION 50 (E10) 1. NH 3 (or RNH 2 )/H+^ 2. H 2 /Ni or hydride such as NaBH 3 CN, aldehyde or ketone J amine, reductive amination, technically this should be classed as two reactions with the addition-elimination (51 (G11) ) first and the hydrogenation second. 51 (G11) NH 2 R, aldehyde or ketone J “imine”, R’s commonly used to make classic derivatives of carbonyls yield oximes (R = OH, NH 2 OH = hydroxylamine), hydrazones (R = NH 2 or NHR’, if 2,4-dintrophenylhydrazine is used, a 2,4- dinitrophenylhydrazone results), semicarbazones (R = NHCONH (^) 2, NH 2 NHCONH 2 = semicarbazide). 52 (H15) RCOO-^ , acyl halide J anhydride. 53 (K10) NH 3 (or RNH 2 or R 2 NH), acyl halide J amide. 54a (J15) H+/H 2 O, acyl halide J carboxylic acid. b (J15) 1. OH-^ /H 2 O 2. H+/H 2 O, acyl halide J carboxylic acid. 55 (J16) ROH, acyl halide J ester. 56 (K10) NH 3 (or RNH 2 or R 2 NH), anhydride J amide. 57a (J12) H+/H 2 O, anhydride J carboxylic acid. b (J12) 1. OH-^ /H 2 O 2. H+/H 2 O, anhydride J carboxylic acid. 58 (I12) ROH, anhydride J ester. 59a (J11) RCOCl (with conjugate base of acid), carboxylic acid J anhydride. b (J11) Δ for formation of intramolecular anhydrides such as phthalic anhydride. 60 (I16) SOCl 2 or PCl 3 or PCl 5 or PBr 3 , carboxylic acid J acyl halide. 61 (K11) NH 3 , carboxylic acid J amide, primarily an industrial reaction as it requires extreme conditions. 62 (K13) H +^ /ROH, carboxylic acid J ester, position of equilibrium important in this reaction. 63 (K14) H+/H 2 O, ester J carboxylic acid, position of equilibrium important in this reaction. 64 (L11) NH 3 (or RNH 2 or R 2 NH), ester J amide. 65a (J10) H+/H 2 O, nitrile J carboxylic acid. b (J10) 1. OH-^ /H 2 O 2. H+/H 2 O, nitrile J carboxylic acid.
87a (C9) Zn(Hg)/HCl/Δ, aldehyde or ketone J alkane, Clemmensen reduction for acid insensitive compounds. b (C9) NH 2 NH 2 //OH-^ /Δ, aldehyde or ketone J alkane, Wolff-Kishner reduction for base insensitive compounds. c (C9) 1. HS(CH 2 ) 2 SH/HCl 2. H 2 /Raney Ni, aldehyde or ketone J alkane, for compounds insensitive to acid or base 88a (E12) 1. LiAlH 4 2. H 3 O+, aldehyde or ketone J alcohol. b (E12) 1. NaBH 4 2. H 3 O+, aldehyde or ketone J alcohol. c (E12) H 2 /Raney Ni, aldehyde or ketone J alcohol. 89 (E14) 1. LiAlH 4 2. H 2 O, oxirane J alcohol, hydride attacks least substituted carbon. 90a (G16) 1. LiAlH 4 2. H 3 O+, acyl halide J alcohol. b (G16) H 2 /Pd, acyl halide J alcohol. 91 (H15) 1. LiAlH[OC(CH 3 ) 3 ] 3 H, -78 o^ C 2. H +^ or H 2 /partially deactivated Pd similar to Lindlar’s catalyst (Rosenmund reduction), acyl halide J aldehyde 92a (I9) H 2 /Pd/C, nitrile J amine. b (I9) 1. LiAlH 4 2. H 2 O, nitrile J amine 93 (I10) 1. DIBAH (diisobutylaluminium hydride)/-80 oC 2. H+, nitrile J aldehyde. 94 (H12) 1. LiAlH 4 2. H+, carboxylic acid J alcohol. 95 (I13) 1. DIBAH (diisobutylaluminium hydride)/-80 oC 2. H+, ester J aldehyde. 96 (H14) 1. LiAlH 4 2. H+, ester J alcohol. 97 (I9) 1. LiAlH 4 2. H 2 O, amide J amine. CONCERTED 98 (B4) Δ for some, alkene + diene J cyclohexene, Diels-Alder reaction, a concerted syn addition that also falls under classifications of pericyclic and [4 + 2] cycloaddition reactions, electronic releasing groups on the diene and electron withdrawing groups on the dienophile generally increase the rate of reaction. The diene must be capable of achieving an s-cis conformation and cyclic dienes such as cyclopentadiene react rapidly. There is a stereochemical preference for electron withdrawing groups on the dienophile to end up in the endo position. MISCELLANEOUS 99a (C5) 1. CH 2 N 2 /Δ or hν 2. alkene, carbene + alkene J cyclopropane, generally a syn addition, also see 107 (L18). b (C5) 1. CH 2 I 2 /Zn(Cu) 2. alkene, Simmons-Smith reagent, carbenoid + alkene J cyclopropane (also see 107 (L18). 100 (B18) 1. Li/Et 2 O 2. CuI 3. R’X, alkyl halide uses Gilman reagent to make symmetrical and unsymmetrical hydrocarbons. 101 (F6) (Ph) 3 P=CHR, Wittig reagent synthesized from 1. Ph 3 P + RBr 2. RLi, aldehyde or ketone J alkene. 102 (H13) 1. X 2 /OH-^ 2. H+, methyl aldehydes and ketones J haloform + carboxylic acid, haloform reaction used to test for methyl ketones (and acetaldehyde and ethanol and other 2-alcohols). 103 (K8) P 2 O 5 or SOCl 2 , amide J nitrile. 104 (L6) Br 2 /OH-^ , Hofmann rearrangement, amide J amine with one less carbon. 105 (L12) Δ, carboxylic acid J carbon dioxide + residue (usually aromatic or β-keto caboxylic acids, others do not easily decarboxylate). 106 (K19) 1. OR -^ 2. R’Br 3. H+/H 2 O/Δ, β-keto ester J ketone, acetoacetic ester synthesis (also consider malonic ester synthesis). 107 (L18) 1. t -butoxide 2. alkene, dichlorocarbene + alkene J dichlorocyclopropane, a syn addition, also see 99 (C5).
Preparation of Functional Groups
Acetals and Ketals Acid catalyzed addition of 2 moles of alcohol to aldehyde or ketone (39 (J3) , 28 (K2) ). Acyl halides Reaction of carboxylic acid with SOCl 2 or PCl 3 or PCl 5 or PBr 3 (60 (I16) ). Alcohols Reaction of an alkyl halide with OH -^ (19 (C13) ). Reaction of an oxirane with a Grignard reagent, an organolithium reagent or a Gilman reagent (organocuprate) (25 (F17, A2) ). Hydration of an alkene (32 (C11) ). Reaction of a carbonyl compound with a Grignard reagent or an organolithium reagent (41 (F7, A2) ). Aldol reaction (42 (G7) ) Reaction of an acyl halide (69 (K11, A3) ) or an ester (70 (I17, A3) ) with a Grignard reagent or an organolithium reagent. Reduction of an oxirane with LiAlH 4 (89 (E14) ). Reduction of carbonyl (88 (E12) ) and carboxyl compounds (90 (G16) , 94 (H12) , 96 (H14) ). Aldehydes Hydration of ethylene (36a (E6) ) or other terminal alkynes (36b (E6) ). Alkylation of conjugate base with an alkyl halide (27 (G7) ). Formation from acetals and hemiacetals (38 (I4) , 40 (J3) ). Aldol reaction (42 (G7) ). Oxidation of an alkene with ozone followed by reductive workup (73 (B3) ). Oxidation of a primary alcohol with PCC. Reduction of an acyl halide (91 (H15) ) or an ester (95 (I13) ). Reduction of a nitrile (93 (I10) ). Aldehyde and ketone derivatives Reaction of appropriate reagent with carbonyl compound (51 (G11) ). Alkanes Reaction of water with a Grignard reagent or an organolithium reagent (8 (A5) ) Reduction of an alkene (82 (B7) ) or an alkyne (83 (B6) ) Reduction of an alcohol (85 (B9) ). Reduction of carbonyl compounds (87 (C9) ). Coupling of two alkyl halides (100 (B18) ). Carbene and carbenoid reactions (99 (C5) ). Alkenes Elimination of water from an alcohol (45 (G4) , 47 (C11) ). Elimination of HX from an alkyl halide (46 (B13) ). Hofmann elimination from an amine (48 (D8) ). Reduction of an alkyne (84 (D7) ). Diels-Alder reaction (98 (B4) ). Wittig reaction (101 (F6) ). Alkyl halides Reaction of NBS at a benzylic or allylic position (9 (E3) ). Radical bromination or chlorination of an alkane (10 (B13) ). Nucleophilic substitution of an alcohol (20 (C15) ). Addition of HX to an alkene (30 (B11) ) or alkyne (35 (F10) ).
Carboxylic acids Reaction of carbon dioxide with a Grignard reagent or an organolithium reagent (44 (M7, A2) ). Hydrolysis of an acyl halide (54 (J15) ), anhydride (57 (J12) ), ester (63 (K14) ), nitrile (65 (J10) ) or amide (67 (K11) ). Oxidation of an alkyl benzene (75 (F3) ). Oxidation of a primary alcohol (79 (I13) ) or an aldehyde (80 (H12) ). Haloform reaction of a methyl ketone (102 (H13) ). Cyanohydrins Reaction of a carbonyl compound with cyanide (43 (H7) ). Diols (1,2) Hydrolysis of an oxirane (24 (F15) ). Oxidation of an alkene (77 (E11) ). Esters Reaction of an acyl halide (55 (J16) ) or anhydride (58 (I12) ) with an alcohol, avoids equilibrium problem involved in direct conversion from the carboxylic acid. Acid catalyzed reaction of a carboxylic acid with an alcohol (62 (K13) ). Claisen condensation (72 (J17) ). Ethers Williamson ether synthesis between an alkyl halide and an alkoxide ion (21 (D13) , 22 (C16) ). Addition of an alcohol to an alkene including alkoxymercuration (31 (C12) ). Hemiacetals and hemiketals Acid catalyzed addition of alcohol to a carbonyl (39 (J3) ). Ketones Friedel-Crafts acylation (6 (D5) ). Alkylation of conjugate base with an alkyl halide (27 (G7) ). Hydration of an alkyne (36 (E6) ). Formation from ketals and hemiketals (38 (I4) , 40 (J3) ). Aldol reaction and condensation (42 (G7) ). Reaction of acyl halide with Gilman reagent (68 (H18) ). Reaction of a nitrile with a Grignard reagent (71 (J7, A3) ). Claisen condensation (72 (J17) ). Oxidation of an alkene with ozone followed by reductive workup (73 (B3) ). Oxidation of a 2 o^ alcohol (78a (F12) ). Acetoacetic ester synthesis (106 (K19) ) Nitriles Reaction of a diazonium salt with CuCN (Sandmeyer reaction) (16 (L1) ). Nucleophilic substitution of an alkyl halide (17 (B18) ). Conversion of an alcohol (23 (C17) ). Reaction of a carbonyl compound with hydrogen cyanide (43 (H7) ). Dehydration of an amide (103 (K8) ). Organometallics Reaction of magnesium (Grignard reagent) or lithium with an alkyl halide in ether (81 (A9) ). Formation of a Gilman reagent (organocuprate) by reacting an organolithium reagent with CuI. This procedure is used in three synthetic pathways on map (25 (F17, A2) , 68 (H18) , 100 (B18) ). Oxiranes Reaction of an alkene with a peroxyacid (76 (D11) ).
Reactions of Functional Groups
Acetals and Ketals Acid catalyzed reaction to carbonyl compounds via hemiacetals and hemiketals (29 (K3) ). Acyl halides Conversion to anhydrides (52 (H15) ), amides (53 (K10) ), acids (54 (J15) ), esters (55 (J16) ). Reaction with Gilman reagent to give ketones (68 (H18) ). Reaction with Grignards and organolithium reagents to give 3 o^ alcohols (69 (K11, A3) ). Reduction to 1 o^ alcohols (90 (G16) ). Reduction to aldehydes (91 (H15) ). Alcohols Conversion to alkyl halides (20 (C15) ), ethers (21 (D13) ), nitriles (23 (C17) ). Dehydration to alkenes (45 (G4) , 47 (C11) ). Reaction with acyl halides (55 (J16) ) and anhydrides (58 (I12) ) to give esters. Oxidation to carbonyls (78 (F12) ) and carboxylic acids (79 (I13) ). Reduction to alkanes (85 (B9) ). Aldehydes Alkylation of α-carbons (27 (G7) ). Reaction with alcohols to give hemiacetals (39 (J3) ) and subsequently acetals (28 (K2) ). Reaction with water to give hydrates (37 (I4) ). Reaction with Grignards and organolithium reagents to give 2 o^ alcohols (41 (F7, A2) ). Aldol condensation to give β-hydroxy carbonyl compounds (42 (G7) ). Reaction with cyanide to give cyanohydrins (43 (H7) ). Reductive amination to amines (50 (E10) ). Reaction with nitrogen compounds to give carbonyl derivatives (51 (G11) ). Reduction to alkanes (87 (C9) ). Reduction to 1 o^ alcohols (88 (E12) ). Wittig reaction to give alkenes (101 (F6) ). For acetaldehyde, haloform reaction to haloform and formic acid (102 (H13) ). Alkanes Reaction with chlorine or bromine with heat or light to give alkyl halides (10 (B13) ). Alkenes Addition of HX to give alkyl halides (30 (B11) ). Addition of alcohols to give ethers (31 (C12) ). Addition of water to give alcohols (32 (C11) ). Addition of X 2 to give vicinal halides (33 (E14) ). Ozonolysis to give carbonyl compounds (73 (B3) ). Reaction with a peroxyacid to give an oxirane (76 (D11) ). Oxidation to a 1,2-diol (77 (E11) ). Hydrogenation to give alkanes (82 (B7) ). Reaction with a diene to give a cyclohexene, Diels-Alder reaction (98 (B4) ). Reaction with a carbene or carbenoid to give a cyclopropane (99 (C5) , 107 (L18) ). Alkyl halides Substitution to give alcohols (19 (C13) ), ethers (22 (C16) ), nitriles (17 (B18) ). Conversion to amines (18 (C14) ). Reaction with acetylide to give larger alkynes (26 (E6) ). Elimination to give alkenes (46 (B13) ). Elimination of dihalides to give alkynes (49 (E8) ). Reaction with magnesium or lithium to give Grignards (81a (A9) ) or organolithium reagents (81b (A9) ). Coupling to give alkanes (100 (B18) ). Alkynes Alkylation via conjugate base and alkyl halide (26 (E6) ).
Grignard and organolithium reagents Reaction with water to give an alkane (8). Reaction with oxiranes (25 (F17, A2) ), carbonyls (41 (F7, A2) ), acyl halides (69 (K11, A3) ), esters (70 (I17, A3) ) to give alcohols. Reaction with carbon dioxide to give carboxylic acids (44 (M7, A2) ). Reaction with nitriles (71 (J7, A3) ) to give ketones. Gilman reagents Reaction with oxiranes to give alcohols (25 (F17, A2) ). Reaction with acyl halides to give ketones (68 (H18) ). Reaction with alkyl halides to give alkanes (100 (B18) ). Oxiranes Hydrolysis to 1,2-diols (24 (F15) ). Reaction with a Grignard or a Gilman reagent (organocuprate) to give an alcohol (25 (F17, A2) ). Reduction to alcohols (89 (E14) ).
