14 C synthesis strategies, Chem 315/316 / Beauchamp 1 Several organolithium compounds are commercially available. Many others can be made. We will use two methods (Li and Mg) to make these carbanion equivalents, and almost any other, from simple RX starting points. While these two classes of compounds are very similar in the chemistry we study, there are some differences that we will mostly ignore. Once organolithium and organomagnesium (Grignard) reagents are made, the metals can be switched with other metals (transmetallation). We will only use copper this way in our course (as CuI = cuprous iodide). This will give us a few more reaction choices than are possible with magnesium and lithium, alone (RX coupling, selective reaction with acid chlorides and beta addition to α,β-unsaturated carbonyl compounds). Magnesium and lithium reagents can be made from the corresponding RX compounds (we will use RBr) when mixed with lithium or magnesium metal. In actuality the carbon/lithium bond is intermediate between very polar covalent and ionic. Some organolithium reagents are soluble in hydrocarbon solvents (hexane), which is an indication that they are not really ionic salts. The actual situation is more complicated because of various “cluster” arrangements However, they all react like powerful carbonanion nucleophiles, and that’s the way we will represent them, because it’s easier to think about the reactions they undergo that way, especially when you are a beginning organic student. Almost always a final acidic neutralization workup step is necessary because the conditions are kept “basic” to prevent destruction of the organometallic reagent. In the examples below, we will represent phenyl as “Ph” to distinguish the part that came from the organolithium reagent (the nucleophilic part) in each newly synthesized target molecule. A lot can be done with these reagents, as shown by many examples below. In each subsequent part, a single compound is highlighted from an earlier part, and several additional compounds are shown that can be made in “one additional reaction” sequence. (One additional reaction means a sequence of steps that can be performed in a single reaction flask.) Highlighted, commercially available compounds: phenyl lithium (Ph-Li), methyl lithium (Me-Li), ethyl lithium (Et-Li), butyl lithium (n-Bu-Li), sec-butyl lithium (sec-Bu-Li), t-butyl lithium (t-Bu-Li), Li Li ≈ Easier to understand its chemistry when viewed this way. phenyl lithium Ph Li shorthand representation Li phenyl lithium Li organometallics RX + (Mg or Li) Br Made from: H 3 C Li Li ≈ methyl lithium H 3 C Li H 3 C Br H 3 C C H 2 H 2 C H 2 C H 3 C C H 2 H 2 C H 2 C Br Li H 3 C C H 2 H 2 C H 2 C Li n-butyl lithium Li ≈ H 2 C HC H 2 C HC H 2 C HC Br Li Li Li ≈ vinyl lithium Z:\classes\315\315 Handouts\organomet_syn_strategies.doc
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C synthesis strategies, Chem 315/316 / Beauchamp 1psbeauchamp/pdf/organomet_syn_strategies.pdf14C synthesis strategies, Chem 315/316 / Beauchamp 1 Several organolithium compounds are
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Several organolithium compounds are commercially available. Many others can be made. We will use two methods (Li and Mg) to make these carbanion equivalents, and almost any other, from simple RX starting points. While these two classes of compounds are very similar in the chemistry we study, there are some differences that we will mostly ignore.
Once organolithium and organomagnesium (Grignard) reagents are made, the metals can be switched with other metals (transmetallation). We will only use copper this way in our course (as CuI = cuprous iodide). This will give us a few more reaction choices than are possible with magnesium and lithium, alone (RX coupling, selective reaction with acid chlorides and beta addition to α,β-unsaturated carbonyl compounds). Magnesium and lithium reagents can be made from the corresponding RX compounds (we will use RBr) when mixed with lithium or magnesium metal.
In actuality the carbon/lithium bond is intermediate between very polar covalent and ionic. Some organolithium reagents are soluble in hydrocarbon solvents (hexane), which is an indication that they are not really ionic salts. The actual situation is more complicated because of various “cluster” arrangements However, they all react like powerful carbonanion nucleophiles, and that’s the way we will represent them, because it’s easier to think about the reactions they undergo that way, especially when you are a beginning organic student. Almost always a final acidic neutralization workup step is necessary because the conditions are kept “basic” to prevent destruction of the organometallic reagent. In the examples below, we will represent phenyl as “Ph” to distinguish the part that came from the organolithium reagent (the nucleophilic part) in each newly synthesized target molecule.
A lot can be done with these reagents, as shown by many examples below. In each subsequent part, a single compound is highlighted from an earlier part, and several additional compounds are shown that can be made in “one additional reaction” sequence. (One additional reaction means a sequence of steps that can be performed in a single reaction flask.)
The following compounds are one reaction pot away from phenyl lithium. Analogous examples are possible using other organometallic reagents, such as those listed just above.
NuE Eclue: COH group could have been C=O group (aldehyde or ketone)
CCO
HO
CC
OH
ONu
EE
clue: COH group could have been C=O group (carbon dioxide)
Nu
clue: COH group could have been an epoxide group
CCR
C
HO
Nu
E
clue: COH group could have been C=O group (ester)
CC
OH
R
CNu
E
In our course every carbon carbon bond made with a starred carbon must be made with a nucleophile/electrophile reaction.
CCnuclephile (Nu) = ?
electrophile (E) = ?Nu
C
O
R HC
O
OC
O
R RC
O
R ORO
BrRMg or 2 Li
(MgBr) or LiR
electrophiles = (E)
nucleophiles = (Nu)
1. Propose a synthesis for the following compound using only *CH3OH and *CO2 as your source of radioactive 14C isotope. Bromobenzene, methanol, ethene and propene are also available. Work backwards from the target. The last step of the synthesis should be your first step. Show the reagents and reactant for each backwards step until you reach either of the 14C compounds above. Do not show mechanisms. Could you make the same molecule if you had to use Na*CN instead of *CO2?
Starting sources of carbon, plus any reagents studied in the course.
1 2 3 4
1
1
1
1
2
2
2
2
3
3
3
3
4
4
4
4
5 6
75
5
6
6
1
1
1
1
2
2
2
2
3
3
3
3
There are many ways to total 7 carbon atoms. 3 + 3 + 1 = 7 3 + 2 + 2 = 7 2 + 2 + 2 + 1 = 7 3 + 3 + 2 - 1 = 7 2 + 2 + 2 + 2 - 1 = 7These are a few examples.
X can be -OH (alcohols), which can be oxidized to aldehydes (1o ROH), carboxylic acids (1o ROH) that can be made into esters or ketones (2o ROH). X can be a leaving group (Cl, Br, I, OTs) made from an alcohol or an alkene, which can then react by SN or E chemistry, or be made into an organometallic reagent (Mg or Li). X can be a 1o amine (-NH2) using phthalimide = Gabriel amine synthesis.
X can be an ether from RO - and a methyl or 1o RX electrophile (SN2, Williamson ether synthesis) or from ROH and 2o/3o RX (SN1, R+ intermediate). X can be a cyano group (-CN) from an SN2 reaction of cyanide at methyl, 1o, 2o RX. X can be an H from SN2 using nucleophilic hydride (LiAlH4 or NaBH4). This reaction can be distinguished by using deuterium in place of hydrogen. X can lead to alkenes via E1 (H2SO4/∆ with ROH) or E2 reactions (very strong or strong and bulky bases with RBr) A Wittig reaction puts the C=C where desired. X can be an alkyne if a leaving group is at a primary position. Remember the limitations of each type of reaction (SN2, E2, SN1, E1, etc.).
O
O
**
N
O
**
H
O **
*
*
*
*
*
O
2 problems in one structure (ester)joined (acid + RX) by SN chemistry, (acid-Cl + alcohol),(acid + alcohol) by acyl substitution
2 problems in one structure (amide)(joined acid-Cl + amine) by acyl substitution, amine = NH3,RNH2,R2NH
2 problems in one structure (ether)(alcohol/alkoxide + RX),(alcohol + alcohol) by SN chemistry
2 problems in one structure (alkyne) by terminal acetylide + Me or 1o RX,SN chemistry
Up to 4 problems in one structure,can have 1, 2, 3 or 4 branches
**
2 problems in one structure (alkene, E or Z) from reduction of alkyne or Wittig reaction.
**
2 problems in one structure (ketone)(acid chloride + cuprate),(aldehyde + RX)(cyanide to nitrile to ketone)
O
Multiple problems in one.
How can one cut up these molecules into simpler parts?
Wittig
either sideeither side
both sides
either side
*all sides
alkynealkyne
Some of the Synthetic Strategies in 14C Game 1. Every *C-C (carbon-carbon) bond to a *C must be made. If atoms have been joined together, is there an obvious nucleophile
(alkyne, cyanide, Mg or Li reagent) and/or electrophile (an OH that was a C=O or an epoxide)? You need one of each. If one part is obvious, can you think of how the other part might be made? Could you join the atoms in the opposite fashion (umpolung)? Think in both directions.
2. Functional Group Interconversions (FGI) are often used (i.e. ketone to alcohol, or alcohol to ketone, or alcohol to bromoalkane, which can be a leaving group for an SN reaction or made into Grignard or Lithium reagents). Which carbon could have been a carbonyl (C=O) functional group and altered by the reactions shown? (such as methanal, general aldehyde, ketone, ester, carbon dioxide)? Or, could have been some other functional group (alkene, RX compound, epoxide)?
3. Alcohols are often oxidized to carbonyls (alcohols aldehydes, ketones, carboxylic acids) (carboxylic acids esters, acid chlorides) (acid chlorides esters, 1o,2o,3o amides, ketones, aldehydes, thiolesters), which can be used as electrophiles (etc.).
4. Many organic groups can be reduced (alkene alkane, alkyne Z-alkene, E-alkene, alkane, carbonyl alcohol, alkane, etc.)
5. Additional special reactions of course (Wittig, Wolff-Kishner, Clemmenson, enamine, imines, cuprates, etc.).
6. Protections are sometimes necessary (acetals, ketals “C=O” protected with ethylene glycol or “ROH” protected as THP ether). There are many other kinds of protections besides those discussed in our course.
7. If starting from some “functional group”, what features are retained in the target structure?
8. If thinking back from the product, what features need to be generated in the product?
9. Draw a possible starting structure and consider what reactions possible reactions that we have studied could make the target functional group? Does one seem better suited than another?
Where can we go starting with a 2 carbon alkane? Fill in the missing reagents below to show how each step could occur? These are important reactions for you to be able to make the transformations necessary to do well in this course. Each step has a mechanism, and you should also have an idea how these work. Use any reagents that we have studied, as you need them.