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Introduction
Why bother with organic synthesis?Organic molecules are required for:
Most of the required molecules are not available from natureand for those that are, most are not available in sufficient quantities.
When presented with a "target" compound, how to chemists decide how to make it?
The best way is to start from the target molecule, and to work backwards with a series of disconnections until we get back to readily available starting materials.
This procedure is known as retrosynthetic analysis.
Pharmaceuticals and agrochemicalsPolymersDyesFood colouringsDyesEtc.
Chemists need to make them!
NH
O OH
O
O
Me
Me
Me
omuralide
OH
O
OAcOMe
HOBz OAc
Me MeMe
OOH
O
Ph
NHBz
OH taxol
These two molecules are derivedfrom natural sources, and exhibithigh biological activities.
(moderate complexity) (high complexity)
Retrosynthetic Analysis
Even for a molecule of only moderate complexity (e.g. omuralide), it is not easy to "imagine" a complete synthesis from scratch.
Targeted Organic Synthesis Lecture 1 1
1
Retrosynthetic Analysis
O
Me
O
OEt
O
Me
O
OEt
O
Me
O
OEtBr
The principles behind retrosynthetic analysis are best explained with a simple example:
Target molecule (TM)
retrosynthetic arrow
disconnection
Synthons:
acceptor synthon(electrophile)
donor synthon(nucleophile)
Synthetic equivalents:
Forward synthesis:
O
OEtBr Zn
O
OEtBrZn
Reformatsky reagent(a nucleophilic zinc enolate)
O
MeO
Me
O
OEtMichael reaction
(Work backwardsfrom target)
12
12
3
Retrosynthesis:
Targeted Organic Synthesis Lecture 1 2
2
TerminologyTargeted Organic Synthesis Lecture 1
Real reagents carrying out the function of a synthon.
Definition of terms used (Warren p. 15)
Retrosynthetic analysis:
Disconnection:
Synthons:
Synthetic equivalents:
Retrosynthetic arrow: Backwards arrow used to show a retrosynthetic step.( )
Process of breaking down a target molecule (TM) into available starting materials by disconnections and/or functional group interconversions (FGI).
The reverse operation to a reaction. The imagined cleavage of a bond to "break" the molecule into possible starting materials.
Imaginary fragments (usually a cation or anion) from which the TM might be made
3
3
Donor Synthons
Ar
R1
R2
R3
R3
R
R1
R2
O
OR
O
R
Ar M
R1
R2
R3M
R3
R1
R2 M
R M
CN
S S
Li R
NO2
R
Ar-H,O
R1
H
NR22
HR1
O
R
O
R Me
O
R
O
OEt
O
EtO
O
EtOBr
O
EtO
O
OEt
O
H
MgBr
MgBr
OMe
MeO MgBr
(M = Li, MgBr, CuR)
(R = H)
(Reformatsky)
(masked C=O)
(masked C=O)
Synthon Synthetic equivalent(s) Synthon Synthetic equivalent(s)
Some common donor synthons (carbon nucleophiles):
The only real way to learn the information presented in this table is to practice example questions again and again!
Targeted Organic Synthesis Lecture 1 4
4
Acceptor Synthons
Synthon Synthetic equivalent(s) Synthon Synthetic equivalent(s)
Some common acceptor synthons (carbon electrophiles):
The only real way to learn the information presented in this table is to practice example questions again and again!
Ar
R1
R2
R3
O
OR
R1
R2
R3Hal
Ar-N2
OH
R1 R2
O
R1 R2
O
R
O
RXX = Cl, OEt
O
ORXCO2
O
R
O
EtO
O
EtOBr
O
R
OH
R R
O
O
RHal
RHal
O
R
MeO OMe
R Br
(masked C=O)
Targeted Organic Synthesis Lecture 1 5
5
Disconnection GuidelinesHow to choose a good disconnection? What follows are some guidelines:
Use two-group disconnections - e.g. between two C=O groups, or other pairs of groups.
O
Me
O
OEt
O
Me
O
OEt
Synthons
Synthetic equivalents
O
Me OEt
O
Me OEt
Forward synthesis:
O
Me OEtNaOEt
O
OEtO
Me OEt
O
Me
O
OEtClaisen condensation
Example 1
See Warren, p. 86-92Make disconnections corresponding to known, reliable reactions.
O
Me
OH
Me
Me
OSynthons
Synthetic equivalents
Forward synthesis:
NaOH
Example 2
Me
OH
Me
Me
Me
O
MeMe
O
MeMe
Me
O
MeMe
O
MeMe
O
Me
O
MeMe
O
MeMe
O
Me
OH
Me
Me
Me
H3O
Aldol reaction
Me
In each case, disconnecting between two functional groups is a simplifying operation, and is often the easiest way to get back to simple starting materials.
Targeted Organic Synthesis Lecture 1 6
6
Disconnection Guidelines
For compounds consisting of two parts joined by a heteroatom, disconnect next to the heteroatom.Why? Carbon-heteroatom bonds are almost always easier to make (usually by nucleophilic substitution
reactions such as alkylation or acylation) than carbon-carbon bonds.
S
Cl
Cl
S
Cl
Cl
Synthons
Synthetic equivalents
SH
Cl
Cl
Cl
Forward synthesis:
SH
Cl
NaOEtS
Cl
Cl
Cl
S
Cl
Cl
Disconnect towards the middle of a molecule to make two reasonably equal halves.Disconnect at branch points, as this strategy is more likely to give straight chain fragments.
Simplifying operations that are more likley to give reasonable starting materials
Ph
OH
Me
Me
O
Ph H Me
MeBrMg
OH
Ph Me
Me
Synthons
Synthetic equivalents
Me
MeBr Mg
Me
MeBrMg
O
Ph HPh
OH
Me
Me
Forward synthesis:
(after work-up)
Targeted Organic Synthesis Lecture 1 7
7
Disconnection Guidelines
Disconnect back to readily available starting materials.
Use symmetry if possible in a helpful way.
O
Me OEtPh Ph
OH
MeDisconnect twice at
branch points
2 x PhMgBr
Synthetic equivalents Forward synthesis:
O
Me OEt
PhMgBr
This ketone is more reactive than thestarting ester (do you know why?),and reacts with more PhMgBr as soon as it is formed.
O
Me Ph
PhMgBrPh Ph
OH
Me
Use a convergent strategy, rather than a linear strategy if possible.
A B C D A target molecule (TM) made up of four fragments A, B, C, D
Linear strategy: A A B A B C90% 90% 90%
A B C D 3 steps, 73% overall yield (0.90 x 0.90 x 0.90)
Convergent strategy:
A A B90%
C C D90%
90% A B C D2 steps longest linear sequence, 80% overall yield (0.90 x 0.90)
Consider:
Some of the previous guidelines amount to a convergent strategy (disconnecting towards the middleof molecules and at branch points).
Targeted Organic Synthesis Lecture 1 8
8
An Example of the Disconnection Approach
The disconnection approach applied to a perfumery compound:
O
Me
O
Me
Me
O
Me
OH HO
Me
Me+ A branched alcohol. This is actually commercially
available but we can simplify further for illustrative purposes.
Not commercially available
Disconnect at branch point
Me
O
OH
use: CO2 =
O
C
O
Me
Synthons Synthons
HOMe
Me
Synthetic equivalents
Synthetic equivalents
MeBr
acetylene
O
H H Me
MeBrMg
Me
MeBr
Grignard reagent
Make Grignard from:
Disconnect at ester first (disconnection at a carbon-heteroatom bond and towards the middle of the molecule).
Targeted Organic Synthesis Lecture 2 9
9
An Example of the Disconnection Approach
Forward synthesis:
Br
Me
Me
O
Me
O
Me
Me
O
Me
OH
HO
Me
Me
MeBr
O
H H
Me
MeBrMg
Me
Mg1.
2. H3O
1. BuLi 1. BuLi2. CO23. H3O
Preparation of alcohol:
Preparation of carboxylic acid:
Preparation of final target:
O
Me
OH HO
Me
Me+H (cat.)
Targeted Organic Synthesis Lecture 2 10
10
Available Starting Materials
What follows is not a comprehensive list, but to just give a basic idea:
Straight chain aliphatic compounds: C1 to about C8
alcohols, alkyl halides, acids, aldehydes, amines
Branched aliphatic compounds: X = functional group (as above)
Me
Mex
Me
MeMe X
Me
Me
XMe Me
MeX
Me
Me
X Me
Me Me
X Me
Me
X
Cyclic alcohols and ketones: C4 to C8
Acyclic ketones:
O
Me Me
O
MeMe
O
MeMe
O
Me
Me
Me
Monomers used to make plastics etc:
O
Me
Me
Ph CO2Me
H (or Me)
CN
H (or Me)
CHO
H (or Me)
butadiene isoprene styrene methyl acrylatemethyl methacrylate
acrylonitrilemethacrylonitrile
acroleinmethacrolein
Warren p.90
Targeted Organic Synthesis Lecture 2 11
11
Available Starting Materials
Chiral pool compounds:
Amino acids Hydroxy acids
TerpenesSugars
NH2
Me
Me
CO2H
NH2
PhCO2H
valine phenylalanine
Me CO2H
OH
HO2CCO2H
OH
OHPh CO2H
OH
lactic acid mandelic acid tartaric acid
Me MeMe
O
camphor
O
OHOHHOHO
OH
glucose
Me
Me
Me
OHgeraniol
O
OHHOHO
OH
mannose
OH
Targeted Organic Synthesis Lecture 2 12
12
Summary of Useful Reactions
R OH
R1 NO2
R2
R1 OH
R2
R OH
R O
H
R1 O
R2
R O
OH
R
Me
OR
R1 O
R2
Jones reagent[CrO3, H2SO4]
Jones reagentor PCC
HgSO4, H2O
TiCl3, H2O
PCC
alcohol oxidation
alcohol oxidation
alcohol oxidation
alkyne hydration
Nef reaction
R1
R2
R1 O
R2
R1
R2
OHOH
R1
R2
O
R1
R2
OH
R1
R2
R1
R2
R1
R2
1. O32. PPh3
1. BH32. NaOH, H2O2
m-CPBA
OsO4
ozonolysis
hydroboration-oxidation
epoxidation
dihydroxylation
Transformation Reagents Transformation Reagents
Targeted Organic Synthesis Lecture 2 13
13
Summary of Useful Reactions
Transformation Reagents Transformation Reagents
R1 O
R1 O
OR2
R O
R1 OH
R2
R1 OH
R OH
LiAlH4
carbonyl reduction
carboxylic acid reduction
ester reduction
amide reduction
nitrile reduction
R2
OH
LiAlH4
NaBH4or LiAlH4
LiAlH4or DIBAL (iBu2AlH)
R1 O
NR2 R3
R1
NR2 R3
LiAlH4
R N RNH2
R ODIBAL
H2, Lindlar's catalyst
H2, Pd/C (cat.)
nitrile reduction
alkyne "semi-reduction"
alkene reduction
R N
H
R2
R1 R2
HH
(Pd/C, BaSO4)
alkyne "semi-reduction"
R2
R1 H
R2H
Li, NH3
R1 R2 R1 R2
R1
R1
Targeted Organic Synthesis Lecture 2 14
14
Latent Polarity
Addition of a nucleophile:
O
R R
Nu
O
R R
Nuor so:
O
R R
"natural" synthons
R
O
R
HB
R
O
RR
O
R
H
R
O
BR
O
12
3or
So:1 2
3
"natural" synthons4
Deprotonation to give an enolate:
R
O
R
O
412
3
R
O
PhR
OH
PhR
Br
Ph
get both of these from carbonyl
Applying this to different functional groups:
latent polarity of a carbonyl
Latent polarity is the imaginary pattern of alternating positive and negative charges used to assist in the choice of disconnections and synthons. Sticking to latent polarity usually gives the best choice of synthons. However, this is not always possible!
For example:
Willis p. 15
Targeted Organic Synthesis Lecture 3 15
15
Functional Group InterconversionsTargeted Organic Synthesis Lecture 3
Must recognise functional group relationships!
O
Ph Ph
O
Ph Ph
OH O
Ph Ph
OH
O
Ph Me Ph
O
H
FGI
benzophenone benzaldehyde
N.B. NOTO
Ph Ph
O
Ph Ph
FGI
OHdoes not fit with "normal" reactivity pattern
Oxidations
R OHOx
R O
H
R O
OHOx
aldehyde carboxylic acidalcohol
Hydration of double bonds
O
R1 OR2LiAlH4
R1 OH
Esters:
Reductions
Amides:O
R NH2R NH2
LiAlH4
O
R1 NH
R1 NH
LiAlH4R2 R2
Most complex molecules contain many more functional groups than simply the carbonyl group. Many of these can often be prepared from carbonyl-containing functional groups.
Willis p. 27-32
16
16
Functional Group Interconversions
Nitriles:
R NR NH2
LiAlH4 1. DIBAL
2. H3O
O
R Hvia
R
NAl
Me
Me Me
Me
H
We can use the chemoselectivity of different reducing agents in a useful way:
O
R1 OR2
NaBH4 no reaction (most of the time)
O
R1 R2
NaBH4OH
R1 R2
Compare with LiAlH4 reactivity!
So: O
OEtR
ONaBH4
O
OEtR
OHOH
R
OHLiAlH4
O
OEtR
OO
OHHO , H
Use acetal formation to protect ketoneOH
R
O 1. LiAlH4
2. H3O
Reductions continued
Targeted Organic Synthesis Lecture 3 17
17
Functional Group Interconversions
Aldehydes/ketones
O
R1 R2R1 R2
SSR1 R2
R3O OR3 R3OH, H
H3O
HS SH , H
HgCl2, H2O
Alcohols
R OH R ClR BrPCl5
or SOCl2
CBr4, PPh3 To convert a complex alcohol into a bromide/chloride for use in alkylationreactions.
dithioacetalsacetalsAcetals serve as carbonyl protecting groups.
Dithioacetals can serve as carbonyl protecting groups and are also used when Umpolung chemistry is required (see later).
Carboxylic acids
R1
O
OHR1
O
OR2 R1
O
Cl
R1
O
NH2
R1
O
OR2
R2OH, H
H3O
SOCl2
NH3
R2OH
H3O
H2Oor OH
Targeted Organic Synthesis Lecture 3 18
18
1,3-Difunctional Compounds
Warren, Chapter 19Recognise different oxidation levels:
O O
RR
O OH
RR
O
RR(-H2O)
12
3 12
3 12
3
1,3-Dicarbonyls
O O
MePh
O
Ph
O
MePh
O
Me
O
MeEtO
12
3
Use:
Forward synthesis
O
Ph
NaOEtH
OEt
O
Ph
O
MeEtO
O O
MePhOEt
O O
MePh
Claisen condensation
Targeted Organic Synthesis Lecture 3 19
19
1,3-Difunctional Compounds
The cyclic case:
O
CO2Et
O
CO2Et
O
O
OEt
OEtUse symmetrical 1,6-diester readily available
O O
OEt UseO
OEtEtO
A
B
Path A
Path B
Path BForward synthesis:
O
O
OEt
OEtNaOEt
O
CO2Et
Dieckmann Cyclisation
Path AForward synthesis:
O O
OEtEtO+
NaOEtO
CO2Et
Targeted Organic Synthesis Lecture 3 20
20
1,3-Difunctional Compounds
β-Hydroxyketones
Same disconnection at a lower oxidation level
O
Me
OH
MeMe
O
Me
Synthons
Forward synthesis:OH
MeMe
O
Me Me
O
Me Me
O
Me MeAldol
reaction
O
Me
OH
MeMe
NaOEt
Use:
α,β-Unsaturated carbonyl compounds
O
Me
OH
MeMe
O
Me
Me
MeH
acidic protonα to carbonyl
acid or baseelimination
(-H2O) proceeds via enolate/enol formation
Hence
O
Me
Me
Me
O
Me
OH
MeMe
O
Me Me
FGI2 x
Targeted Organic Synthesis Lecture 3 21
21
1,4-Difunctional Compounds
Warren Chapter 25
R
O
OEt
OR
O
OEt
O
disconnect in the middle
'Umpolung' synthon required
12
12
normal reactivity; use enolate
German word used to describe cases in which asynthon of opposite polarity to that normallyassociated with a required functional group must be used.
Umpolung:
R
O
Br
Some umpolung acceptors
Good strategy for C=O oxidation state (but avoid haloaldehydes because they are unstable).
Need an enolate equivalent which is "soft" and will displace the halogen rather than reacting with the C=O group.
O CO2Et OCO2Et
e.g.
12
4
3 12
Use of an enamine of the ketone as an enol/enolate equivalent here gives good results.
CO2Et
, H
O CO2Et
an enamine (soft nucleophile)
N
O
H3O
N
O
CO2EtBr
NH
O
N
O
CO2Et
α-Halocarbonyls
O
Targeted Organic Synthesis Lecture 4 22
22
1,4-Difunctional Compounds
Epoxides
R2
OH O
R2use
epoxide
R1 R1
OH
CO2H
OH
O
e.g. 1
23
4
use:
CO2H
OH
CO2Et
CO2Et
(-CO2)enolate attacks epoxide on
opposite face from epoxide oxygen (SN2)
1. NaOH
2. H3O, heatO
1. NaOEt
2.OH
CO2HForward synthesis:
Synthons
Unnatural nucleophilic synthonsHow about?
O
R1
O
R2O
R1
O
R2O
R1
O
OR2O
R1
O
OR2
EtO2C CO2Et
EtO2C CO2Et
Targeted Organic Synthesis Lecture 4 23
23
1,4-Difunctional Compounds
We need an umpolung synthon that will add in a Michael fashion:
R2 NO2
Hvery acidic proton
pKa ~ 10
base R NO2 R N
O
O
Resonance stabilised
O
OHIf we need we can use CN
If we need we can use
O
R2
O
OR2
or
For example:
O
Me
Me
O
O
Me
Me
O
Me
O
Me
O
MeMe
O2N
FGI1
2
34aldol
MeNO2
H
Me Me
NO2
OTiCl3
H2O Me Me
O
O iPr2NEt
Me
O
Forward synthesis:
Nef reactionO
Me
Me
NaOHcyclisation gives the mostsubstituted double bond
O
O
Me
Me
Targeted Organic Synthesis Lecture 4 24
24
1,2-Difunctional Compounds
Y
R2R1
X
R1
X Y
R2Use: RCHO
Problem: unusual reactivity requireds an umpolung nucleophilic synthonSolution: devise a reagent for the required synthon or avoid problem altogether by a different strategy
Acyl anion equivalents
O
MeR
HO
R
HO O
Me
Use: RCHO Use appropriate acyl anion equivalentAcetylide anions
HR
O
R
OHHg(II), H2O
R
OH
Me
Ooxymercuration
of acetylene
Li1.
2. H3O
HMe
OHS SH
HS S
HMe
R
OH
Me
S S
HgCl2R
OH
Me
O
S S
LiMe
BuLi HR
OThioacetals
H2O
unusual (umpolung) synthon
thioacetal hydrolysis
Targeted Organic Synthesis Lecture 4 25
25
1,2-Difunctional Compounds
MeCO2H
OH
Me
OH
CO2H
Use: aldehydeForward synthesis:
Me
O
HMe
CN
OHMe
CO2H
OH
1. NaCN
2. H
Nitro compounds
R2 NO2
O
R2
Cyanide ion
CN
For example:
CO2H
H3O
hydrolysis of cyano group
CN
MeCO2H
OH
Me
OH
Use: aldehyde
Me
O
HMe
CN
OHMe
CO2H
OH
1. NaCN
2. H
Nitro compounds
We have already seen that nitro compounds serve as nucleophilic umpolung synthons.
R2 NO2
O
R2
Acyl anion equivalents continued
Cyanide ion
CN
For example:
CO2H
H3O
hydrolysis of cyano group
CN
Targeted Organic Synthesis Lecture 4 26
26
1,5-Difunctional Compounds
Warren Chapter 21
R1
O
R2
O
R1
O
R2
O
O
R1
12
3
45
Soft enolate required
Use activating group toensure enolisation and Michael addition
Use:
Often made in situ
CO2H
O O
CO2H
OCO2EtEtO2C
123
4 5
Use:
needs activating group,requires more acidic α-H
diethyl malonate
disconnect at branch point
Esters function wellas activating groups
Example:
Forward synthesis:O
NaOEtCO2EtEtO2C
O
CO2Et
CO2Et1. KOH+
2. H3O CO2H
O
Ester hydrolysis and decarboxylation
Targeted Organic Synthesis Lecture 4 27
27
1,5-Difunctional Compounds
MeCO2Me
CHO
Me
CHO
CO2Me
CO2Me
Me
CHO+
H 1.CO2Me
disconnect at branch point
Use:
aldehyde enolate too reactive,would self-condense
Forward Synthesis:
2. H3O
Use enamine!
NH
OMe
N
O
MeCO2Me
CHO
Me
N
O
Targeted Organic Synthesis Lecture 4 28
28
1,6-Difunctional Compounds
O
MeMe
O
Me
O
O
Me
O
Me
12
3
4
56
Difficult synthon based on carbonyl chemistry (C=O is electrophilic).
Two possible electrophilic sites.Need to control Michael addition.
Use:
We can use a functional group reconnection, rather than a disconnection
O
R2
R1
OR1
R2
Alternative Strategy:
Targeted Organic Synthesis Lecture 5 29
29
1,6-Difunctional Compounds
The intermediate ozonide can be treated in a number of ways:
Me
OH
OH
CHO
Me
O
CO2H
Me
O
NaBH4 reducing: generates diol
mildly reducing: keto-aldehydeoxidising: keto-acid
OO
O
Me
KMnO4
Me2S
Targeted Organic Synthesis Lecture 5 30
How?By using an ozonolysis reaction - using O3 (ozone)
MeO
OO
A 1,3-dipolar cycloaddition
OO
OMe
molozonide
rapid rearrangement
ozonide
OO
O
Me
Clayden p. 938-939
30
1,6-Difunctional CompoundsTargeted Organic Synthesis Lecture 5 31
Me
MeMe
Me
O
CHO
Me
O
Me
MeMe
Me
Me
MeMe
OH
Me
MeMe
MeOH
Me
MeMe
Me
FGI, then 1,3-diO 123
4
5 6
reconnect
FGI
Grignard
Example:
Forward Synthesis:
O
Me
MeMe
Me
Me
MeMe
CHO
Me
O
Me
MeMe
NaOH
MeMgBr H3O , ∆
1. O3 , -78 oC2. Me2S
Me
MeMe
Me
O
OH
Me
MeMe
Me
31
Regioselective Enolate FormationTargeted Organic Synthesis Lecture 5 33
When several sites are available for deprotonation in a substrate, how can we control which enolate is formed?
Me
O
Me
O
baseand/or
Me
O
kinetic enolateproton removed more
rapidly from less hindered position
thermodynamic enolatedouble bond more stable(more highly substituted)
For example:
We can exhibit control over which enolate is formed by altering the reaction conditions.
N
Me
Me
Me
Me
Lilithium
diisopropylamide (LDA)
Using a bulky non-nucleophilic base such as LDA at low temperatures (conditions that favour irreversible deprotonation), we can generate kinetic enolates with high selectivity.
Me
O
LDA, -78 °CMe
O
MeMe
O Li
MeI
MeMe
OLDA, -78 °C
Me
O LiO
H Ph Me
O OH
Ph
Nitrogen atom sterically shielded by bulky isopropyl groups.Non-nucleophilic.Removes least hindered proton in irreversible (kinetic) deprotonation.
Willis p. 60-63
32
Regioselective Enolate FormationTargeted Organic Synthesis Lecture 5 34
Me
O
1. LDA, -78 °C
2. Me3SiCl
Me
OSiMe3
Me
OSiMe3
+
1 : 12
Me3SiCl, Et3N, heat
99 : 1
The silyl enol ethers can be isolated,purified and used in further reactions.
Regeneration of lithium enolate:
Me
OSiMe3
Me
O Li
MeLiMe
OSiMe3
Me Li
In contrast, heating a ketone with a weak base such as Et3N in the presence of Me3SiCl promotes reversibleenolisation to generate the thermodynamic enolate preferentially:
Compare with:
Kinetic product Thermodynamic product
Br PhMe
OPh
33
Regioselective Enolate FormationTargeted Organic Synthesis Lecture 5 35
O
Me
O
MeCO2Et
O
OHEtO2C CO2Et
acetoacetate malonate ester
e.g.
O
MeCO2Et 1. NaOEt
2.
Me
Br
O
MeCO2Et
Me
1. NaOEt
2.Ph Br
O
MeCO2Et
MePh
O
Me
MePh
H1. NaOH
2. H3O
hydrolysis and decarboxylation
(2nd Year carbonyl chemistry!)
The above sequence equates to a regioselective controlled dialkylation of an acetone equivalent.
We can also control the regioselectivity of enolisation by the introduction of an additional electron-withdrawing (and hence "acidifying") group. Esters serve as good activating groups, and can be removed later by hydrolysis and decarboxylation.
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