Chapter 19: Aldehydes and Ketones: Nucleophilic Addition eactions The Carbonyl Group C carbon with a double bond to oxygen it is planar has bond angles of 120 is permanently polarized NENCLATUE F ALDEYDES AND KETNES IUPAC uses endings on the alkane name to indicate the functional group. These ones are easy! Aldehyde Ketone Br 7 4 2 1 IUPAC rules select the longest chain containing the principal functional group number such that it gets the lowest possible number attach the appropriate ending add all other substituents and stereochemistry as you normally would E-7-bromo-4,4-dimethyloct-2-enal NATUAL CCUENCE F ALDEYDES Benzaldehyde occurs: almonds, defensive pheromones use: almond extract Vanillin occurs: vanilla bean, potato parings use: synthetic vanilla Geranial occurs: as alcohol in essence of rose use: perfumery C C C 3 C
NATUAL CCUENCE F ALDEYDES Glucose occurs: foodstuffs use: energy source/metabolism etinal occurs: Vitamin A use: vision C C 2 C NATUAL CCUENCE F KETNES Camphor occurs: in the camphor tree use: perfumery, explosives Cortisone occurs: hormone/adrenal gland use: relief of inflammation NATUAL CCUENCE F KETNES Fructose occurs: in sugar (sucrose) use: sweetener C 2 C 2 PEPAATIN F ALDEYDES PCC C 2 Cl 2 78% oneybee pheromone use: attractive substance of Queen bee C N PCC Cr 3 Cl Swern oxidation DS (CCl) 2 then Et 3 N C 2 Cl 2-60 Swern 99% as well as a selective oxidation of 1 alcohols, we could perform a selective reduction from acid derivatives: reducing conditions required in the second stage to produce the aldehyde this can be Zn / Ac or e 2 S
PEPAATIN F KETNES K 2 Cr 2 7 2 S 4, 2 96% Kn 4 Ac, 2 96% XIDATINS F ALDEYDES EACTINS F ALDEYDES & KETNES Carbonyl groups are polar and have a dipole moment: 1 1 This leads naturally to their reactions with nucleophiles Nu 1 Nu 1
what kind of nucleophiles are we talking about? Steric effect Electronic effect Base catalysis Let us deal with mechanism first, then the substituent effect
Acid catalysis 2 ' K + K ' 2.2 x 10 3 C 3 1 (C 2 ) 2 C 3 0.5 C(C 3 ) 2 0.5-1 Ph 0.3 x 10-3 C 3 C 3 1.4 x 10-3 C 3 Ph 6.6 x 10-6 Ph Ph 1.2 x 10-7 ClC 2 37 CCl 3 2.8 x 10 4 ClC 2 ClC 2 10 CF 3 CF 3 too large to measure 2 + ' K 2.2 x 10 3 C 3 1 (C 2 ) 2 C 3 0.5 C(C 3 ) 2 0.5-1 Ph 0.3 x 10-3 C 3 C 3 1.4 x 10-3 C 3 Ph 6.6 x 10-6 Ph Ph 1.2 x 10-7 ClC 2 37 CCl 3 2.8 x 10 4 ClC 2 ClC 2 10 CF 3 CF 3 too large to measure K ' 2 + ' K K 2.2 x 10 3 C 3 1 (C 2 ) 2 C 3 0.5 C(C 3 ) 2 0.5-1 Ph 0.3 x 10-3 C 3 C 3 1.4 x 10-3 C 3 Ph 6.6 x 10-6 Ph Ph 1.2 x 10-7 ClC 2 37 CCl 3 2.8 x 10 4 ClC 2 ClC 2 10 CF 3 CF 3 too large to measure ' 2 + ' K ' some adducts are just not stable: K 2.2 x 10 3 C 3 1 (C 2 ) 2 C 3 0.5 C(C 3 ) 2 0.5-1 Ph 0.3 x 10-3 C 3 C 3 1.4 x 10-3 C 3 Ph 6.6 x 10-6 Ph Ph 1.2 x 10-7 ClC 2 37 CCl 3 2.8 x 10 4 ClC 2 ClC 2 10 CF 3 CF 3 too large to measure
CYANYDINS IN NATUE Addition of organometallic reagents to aldehydes & ketones andelonitrile a defensive secretion in the millipede Apheloria corrugata CN Amygdalin / Laetrile occurs in pits of apricots, plums, bitter almonds, lima beans, casava CN Depending on the starting material, different types of targets may be synthesized S reagent target comments gx Li primary alcohol with one added carbon ' gx ' Li secondary alcohol ' ' gx ' ' Li tertiary alcohol gx Li primary alcohol with two added carbons
etrosynthetic analysis for a secondary alcohol etrosynthetic analysis for a tertiary alcohol X = gbr, Li X = Br, Cl, I X = gbr, Li X = Br, Cl, I Addition of nitrogen nucleophiles to the carbonyl group i the addition phase Addition of nitrogen nucleophiles to the carbonyl group ii the elimination phase C 3 C N nucleophilic attack on carbonyl carbon C 3 N B + B protonation and deprotonation C 3 N addition compound B + C 3 N protonation of hydroxyl group 2 C 3 N loss of water 2 C 3 N deprotonation B C 3 N imine this, and the following slide, are a re-write of the text Fig 19.8 N 2 + K + N 2 + N 83% N 95% Enamines form when the reagent has only one which may be eliminated
we can see the difference here: 1 amine yields an imine 2 amine gives the enamine Where is this important??? phenylpyruvate Transamination L-phenylalanine deaminase N 2 P N pyridoxamine C 2 N 2 C 3 L-amino acid sythetase P = phosphate C P N C 3 pyridoxal phosphate C N 2 P imine 1 C N P + A useful extension of this type of reaction is the Wolff-Kischner eduction C C N P 2 N P imine 2 P = the rest of the cofactor solvent DS for those of you who want to know what s going on: Addition of alcohols: formation of hemiacetals and acetals B + B C C C 3 C 3 3 C 3 C 3 B protonation of the carbonyl group nucleophilic attack on carbonyl carbon deprotonation Sequence of events: protonate attack deprotonate this one can be acid or base catalyzed C 3 C 3 a hemiacetal -- one, one
Conversion of a hemiacetal to an acetal Glucose as a hemiacetal C 3 B + C 3 protonation of thehydroxyl group C 3 2 + C 3 loss of water C 3 C 3 C 3 resonance stabilized carbocation C 3 C 2 C 2 C C 3 C 3 C 3 C 3 C 3 glucose in its open chain conformation glucose cyclized as a hemiacetal new chiral centre: two diastereomers formed C 3 C 3 B C 3 C 3 nucleophilic attack on carbonyl carbon deprotonation an acetal -- two groups see text p 954 this one can be only be acid catalyzed altose is both an acetal and a hemiacetal C 2 acetal C 2 hemiacetal β and C 2 are cis α and C 2 are trans 4--(α-D-glucopyranosyl)-β-D-glucopyranose Sucrose is an acetal in both rings C 2 acetal C 2 acetal pyranose = 6-membered ring C 2 furanose = 5-membered ring see p 967 β-d-fructofuranosyl-α-d-glucopyranoside see p 969 Acetals as protecting groups The text deals with the following example Et Brg what is wrong, of course, is that the two functional groups in this molecule are incompatible so, we must protect the ketone before making the Grignard We will do a different one. Suppose you want to make the compound below Brg the logical disconnection is one of the C-C bonds on the alcohol carbon, and it makes most sense for this not to be one of the ring bonds. but, what is wrong with this? Br + Brg + Br remember, these are stable to base and Nu dry Et 2 3 + g dry Et 2 Brg dilute acid work-up not only hydrolyzes the g salts off, but also cleaves the acetal
The Wittig reaction This is the reaction of a carbanionic component with a carbonyl component to produce a new alkene. The carbanionic component is readily formed using triphenylphosphine 3 C PPh 3 nucleophilic P displaces leaving group I I TF Ph 3 P C 2 Bu Li base pulls off acidic proton α to P + I Ph 3 P C 2 + Bu + LiI Ph 3 P C 2 Wittig reagent is stabilized by resonance The huge advantage is that you know exactly where, in the molecule, the new double fond forms. An example: etrosynthetic analysis in a Wittig-based reaction Target: Ph 3 P PPh 3 the normal Wittig reagent is primary, so one would by preference choose the blue route There is one further aspect of this reaction which makes it even more synthetically useful one can control the stereochemistry of the resulting alkene to be E- or Z- Prostaglandin F 2α This target has two alkenes, which we can stereoselectively produce by simple modification of the Wittig reaction conditions C 2 for the lower side chain: Ac P C 5 11 (Et)2 Na C 2 SC 3 Ac stereoselection for E-alkene due to stabilized ylide
for the upper side chain: We have previously looked at conjugated dienes, now let us look at conjugated carbonyl systems: enones and enals Br Ph 3 P + (C 2 ) 4 C 2 C 2 once again, this reacts like a single functional group: TP C 5 11 TP Na C 2 SC 3 TP TP stereoselection for Z-alkene normal non-stabilized ylide both carbonyl carbon and β-carbon are electrophilic Essentially this means that this type of double bond is reactive towards electrophiles, whereas a normal double bond would not be When the addition occurs to the β-carbon, it is called conjugate addition Amines add readily: ther adducts: 2 5 60% KCN CN Ph Ph Ac Ph Ph 93%
rganometallics can add in a conjugate fashion, but they must be modified from the normal g or Li reagent: which then leads to regioselectivity: nce again, there are good synthetic possibilities. Let us go back to prostaglandins and see what we might do. C 2 1 1 2 TBDS normally we use copper to effect the ichael addition of an organometallic, but many other metals can be used. In this case, Noyori found that zinc worked very well: Li e 2 Zn 2 2 TBDS = t-butyldimethylsilyl Exclusively 3,4-trans and, notice that the large group adjacent to the reacting site completely governs the face of the double bond which is attacked It turns out that the intermediate in this first addition is an enolate -- we can take advantage of that to introduce the second side chain Li - e 2ZnLi + e 2Zn TBDS -78 ºC 1h. I C 2Et PA, -78ºC to -40ºC 71% only product exclusively trans- anti C 2Et